Polyacetylenes of Marine Origin: Chemistry and Bioactivity - Chemical

Review pubs.acs.org/CR

Polyacetylenes of Marine Origin: Chemistry and Bioactivity Zhen-Fang Zhou,† Marialuisa Menna,‡ You-Sheng Cai,† and Yue-Wei Guo*,† †

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zu Chong Zhi Road 555, Shanghai 201203, China ‡ The NeaNat Group, Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy Author Information Corresponding Author Notes Biographies Acknowledgments References

1. INTRODUCTION Assessment of the chemical diversity contained in the oceans is an established field with a great deal of research focused on extraction of chemicals from algae and sessile invertebrates (sponges, mollusks, and tunicates). These organisms live in a complex and highly competitive environment, with high concentration of salts, high pressure, low concentration of oxygen, and dark conditions. Most marine invertebrates lack physical protection in the form of an exoskeleton, for example, spines, stings, or shells.1 This is why marine organisms developed unique metabolic pathways and, thus, the capability to produce a wide variety of toxic chemicals to mediate spatial competition as well as to prevent parasitism and predation. The chemical diversity produced by marine life thus represents an exceptional reservoir of molecules, some without terrestrial counterpart or analogy, often forming large classes of related structures, and mostly exhibiting unique bioactivities at an extremely low concentration. As for plants, chemists and pharmacologists have recognized the potential of this chemical arsenal to discover molecules useful as lead structures in the search and development of new drugs or as biological probes for physiological investigation. Acetylene compounds or “polyacetylenes” (the latter term is often used interchangeably to describe this class of natural products, although they are not polymers and many precursors and metabolites contain only a single acetylenic bond) are a general name for a substantial class of natural products,2 of which all contain one or more carbon−carbon triple bond functionalities in their molecules. In this Review, acetylenes are specially referred to as the cyclic and linear enyne compounds with one triple bond, whereas polyacetylenes are specially referred to as the metabolites with more than one enyne moiety. Naturally occurring polyacetylenes, although often unstable molecules, feature a wide range of structural diversity and are widespread in plants and animals.2 In the marine environment, they have been isolated mainly from algae and invertebrates,2 and have displayed a broad array of biological

CONTENTS 1. Introduction 2. Algae 2.1. C15 Linear Acetylenes from Algae 2.2. C15 Cyclic Acetylenes from Algae 2.2.1. Monocyclic C15 Acetylenes 2.2.2. Bicyclic C15 Acetylenes 2.2.3. Polycyclic C15 Acetylenes 2.3. Long-Chain (More than C15) Acetylenes/ Polyacetylenes from Algae 3. Sponges 3.1. Short-Chain (Less than C15) Acetylenes/ Polyacetylenes from Sponges 3.2. C15 Acetylenes/Polyacetylenes from Sponges 3.3. Long-Chain (More than C15) Polyacetylenes from Sponges 3.3.1. Symmetric Polyacetylenes 3.3.2. Asymmetric Polyacetylenes 4. Corals 4.1. Short-Chain (Less than C15) Polyacetylenes from Corals 4.2. C15 Polyacetylenes from Corals 4.3. Long-Chain (More than C15) Polyacetylenes from Corals 5. Mollusks 5.1. C15 Acetylenes from Mollusks 5.2. Long-Chain (More than C15) Polyacetylenes from Mollusks 6. Miscellaneous 7. Conclusions 7.1. Differences and Distribution of Polyacetylene Structures among the Species of Algae and Invertebrates 7.2. Bioactivity and Microelectronic Properties of Polyacetylenes 7.3. The Biosynthesis of Polyacetylenes: A Potential Microbial Link © XXXX American Chemical Society

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dx.doi.org/10.1021/cr4006507 | Chem. Rev. XXXX, XXX, XXX−XXX

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Figure 1. Structures of compounds 1−32.

properties, including antifungal activity,3 antimicrobial activity,4 HIV reverse transcriptase inhibition,5 and cytotoxicity.6,7 In addition, important ecological roles, such as inducing metamorphosis of ascidians’ larvae,8 preventing fouling by barnacle larvae,8 and inhibiting fertilization of starfish gametes,9 have been ascribed to these metabolites. Despite the appearance in the literature since 1972 of several reviews related to acetylenic natural products, none of them gave a thorough insight into the chemistry and biological activities of polyacetylenes of marine origin. Bohlmann’s monograph covers the synthesis, isolation, and chemotaxonomy of naturally occurring acetylenes through 1972.10 Several reviews are focused on the systematic relationships of polyacetylenes within specific plant families or sponge species.11−17 The structures of unusual fatty acids, including acetylenic acids, as well as their occurrence, synthesis, and biotechnological aspects, have been reviewed by Pasha et al.18 Two comprehensive reviews dealing with the anticancer activity of both natural and synthetic acetylenic lipids have recently been published,19,20 whereas the importance of acetylenic fatty acids as antifungal agents has been amply illustrated by Carballeira, which reports the most recent findings on the antimalarial, antimycobacterial, and antifungal properties of fatty acids.21 Further, two reviews describing the advances in the synthesis of acetylenic natural products,22,23 with one emphasizing the total synthesis of the polyyne glycosides, were also appeared. Finally, an excellent up-to-date survey reviewing the biological activities and possibly biogenetic origins of both terrestrial and marine polyacetylenes has been recently published.2 This Review provides a comprehensive overview of acetylenes/polyacetylenes isolated from marine algae and invertebrates (mainly sponges and mollusks) in the last five decades (from 1965 to 2013), focusing on the isolation, structural characterization, and classification of more than 600 acetylenic molecules, as well as their biological relevance, thus highlighting both the structural diversity generated in this unique class of marine natural products and their potential in drug discovery. Although an increasing number of reports on synthetic achievements have been published reflecting great efforts made on the total synthesis of acetylenic compounds, the synthetic progress of polyacetylenes is just briefly outlined in this Review. Moreover, the biosynthetic aspects are also not

covered in this Review because the up-to-date knowledge in polyacetylene biosynthesis has been recently reviewed.2 For a better clearness and ease for readers, the acetylenic molecules described in this Review have been divided into five sections on the basis of their biological sources (algae, sponges, corals, mollusks, and miscellaneous); within each section, they have been presented in an order based on their general structural framework type. Taking into account that the main differences between polyacetylenes’ structures are the chain length and the functional groups and that acetylenes with 15 carbons are the most common in marine organisms, the structures have been divided into three main classes: those with less than 15 carbons, those with 15 carbons, and those with more than 15 carbons. The acetylenes with 15 carbons have been further separated into monocyclic, bicyclic, and polycyclic on the basis of their structural complexity, while those with more than 15 carbons have been split into symmetric and asymmetric polyacetylenes. Summary tables reporting, for each group of molecules, the names and sources of the presented structures, as well as their geographical distribution and literature references, are embedded in the text.

2. ALGAE Acetylenes isolated from algae are mostly C15 metabolites, a group of compounds of great importance. Almost all of them were isolated from the red algae belonging to the Laurencia genus, making them characteristic metabolites of the Laurencia algae. In fact, C15 acetylenes play an important role in chemotaxonomy because they can be used to discriminate morphologically similar red algae. In addition, red seaweeds in the genus Laurencia are the only other organisms that rival the dinoflagellates in imagination as builders of unusual cyclic ethers, some of which are transferred through the diet to herbivorous opisthobranch mollusks. The interest in these cyclic ethers has revived methods for the synthesis of medium size rings. 2.1. C15 Linear Acetylenes from Algae

The C15 linear acetylenes, particularly those without any functional groups, play a fundamental role in the biosynthetic pathway leading to all varieties of both linear and cyclic C15 acetylenes. Laurencenyne (1, Figure 1) and neolaurencenyne (3), together with their relevant geometrical isomers, transB


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Table 1. Summary Information for Compounds 1−31

a

no.

compounds

sources

1 2 3 4 5 6 7−10 11−14 15 16

laurencenyne trans-laurencenyne neolaurencenyne trans-neolaurencenyne (3E,6Z,9Z,12E)-pentadeca-3,6,9,12,14-pentaen-l-yne (3E,6Z,9Z,12E)-pentadeca-3,6,9,12-tetraen-1-yne trans-laurediol cis-laurediol −a (6R,7R)-3-cis,9-cis,12-cis-6-acetoxy-7-chloro-pentadeca-3,9,12-trien-1-yne

17−20 21−26 27 28 29 30 31

−a −a prerogioloxepane (±)-(3Z,12Z)-laurediol diacetate (±)-(3E,12Z)-laurediol diacetate (±)-(3Z)-12,13-dihydrolaurediol diacetate (±)-(3E)-12,13-dihydrolaurediol diacetate

L. okamurai L. okamurai L. okamurai L. okamurai L. majuscula L. majuscula L. nipponica L. nipponica L. glandulifera L. pinnatifida Aplysia fasciata L. pinnatifida L. pinnatifida L. microcladia L. nipponica L. nipponica L. nipponica L. nipponica

distribution Mie Prefecture, Japan Mie Prefecture, Japan Mie Prefecture, Japan Mie Prefecture, Japan Queensland, Australia Queensland, Australia −b Crete Island, South Aegean Sea, Greece Los Cristianos, Tenerife, Spain Alfacs Bay, Delta de l’Ebre, Spain Tenerife Island, Spain Tenerife Island, Spain Mediterranean off the torrent II Rogiolo Pon-Oshoro bay in Hokkaido, Japan Pon-Oshoro bay in Hokkaido, Japan Pon-Oshoro bay in Hokkaido, Japan Pon-Oshoro bay in Hokkaido, Japan

ref 24 25 25 25 26 26 27 27 31 32 297 34 34 35 36 36 36 36

The name of the compound was not given. bThe place of the sample collection was not mentioned.

laurencenyne (2) and trans-neolaurencenyne (4), were first isolated from Laurencia okamurai by the Japanese scientists Yamada et al.24,25 Their chemical structures were deduced by chemical transformation and their spectral evidence. To unambiguously confirm the structures of compounds 1−4, their total syntheses were also achieved.24,25 Biogenetic significance of the isolation of laurencenyne (1) and translaurencenyne (2) was also discussed, both of which may be intermediates in the earlier stage of the biosynthetic pathway to a variety of halogenated C15 metabolites.25 Chemical study of L. majuscula collected from Queensland, Australia, led to the isolation of compounds 5 and 6,26 presumably the precursors of compounds 7−14, isolated as a mixture of optical isomers from L. nipponica, where the Δ6,7 double bond is oxidized to diol or derivatives.27 Compounds 7−14 were synthesized by using acetylenic coupling procedures, asymmetric epoxidation, and stereo- and regioselective openings of the epoxides. 28 Masamune et al. accomplished a synthesis of trans-(+)-laurediol (8) in 21 steps from (2R,3R)-(+)-tartaric acid.29 Almost simultaneously, an enantioselective synthesis of both cis- and trans-laurediol in 28 steps from propargylic alcohol was published.28 More recently, a highly convergent and short synthesis of 8 was presented, which features a highly efficient construction of a cis3-hydroxy-γ-butyrolactone through a Sharpless AD reaction of a β,γ-unsaturated ester.30 Several chlorine-containing linear C-15 acetylenes, in which the halogen atom is linked at C6 or C7 (compounds 15−24, 27), were obtained still from algae belonging to Laurencia genus.31−35 Compound 16 was isolated from spanish alga L. pinnatifida, and its absolute configuration was determined by chemical correlation.32 Later, an enantioselective total synthesis of 16 and of its 3-trans isomer revealed that the natural metabolite was a mixture of cis- and trans-enyne.33 Reinvestigation of the same alga from the same Tenerife Island, Spain resulted in the isolation of compounds 17, 18, and 21−23.34 Compound 17 was isolated as a minor component of its mixture with compound 18, because all of the attempts separating the mixture through silica gel or Sephadex LH-20 chromatographies failed; only small amounts of compound 17

could be isolated by using neutral alumina column chromatography. However, the mixture of 19 and 20, obtained by treatment of 17 and 18 with K2CO3/MeOH at 0 °C, could be easily separated by the neutral alumina column chromatography. Compounds 21−24 were also isolated as a mixture of geometrical isomers, and the structures of compounds 22−24 were established on the basis of their spectroscopical data and by trivial chemical correlations with 21 and between each other (Table 1). Catalytic hydrogenation of 21 and 22 gave 6hydroxy-7-chloropentadecane 26, while 23 and 24 gave 25. The stereochemistry of compounds 17, 18, and 21−24 at C-6 and C-7 was established by chemical transformation.34 Prerogioloxepane (27) was obtained from L. microcladia Kützning, and its absolute configuration at C-6 and C-7 was established via Mosher’s NMR method.35 With respect to the biogenesis of prerogioloxepane (27), the author considered that laurencenyne (1), also produced by L. microcladia from torrent II Rogiolo, Italy, was depleted to form a 6,7-cis-epoxide, which undergoes Cl− attack to give 27.35 Compounds (±28), (±29), (±30), and (±31), four enatiomeric mixtures of enyndiol intermediates linking laurencenyne or neolaurencenyne with the laurediols, were isolated as their diacetates from Hokkaido alga L. nipponica. The ratio of the two enantiomers (−28) and (+28) was calculated to be 77:23 on the basis of their optical rotation. Furthermore, (±28) was shown to be a mixture of threo isomers by formation of the acetonide (32), whose 1H NMR spectrum showed a two-methyl signal equivalent at δ 1.38 (6H, s). (±29), (±30), and (±31) were calculated on the basis of optical rotations to be the mixtures of (6R,7R)-(+)- and (6S,7S)-(−)-isomers in the ratios of 17:3, 4:1, and 51:49, respectively.36 2.2. C15 Cyclic Acetylenes from Algae

2.2.1. Monocyclic C15 Acetylenes. Medium-ring cyclic ethers are important structural features present and widespread in many marine natural products. Lauroxanes are a series of nonterpenoid C15-metabolites that have been isolated from either the Laurencia species of red algae or mollusks, which feed C


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graciosin (37),40 and they also determined the absolute configuration of the alcohol 35 through X-ray diffraction analysis by crystallization of 35 from n-hexane (Table 2). From the same alga, the allenic acetylene graclosallene (38) was isolated.40 Its stereochemistry at C-4, C-6, C-7, C-9, and C-10 was established through chemical correlation, and the strong negative rotation of graciosallene was indicative of the R configuration of the bromo allene moiety by the application of Lowe’s rule.41 Itomanallene B (39), isolated from L. intricata collected in Okinawan waters, also features a terminal bromoallene moiety.42 In this compound, a cis relationship between the substituents at C-6 and C-7 was indicated by a NOE correlation between H-6 and H-7. The S configuration of the bromoallene moiety was deduced from the strong positive optical rotation value. Four acetylenes with unusual pentenynyl and hexenyl side chains, trans-kumausyne (40), cis-kumausyne (41), trans-deacetylkumausyne (42), and cis-decetylkumausyne (43), were isolated from Hokkaido alga L. nipponica, and their structures were determined by spectral and chemical evidence.43 The first total synthesis of (+)-trans-kumausyne (40) was achieved by Overman, in which the pivotal cishydrobenzofuranone intermediate was obtained from 1-vinylcyclopentane-1,2-diol and α-(benzyloxy)-acetaldehyde via Prins-pinacol rearrangement strategy.44 Different total syntheses of (−)-trans-kumausyne (40) were reported; the first one performed by Sugimura uses the stereoselective formation of substituted tetrahydrofurans in the BF3-promoted reaction of 2,3-O-isopropylidene derivatives of aldehydo-aldose with allylsilanes.45 Martiń disclosed a 22-step synthesis starting from propargyl alcohol and employing brominative cyclization as the key step.46 A considerably shorter and simpler synthesis through tandem intramolecular alkoxycarbonylation lactonization was achieved starting from dimethyl (R)-malate (13 steps, 6.2% overall yield).47 A convergent and stereocontrolled synthesis route of trans-(+)-deacetylkumausyne (42), in

on Laurencia algae. Although structural diversity of this kind of molecules is very wide, all of them are characterized by the presence of common halogenated cyclic ethers with the ring size ranging from five to nine members. Further, the side alkyl chains substituted at the positions adjacent to the oxygen atom of the cyclic ether among the lauroxanes are mostly cis oriented. Such C15 cyclic ethers are considered to be biogenetically originated from linear laurediols, which occur in nature as various stereoisomers, through electrophilic cyclizations usually induced by a bromonium ion. Although C15 monocyclic acetylenes bear quite simple structures, the determination of their absolute configurations is a challenging task for chemists. In some cases, the X-ray crystallography and total synthesis are necessary and also efficient for the final structural confirmation. Compounds 33−43 (Figure 2) share the same tetrahydrofuran (THF) ring in their molecules. Hurgadenyne (33) was isolated from the alga L. obtusa collected from the Gulf of Suez, Egypt.37 Its structure was established through extensive spectroscopic analysis, including NOE and J values evaluation, which allowed the all-cis relative stereochemistry to be assigned; however, the stereochemistry at C-9 remained to be determined. Bisezakyne-A (34), from a Japanese Laurencia species, had an E geometry at C-3 and a bromine substituent at C-13.38 The relative stereochemistry of the substituents on the THF ring was determined by NOESY experiment, whereas the configuration at C-13 was suggested from biogenetic consideration. It has been indeed hypothesized that 34 is biosynthesized either from (6S,7S)- or from (6R,7R)-laurediol via (12S,13S)-bromonium ion, so the configuration at C-9, C10, C-12, and C-13 would be expected to be R*, R*, R*, and S*, respectively. The structure of compound 36, possessing an unusual propargylic bromide side chain, was first isolated from L. obtusa collected at Graciosa Island, Spain in 1984;39 however, in 1988 Norte and his colleagues corrected the structure of 36 as D


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through molecular-mechanics calculation, while the absolute stereochemistry of 49 was established by modified Mosher’s method. An insecticidal component, isolaurepinnacin (48), the structure of which was assigned by spectroscopic data and chemical correlation, was obtained from L. pinnata Yamada collected at Motsuta point, Hokkaido, Japan.49 The first total synthesis of (+)-isolaurepinnacin (48) has been achieved with high stereoselectivity in 12 steps and 15% overall yield from cis-2-penten-1-ol; the synthesis rigorously established the S configuration at C(13), previously suggested on biosynthetic grounds, and the correct optical rotation properties (dextrorotatory) of 48.50 Later, isolaurepinnacin (48) was synthesized by Overman et al. by an acetal-vinylsilane cyclization to stereoselectively form the cis-2,7-disubstituted oxepene ring and introduce Δ4 olefin.51 Rogiolenynes B and D (50 and 51) were obtained from the Italian alga L. microcladia Kützning;52 their absolute configuration was determined by molecular-mechanics calculations and Mosher’s NMR method. The brominated allene nipponallene (52) was isolated from L. nipponica, collected near the Russian shore of the Sea of Japan;53 its stereochemistry was elucidated using NMR spectroscopy, chemical transformation, modified Mosher’s method, and on the basis of biogenetic understanding, while the configuration of bromoallene moiety was assigned as R by application of Lowe’s rule. Marine-derived eight-membered Oheterocyclic C15 acetogenins are quite common; usually, they are substituted by chlorine or bromine atoms and play important roles in chemotaxonomy. For instance, intricenyne (53, Figure 3) was isolated as one of 11 C15 nonterpenoid halogenated compounds from L. intricata, collected in shallow water in Key Largo, FL.54 The finding of many different compounds in this alga raised the question if all of these compounds are indeed produced by this single species in its natural, undisturbed habitat or by several morphologically similar species. Later, both of the observations that the isolation of different natural products from L. pacifica was attributed to the existence of several new morphologically similar species and that algal halogenated products were largely independent of the habitat or reproductive stage of the algae supported that L. intricata is the real producer of all of the halogenated products isolated. Laurepinnacin (54), from Hokkaido alga L. pinnata,49 has the same planar structure as that of intricenyne (53); the absolute configuration of 53 and 54 was established by chemical correlation.49,55 The dichloro trienyne (55) was obtained from New Zealand red alga L. thyrsifera;55 chemical investigation of the same alga led to the isolation of two enyne diols 56 and 57, which occurred as an approximately 1:1 mixture of the olefinic isomers.56 The isolation of compound 56 was later reported as the first metabolite of L. glandulifera collected at Crete Island in South Greece, together with five C15 eight-membered cyclic ethers 58−62.57 All of the compounds except 56 were tested for antistaphylococcal activity against a panel of multidrug and methicillin-resistant Staphylococcus aureus in a minimum inhibitory concentration (MIC). All of the tested compounds, apart from compounds 61 and 62, which were inactive at the concentration of 128 μg/mL, exhibited significant antistaphylococcal activity having MICs in the range of 8−256 μg/mL; compound 58 was found to be the most active in this series (MIC 8−16 μg/mL). Laurencin (63) was first isolated by Irie et al. in 1965, and its planar structure was determined through NMR analysis and chemical correlation;58 however, its stereochemistry was

Table 2. Summary Information for Compounds 33−52 no.

compounds

sources

33

hurgadenyne

L. obtusa

34

bisezakyne-A

Laurencia sp.

36 37 38 39

− graciosin graclosallene itomanallene B

L. L. L. L.

40 41 42

L. nipponica L. nipponica L. nipponica

44

trans-kumausyne cis-kumausyne transdecetylkumausyne cisdecetylkumausyne scanlonenyne

45

bisezakyne-B

Laurencia sp.

46

dactylyne

Laurencia sp.

47

rogioloxepane A

Aplysia dactylomela L. microcladia

48

isolaurepinnacin

L. pinnata

49

rogioloxepane C

L. microcladia

50

rogiolenyne B

Spongia zimocca

43

a

obtusa obtusa obtusa intricata

ref 37

L. nipponica L. obtusa

L. microcladia

a

distribution Hurgada, the Gulf of Suez, Egypt Motobu, Okinawa Prefecture, Japan Graciosa Island, Spain Graciosa Island, Spain Graciosa Island, Spain Itoman, Okinawa Prefecture, Japan Kumausu, Hokkaido, Japan

51

rogiolenyne D

L. microcladia

52

nipponallene

L. nipponica

38 39 40 40 42 43 43 43 43

Scanlon’s Island, Ireland Motobu, Okinawa Prefecture, Japan Motobu, Okinawa Prefecture, Japan Environs of Bimini, Bahamas off the torrent II Rogiolo, Italy Motsuta point, Hokkaido, Japan off the torrent II Rogiolo, Italy torrent II Rogiolo, south of Livorno, Italy off the torrent II Rogiolo, Italy off the torrent II Rogiolo, Italy Troitsa Bay, Japan

48 38 38 299 35 49 35 113 52 52 53

The name of the compound was not given.

which the key step is a bromonium ion-induced cyclization of a suitable hydroxy alkene, was accomplished;47 this type of reaction could be involved in the biogenetic origin of Laurencia halogenated cyclic lipids. Scanlonenyne (44),48 bisezakyne-B (45),38 and dactylyne (46),38 isolated from Laurencia red algae collected from Ireland and Japan, respectively, display a common tetrahydropyran (THP) ring (Figure 2). They differ from each other either by the substituents or configuration of the substituted functionalities. Scanlonenyne (44) features a ketone moiety at C-7; its relative configuration was determined through J values analysis and confirmed by the NOESY experiment. Furthermore, the modified Mosher’s method was applied to determine the absolute configuration of the secondary hydroxyl group at C-10. Bisezakyne-B (45) and dactylyne (46) show an uncommon substitution pattern, exhibiting both chlorine and bromine atoms in their structures. Although eight-membered O-heterocyclic polyacetylenes were commonly encountered in marine environment, few seven-membered ones were found. Two oxepanes, rogioloxepanes A and C (47 and 49, Figure 2), were isolated from L. microcladia Kützning, collected in the Mediterranean Sea off the torrent II Rogiolo.35 These compounds most likely descend biogenetically from the acyclic C15 acetogenins with a single OH group at C(7). Their relative configuration was assigned E


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Table 3. Summary Information for Compounds 53−77 compounds

sources

distribution

ref

53 54 55 56

no.

intricenyne laurepinnacin (3Z,6ξ)-6,10-dichlorolauthisa-3,9,11-trien-1-yne −a

57 58−62 63 64 65 66 67 68/70c 69/71c 72

−a −a laurencin bermudenynol −a prelaureatin −a trans-pinnatifidenyne cis-pinnatifidenyne cis-dihydrorhodophytin

Key Largo, FL Motsuta point, Hokkaido, Japan Seal Reef, Kaikoura, New Zealand Seal Reef, Kaikoura, New Zealand Loutraki bay, Crete Island, Greece Seal Reef, Kaikoura, New Zealand Loutraki bay, Crete Island, Greece Japan Castle Harbour, The United Kingdom

54 49 55 56 57 56 57 58−61, 153 68

73 74 75/76c

trans-dihydrorhodophytin (3Z)-13-epipinnatifidenyne (3E)-13-epipinnatifidenyne

77

(3Z)-venustinene

L. intricata L. pinnata L. thyvsifera L. thyrsifera L. glandulifera L. thyrsifera L. glandulifera L. glandulifera L. intricata L. intricata L. nipponnica L. obtusa L. pinnatifida L. pinnatifida L. pinnatifida Aplysia brasiliana L. pinnatifida L. claviformis L. obtusa Aplysia dactylomela L. venusta

Duwa, Sri Lanka Aydin, Turkey Los Cristianos, Tenerife, Spain Los Cristianos, Tenerife, Spain Tenerife, Canary Islands, Spain −b Tenerife, Canary Islands, Spain Easter Island, Chile Aegean Sea, Greece Hainan Island, China Aomori Prefecture, Japan

69 70 32, 34 32, 34 73 302 73 74 75 76 77

a

The name of the compound was not given. bThe place of the sample collection was not mentioned. cTwo different structures for the same compound.

finally confirmed by the heavy-atom method and refined by least-squares calculations, and the crystallographic measurement with Cu Kα radiation.61 The complex structure of laurencin (63), characterized by its eight-membered cyclic ether ring, the bromine substitution, and the enyne group, as well as the notable challenge in assembling medium ring ethers, have

undetermined until the measurement of its crystal structure.59 In 1968, Irie and his colleagues disclosed the full details of the isolation and structural elucidation of the compound 63. Furthermore, the absolute configuration on C-6 was determined by applying Prelog’s atrolactic acid method to octahydrodeacetyllaurencin.60 The suggested structure was F


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been attracting the interest of synthetic chemists. It was first total synthesized starting from cis-2-ethyl-8-formyl-7,8-dihydro2H-oxocin-3(4H)-one 3-ethylene acetal in the overall yield of 1.1%.62 The total synthesis of laurencin (63) was also achieved involving the conversion of readily available medium-sized lactones to α-alkyl cyclic ethers via enol triflates.63 An enantioselective synthesis of 63 was completed in 26 steps.64 Two synthetic strategies were applied to achieve the efficient synthesis of laurencin (63), the intramolecular allylboration reactions and an asymmetric alkylation-ring-closing metathesis approach.65,66 Moreover, a direct enzymatic synthesis of deacetyllaurencin from laurediol (7) was also reported, which provides a strong support to the hypothesis that laurediols are the real biosynthetic precursors of deacetyllaurencin and its related cyclic ether compounds of marine origin.67 Bermudenynol (64) and its acetate (65) are characterized by the presence of three halogens in their structures, which were unambiguously determined by means of X-ray diffraction analysis based on heavy atom techniques.68 All of the eight-membered ethers are flanked with two side alkyl chains adjacent to C-1 and C-13. The so far described compounds bearing a two carbon alkyl chain in one end and a six carbon alkyl chain in the other side belong to the group of lauthisans.55 Prelaureatin (66) and its acetate (67), found in L. nipponnica and L. obtusa, respectively,69,70 are examples of another group of C15 eight-membered cyclic ethers, bearing two different lengths of side chains, one with three carbons and the other with five carbons. The structure of 66 was chemically established, while the structure of 67 was determined by comparing the NMR data with those of known related compounds. Prelaureatin (66) can be obtained enzymatically from its original precursor, (3Z,6S,7S)-laurediol, in a single step by lactoperoxidase.71 Recently, compound 66 was totally

synthesized; the oxocene core was constructed by a ringclosing metathesis to give the eight-membered ring in seven steps from (R)-benzylglycidyl ether.72 Chemical examination of another Laurencia species collected near Los Cristianos, Tenerife, Spain resulted in the isolation of the two isomers, trans- and cis-pinnatifidenynes (68 and 69).32 The structure of the former (68) was determined by spectral, chemical, and Xray diffraction analysis, whereas the structure of the latter (69) was elucidated on the basis of spectral comparison with that of the trans-isomer 68 and chemical interconversion from 68. Actually, it has been found that lauroxanes, no matter with either ethyl or bromopropyl side chains, which established the ether linkage through C-6, always had an S,S absolute configuration at C-6 and C-7.34 Because the assigned absolute configurations of trans- and cis-pinnatifidenynes (68 and 69) failed to fulfill this rule, Norte and his colleagues remade the chemical characterization of 68 and 69 by both chemical transformation and X-ray diffraction analysis through Cu Kα radiation. As a result, the author revised the structures 68 and 69 as their enantiomers 70 and 71, respectively (Table 3).34 Further, pairs of geometric isomers were isolated from different Laurencia species from different waters; examples are cis- and trans-dihydrorhodophytins (72 and 73),73 (3Z)- and (3E)-13-epi-pinnatifidenynes (74 and 75).74,75 The structure of (3E)-13-epi-pinnatifidenyne (75) was revised as 76 by Manzo et al.76 Compound 76 showed to exert a gradual toxicity against the Pheidole pallidula ants, which escalated at the fourth day of the experiments (mortality >70%). The (3Z)-venustinene (77), isolated from the Japanese red alga L. venusta Yamada,77 is the only example of lauroxane with a propyl side chain at C-12. The eight-membered halogenated acetylenes with exocyclic double bonds are scarce in nature. Chondriol is the first example of this group of metabolites. It was isolated from a red G


Chemical Reviews

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alga originally identified as Chondria oppositiclada but later known as L. yamada in 1973, and its structure was wrongly assigned by spectroscopic means as 78 (Figure 4).78 Successively, the correct structure of chondriol was revised to 79 via X-ray crystallography.79 Within a study aimed to assess the diversity of halogen-based secondary metabolite biosynthesis in the genus Laurencia, cis- and trans-rhodophytins (81 and 82) were isolated, along with chondriol (79) and transchondriol (80).80 Meanwhile, the structure of cis-rhodophytin (81) was revised as the vinyl ether rather than the vinyl peroxide originally proposed.80,81 The structures of 80 and 82 were assigned by comparison of their spectral data with those of the known compounds 79 and 81. A pair of geometric isomers, venustin B (83) and (3Z)venustin (84), were isolated from L. venusta Yamada collected from two different waters in Japan,77,82 whereas 3E- and 3Zlaurenynes (85 and 86) were isolated from two different Laurencia species, L. obtusa and Laurencia yonaguniensis, respectively.83,84 The structure of 85, including the absolute configuration, was determined via X-ray analysis, allowing also the structure of 86 to be determined by direct comparison of its spectroscopic data with those of 85. However, later a highly stereocontrolled and enantioselective synthesis of 85 indicated that the absolute configuration assigned for the natural compound has to be revised as 2R,7R,8R.85 The assessment of biological activities of compound 86 showed that it was inactive against two bacteria, Alcaligenes aquamarines and Escherichia coli at 100 μg/disk, but it exhibited toxicity toward brine shrimp with LC50 values of 467.0 μM. The halogens present in linear C15 acetogenins of marine origin play a biosynthetic role for the cyclic ether formation; thus, C15 acetogenins with halogens are ubiquitous in nature and nonhalogenated C15 acetogenins are scarcely isolated. Compounds 87 and 88, isolated from the Laurencia species from Newzealand waters, belong to this group.86 Because storage of compound 87 in C6D6 at −4 °C resulted in its quantitative conversion to compound 88, the latter could thus be an artifact. The halogenated analogue 89 was isolated from the same collection too (Table 4).86 Laurencienyne (90), possessing the same skeleton as that of 89 but bearing two chlorines and one bromine, was isolated from L. obtusa collected in Castelluccio, Sicily Island, Italy.87 Its structure was established by X-ray and spectroscopic analysis. From the same species but in different locations, both laurencienyne (90) and its isomer laurencienyne B (91) were isolated.88 Two pairs of geometric isomers, 92 and 93, 94 and 95, were isolated from the same alga collected in Greece.75,89 The mortality exerted to the Pheidole pallidula ants was evaluated. The results of the assays showed that the cis isomers 92 and 94 had strong ant toxicity with a knockdown effect on the first day of application, while the trans isomers 93 and 95 showed a gradual toxicity that was escalated at the fourth day of the experiments. C15 acetylenes with a nine-membered ether ring were uncommon. Additionally, all of them contained halogens such as bromine and chlorine. Obtusenyne (96), belonging to this class, was isolated from L. obtusa collected from two different geographical areas (Greece, Italy). Its structure was established by both X-ray diffraction analysis and by combination of chemical and spectral methods. 90,91 The 12-epimer of obtusenyne (98) and its trans-isomer (97) were isolated from spanish alga L. pinnatifida by Norte et al.34 To determine the


compounds c

sources

80 81 82 83

trans-chondriol cis-rhodophytin trans-rhodophytin venustin B

Chondria oppositiclada Laurencia sp. Laurencia sp. Laurencia sp. Laurencia sp. L. venusta

84

(3Z)-venustin

L. venusta

85

3E-laurenyne

L. obtusa

86

3Z-laurenyne

L.

87−89

−a

yonaguniensis L. gracilis

90

laurencienyne

L. obtusa

78/79

chondriol

L. obtusa 91

laurencienyne B

L. obtusa

92−95

−a

L. obtusa

96

obtusenyne

L. obtusa

97

(3E)-12-epiobtusenyne

98

(3Z)-12-epiobtusenyne

99

rhodophytin

101−102

−a

L. obtusa L. pinnatifida A. dactylomela L. pinnatifida A. dactylomela C. oppositiclada A. dactylomela L. implicata

distribution −

b

Guaymas, Mexico Guaymas, Mexico Guaymas, Mexico Guaymas, Mexico Hakodate Bay, Hokkaido, Japan Aomori Prefecture, Japan Aegean Sea, Greece Yonaguni Island, Japan Matheson Bay, New Zealand Castelluccio, Sicily Island, Italy Ionean Sea, Greece Ionean Sea, Greece Aegean Sea, Greece Aegean Sea, Greece Positano, Italy Tenerife Island, Spain Bimini, Bahamas Tenerife Island, Spain Bimini, Bahamas Gulf of California Bimini, Bahamas Magnetic Island, Australia

ref 78, 79, 81 80 80 80 80 77 82 83 84 86 87 88 88 75, 89 90 91 34 304 34 304 81 304 93

a


absolute configuration of obtusenyne (96), (12R,13R)-(−)and (12S,13R)-(+)- obtusenynes were synthesized. Comparison of the optical rotation and 13C and 1H NMR data of the synthetic compounds with those of natural obtusenyne revealed that the stereochemistry for natural compound is 12R,13R.92 A vinyl peroxide, rhodophytin (99), was first isolated from the alga Chondria oppositiclada from the gulf of California, along with the above-mentioned chondriol (78).81 Although 99 exhibited unusual thermal and base stability, when it was kept in unpurified CCl4, it could slowly but quantitatively change into the conjugated diene peroxide 100. Compound 101 was identified from L. implicata from Magnetic Island, Australia.93 The 3JH12−H13 values implied a favored anti-gauche conformation for these hydrogens in solution. In addition, from the same alga, a rare 10-membered acetylene (102) was isolated. The anti-gauche conformation between H12 and H13 was also determined on the basis of their coupling constant value. 2.2.2. Bicyclic C15 Acetylenes. The formation of ether rings of different sizes among C15 acetylenes can be ascribed to the presence of hydroxyl and halogen substitutions in the parent compound. The resulting metabolites are often characterized by the terminal conjugated enyne or allene moieties in their structures (Figure 5). It may be worth H


Chemical Reviews

Review



a

compounds

103 104 105 106 107 108 109

laureepoxide laureoxolane −a −a −a notoryne kumausallene

110

−a

111 112 113−115 116 117 118 119 120

laurenenyne A laurenenyne B −a −a japonenyne-A japonenyne-B japonenyne-C elatenyne

121 122

laurendecumenyne B −a

sources

distribution

ref

L. nipponica L. nipponica L. obtusa L. obtusa L. majuscula L. nipponica L. nipponica Aplysia kurodai L. okamurai A. kurodai Laurencia sp. Laurencia sp. L. majuscula L. obtusa L. japonensis L. japonensis L. japonensis Lurencia elata L. decumbens L. decumbens L. majuscula

Hokkaido, Japan Hokkaido, Japan Graciosa Island, Portugal Graciosa Island, Portugal Hawaii Hokkaido, Japan Hokkaido, Japan Echizen Coast of Fukui, Japan Hokkaido, Aomori, Niigata, Mie, Japan Echizen Coast of Fukui, Japan Mie Prefecture, Japan Mie Prefecture, Japan Queensland, Australia Canary Islands, Spain several locations, Japan several locations, Japan several locations, Japan Mornington Peninsula, Victoria Weizhou Island, China Weizhou Island, China Queensland, Australia

94 95 39 96 97 98 99 305 100 305 101 101 26 96 103 103 103 104 105 105 26


same specimen suggested that the enzymatic formation of the bromo-ether in vivo would not be so regioselective and that bromo-cation might initiate the reaction. Two unusual oxolane derivatives 105 and 106 possessing a propargylic bromide side chain had been isolated from the same Laurencia species collected at Graciosa Island, Portugal.39,96 The structure of 105 was postulated by comparing its spectroscopic data with those of another compound having a similar skeleton. The structure and absolute configuration of

pointing out that bicyclic acetylenes were also mostly isolated from algae belonging to the Laurencia genus. The two bromo-bearing acetylenes, laureepoxide (103) and laureoxolane (104), containing both a THF and an epoxide ring, were isolated from the same Japanese alga L. nipponica Yamada.94,95 The structure of 103 was determined by chemical degradation and spectral properties, while the structure of laureoxolane (104) was deduced by its physical properties and synthetic correlation. The co-occurrence of 103 and 104 in the I


Chemical Reviews

Review


may be an artifact formed during extraction. The stereochemistry at C-6 and C-7 of 119 remained unsettled because compound 119 was decomposed while measuring the NOESY spectrum. Differing from those acetogenins contaning saturated furan and pyran rings, elatenyne (120), obtained from L. elata collected at St. Paul’s Beach, Victoria, possesses two fused saturated pyran rings. The structure of elatenyne (120) characterized by the pyrano[3,2-b]pyranyl vinyl moiety was established by detailed analysis of its 2D NMR spectra. The relative stereochemistry of 120 was assigned by analysis of its coupling constant data provided by the 1H NMR spectrum recorded in (D6)benzene and that of the acetate in the same solvent on gradual addition of Eu(fod)3 shift reagent.104 Elatenyne (120) was reisolated from Chinese red alga L. decumbens along with its analogue laurendecumenyne B (121), of which one bromine atom at C-7 is replaced by a chloride. Interestingly, compounds 120 and 121 were obtained as a colorless oily mixture with a 1:1 ratio, and all attempts to separate them from each other failed.105 Both of them were evaluated for the cytotoxicity against a human lung adenocarcinoma cell line; however, they were found to be inactive. The compound 122, whose structure is closely related to 121, and its relative stereochemistry at all of the chiral centers was the same as that of elatenyne (120), was isolated from L. majuscula collected from Queensland, Australia.26 However, it may be worth noting that the spectroscopic data of 122 and 120 did not correspond with those of synthetic compounds.106 The first bicyclic acetylene containing seven-membered ether ring, (3E)-isoprelaurefucin (123, Figure 6), was isolated from L. nipponica Yamada.107 Its structure, including the absolute

compound 106 were determined by spectroscopic and chemical methods (Table 5). 2,2′-Bis-tetrahydrofuran lauroxane 107, from Hawaii red alga L. majuscula,97 and notoryne (108), from L. nipponica collected from Hokkaido, Japan,98 share the same structural skeleton with two THF rings and differ from each other mainly in the nature of the halogen substitution. Kumausallene (109) and its derivative 110, isolated from the Japanese species of the genus Laurencia,99,100 feature a 2,6dioxabicyclo [3.3.0] octane skeleton, also found in laurenenynes A and B (111 and 112), a pair of inseparable isomers having bromopropyl and C6-enyne side chains, as well as a vinyl ether moiety at C-7.101 The absolute configuration of the allene moiety in both compounds 109 and 110 was assigned as R by application of Lowe’s rule. The stereochemical assignment of kumausallene (109) was successively confirmed by its total synthesis.102 Compounds 111 and 112 were very unstable, and during storage in a freezer for 3 days both compounds decomposed into a dark brown oily substance. The three bicyclic C15 enynes 113−115, all isolated from L. majuscula from the Great Barrier Reef, Queensland, Australia,26 possess a rare 2,5-dioxabicyclo[2.2.1]heptane system; their stereostructures were determined by spectroscopic means except for the configurations of C-12 and C-13. The structure of compound 116 comprises both a saturated furan and a saturated pyran ring and a bromopropargylic side chain.96 Its structure, including the absolute configuration, was determined by spectroscopic and chemical methods. Japonenynes A−C (117−119), found in various Japanese Laurencia species, possess a 2,7-dioxabicyclo[4.3.0]nonane skeleton and a bromine atom substituent at C-6. 103 Compounds 117 and 118 are geometric isomers, while 119 J


Chemical Reviews

Review

Table 6. Summary Information for Compounds 123−141 compounds

sources

distribution

ref

123 124

no.

(3E)-isoprelaurefucin (3Z)-isoprelaurefucin

125 126 127 128 129 130 131 132 105/133c 134 135 136 137 138 139 140 141

neoisoprelaurefucin rogiolenyne A rogioloxepane B poiteol venustin A (3Z)-epoxyvenustin epoxyrhodophytin −a −a laurallene epilaurallene pannosallene nipponallene −a −a laurendecumallene B −a

L. nipponica L. subopposita L. nipponica L. nipponica L. microcladia L. microcladia Laurencia poitei L. venusta L. venusta Laurencia sp. L. obtusa L. obtusa L. nipponica L. nipponica Laurencia pannosa L. nipponica L. intricata L. implicata Laurencia decumbens L. implicata

−b La Jolla, CA Hokkaido, Japan Niigata prefecture, Japan Livorno, Italy Livorno, Italy Florida −b Aomori Prefecture, Japan Coyote Bay, Japan Canary Islands, Spain Canary Islands, Spain Oshoro Bay, Hokkaido, Japan Oshoro Bay, Hokkaido, Japan Phu Quoc Island, Vietnam Troitsa Bay, Japan Hokkaido, Japan The Great Barrier Reef, Australia Weizhou Island, China The Great Barrier Reef, Australia

107 108 109 110 52, 113 35 91 82 77 80 96 39 114 115 116 53 117 118 105 118

a The name of the compound was not given. bThe place of the sample collection was not mentioned. cTwo different structures for the same compound.

been obtained in a previous study of the same alga, but its structure was wrongly reported as 105.39 Laurallene (134) was fitst isolated from the Japanese red alga L. nipponica Yamada.114 Its epimer at C-4, epi-laurallene (135), was isolated from the same alga.115 The absolute configuration of the allene moiety in both 134 and 135 was assigned as S by application of Lowe’s rule. The finding of 135 inspired a reinvestigation of the alga, and, surprisingly, only epi-laurallene (135) was found. This result seemed to suggest that the major secondary metabolites of L. nipponica may change or interconvert in a few years. However, in 1996 re-examination of the NOESY spectrum of epi-laurallene (135) revealed no correlation was observed between H-4 and H-6 and between H-4 and H-7, thus indicating the structure of 135 was incorrect.116 Within the same study, the authors disclosed the structure of pannosallene (136), whose relative stereochemistry, the same as that of 135, was defined by a NOESY experiment.116 The R configuration of the bromoallene moiety in nipponallene (137), isomer of laurallene (134), was also assigned by application of Lowe’s rule.53 The conversion of prelaureatin (66) into laurallene (134) by enzymatic and chemical bromo-etherification reactions was conducted.85 The total synthesis of laurallene (134) was achieved using the asymmetric aldol ring-closing metathesis strategy in seven steps from (R)-benzylglycidyl ether.72 A similar derivative 138, having a bromoallenic side chain and three bromine substituents, was isolated from L. intricata collected in Hokkaido, Japan.117 Its corresponding acetate 139 was synthesized to locate the bromine atom at C-13. Two years later, compound 139 was found in L. implicata from the Great Barrier Reef Region of Australia, along with compound 141 whose structure was elucidated by comparison of its spectroscopic data with those of 139.118 Laurendecumallene B (140) was isolated from the Chinese red alga L. decumbens, and its structure was established by spectroscopic means.105 The bicyclic system of the bromoallenes, for example, microcladallenes A−C (142−144, Figure 7), is composed by an

configuration, was assigned on the basis of chemical and spectral evidence supported by biogenetic consideration. Three years later, it was reisolated together with its Z isomer 124, as a 2:1 mixture from another red alga, L. subopposita collected in La Jolla, CA.108 (3Z)-Isoprelaurefucin (124) was also obtained from a Japanese species of the genus Laurencia, L. nipponica Yamada, by Suzuki et al.109 Moreover, the authors confirmed the absolute configuration of these two compounds on the basis of chemical evidence. Chemical study of the L. nipponica from Japan led to the isolation of another stereoisomer, neoisoprelaurefucin (125), in 15% yield.110 The first asymmetric total synthesis of 125 was achieved by Kim et al., which confirmed the absolute stereochemistry assigned to the natural compound.111 Neoisoprelaurefucin (125) was also synthesized through a novel protecting group-dependent alkylation RCM strategy in 14 steps and in 12% overall yield.112 Pietra et al. investigated the red alga L. microcladia collected from the same area three times. Rogiolenyne A (126) was isolated the first two times, while rogioloxepane B (127) was found the third time.35,52,113 The structures of compounds 128−131 share a common eight-membered cycle bearing an epoxide moiety. Among them, poiteol (128) was isolated from L. poitei collected at Harry Harris State Park, FL, and its structure was determined by X-ray diffraction analysis,91 while venustin A (129) and its 3Z isomer 130 were isolated from L. venusta Yamada;77,82 a third isomer, epoxyrhodophytin (131), was reported in the early 1980s.80 The structures of compounds 129−131 were deduced from spectroscopy, chemical analysis, and X-ray diffraction analysis (Table 6). The bromo-ethers 132−141 all possess the same bicyclic framework characterized by an eight-membered ring fused to an oxolane moiety, and bearing either a bromoallene moiety or a bromo propargylic side chain at C-4. Compound 132 and its acetate derivative 133 were isolated from the red alga L. obtusa collected in Canary Islands, Spain.96 In fact, compound 133 had K


Chemical Reviews

Review


enzymatic structure elucidation.122 Its derivative, laurendecumenyne A (157) possessing a hydroperoxide, was found in another red alga growing in Weizhou Island, China.105 The 3E- and 3Z-laureatins (158 and 159) and their analogues 3E- and 3Z-isolaureatins (160 and 161) were frequently encountered in L. nipponica collected in diverse Japanese regions (see Table 7).110,125−129 Initially, the structures of laureatins were disclosed but the double bond configuration remained unassigned.125 Later, the absolute configuration of these compounds was unambiguously assigned by crystallographic studies on isolaureatin (160).127 Compounds 158 and 160 were evaluated for their insecticidal activities, and 158 showed the highest activity. (3Z)-Laureatin (158) was enzymatically obtained from its original precursor, (3Z,6S,7S)-laurediol, in a single step by lactoperoxidase.71,85 Highly stereo-, regio-, and chemoselective asymmetric total syntheses of 160 and 158 were accomplished; they feature a number of stereo-, regio-, and chemoselective transformations including an intramolecular amide enolate alkylation to construct the α,α′-cis-oxocene skeleton, novel “lone pair lone pair interaction-controlled” epimerization to the α,α′-transoxocenes, various strategies for the demanding stereoselective introduction of halogen atoms, and novel olefin crossmetatheses for construction of the (Z)-enyne systems.130 A pair of isomers, cis- and trans-chondrins (162 and 163), was isolated from Mexican alga Laurencia sp.,80 and their structures were secured by synthesis from cis- and trans-chondriol (79− 80). Chemical investigation of Laurencia species collected from different waters (see Table 8) yielded a series of unusual acetylenes, isolaurallene (164),131 neolaurallene (165),131,132 itomanallene A (166),42 and laurendecumallene A (167).105 All of these compounds possess the 2,10-dioxa-bicyclo[7.3.0]-

eight-membered ring fused to a tetrahydropyran moiety; their structures were determined by X-ray crystallographic analysis.119 Laurefucin (145) and acetyllaurefucin (146) were obtained from Japanese red alga L. nipponica by Irie et al., and, initially, structures of 148 and 149 were assigned to the two metabolites, respectively.27,120 Successively, the authors revised the structure of laurefucin (148) to 145 by X-ray crystallographic data.121 Three mixtures of geometric isomers, cis- and trans-laurefucin (145) 1:3, cis- and trans-acetyllaurefucin (146) 1:1, and cis- and trans-dehydrobromolaurefucin (147) 1:1, were obtained from Laurencia species collected at La Jolla.108 For compound 147, the stereochemistry was defined at all chiral centers except for the hydroxyl bearing carbon. Derivatives 150 and 151 were found in L. gracilis along with 145 from New Zealand waters;86 they were also found in L. nipponica, along with laurencin (63).122 Compound 152 was isolated from the red alga, Dasyphila plumariodes from Holmes Reef in the Coral Sea, as the methyl ether of isolaurefucin; with respect to laurefucin (145), the configurations at C-10 and of the epoxide carbons at positions C-6, C-7, and C-9 of 152 are reversed.123 Chlorofucin (153), bearing both chlorine and bromine substituents in its structure, was isolated from the L. snyderae collected from La Jolla, CA, and its structure was determined by X-ray diffraction analysis.91 It was also encountered in D. plumariodes and L. pannosa.116,123 Its 3Z isomer 154, found in the Malaysian L. pannosa,124 was tested for antibacterial activity against Chromobacterium violaceum, Proteus mirabilis, and Vibrio cholerae, but was active only against C. violaceum with an MIC value of 100 μg/disk. In bromofucin (155), the chlorine present in 153 was replaced by a bromine; it was first isolated from Australian red alga L. implicata,93 and later found in Vietnamese alga L. pannosa.116 Laureoxanyne (156) was obtained from L. nipponica, and its structure was solved by L


Chemical Reviews

Review


compounds

142 143 144 145/148c

microcladallenes A microcladallenes B microcladallenes C laurefucin

146/149c

acetyllaurefucin

147 150−151 150−151 152 153

dehydrobromolaurefucin −a −a −a chlorofucin

154 155

(3Z)-chlorofucin bromofucin

156 157 158

laureoxanyne laurendecumenyne A (3Z)-laureatin

159

(3E)-laureatin

160

(3Z)-isolaureatin

161 162 163

(3E)-isolaureatin cis-chondrin trans-chondrin

sources

distribution

ref

L. microcladia L. microcladia L. microcladia L. nipponica L. subopposita L. gracilis Aplysia parvula L. nipponica L. subopposita L. subopposita L. gracilis L. nipponica Dasyphila plumariodes L. snyderae D. plumariodes L. pannosa A. parvula L. pannosa L. implicata L. pannosa L. nipponica L. decumbens L. nipponica L. nipponica L. nipponica L. nipponica L. nipponica L. nipponica L. nipponica L. nipponica L. nipponica L. nipponica Laurencia sp. Laurencia sp.

French coast, France French coast, France French coast, France −b La Jolla, CA Matheson Bay, Leigh, New Zealand Tsitsikamma National Park, South Africa −b La Jolla, CA La Jolla, CA Matheson Bay, Leigh, New Zealand −b Holmes Reef, Coral Sea, Australia La Jolla, CA Holmes Reef, Coral Sea, Australia Phu Quoc Island, Vietnam Tsitsikamma National Park, South Africa Sarawak, Malaysia Magnetic Island, Australia Phu Quoc Island, Vietnam −b Weizhou Island, China −b Hakodate Bay, Japan Nagasaki Prefecture, Japan −b Hakodate Bay, Japan Shichigahama, Japan Naoetsu and Kashiwazaki, Niigata prefecture, Japan Hakodate Bay, Japan Nagasaki Prefecture, Japan Shichigahama, Japan Guaymas, Mexico Guaymas, Mexico

119 119 119 27, 120, 121 108 86 309 27, 120 108 108 86 122 123 91 123 116 309 124 93 116 122 105 125 126 129 125 126 128 110 126 129 128 80 80

a



a

compounds

164 165

isolaurallene neolaurallene

166 167 168 169 170 171−172 173

itomanallene A laurendecumallene A obtusallen 10-bromo-obtusallene kasallene −a −a

sources L. L. L. L. L. L. L. L. L. L.

nipponica okamurai implicata intricata decumbens obtusa obtusa obtusa obtusa obtusa

distribution

ref

Akkeshi and Erimo, Hokkaido, Japan Bikuni, Hokkaido, Japan The Great Barrier Reef, Australia Komesu, Itoman, Okinawa Prefecture, Japan Weizhou Island, China Gökceada, Aegean Sea, Greece Kas, Turkey Kas, Turkey Mediterranean Sea, Turkey Kas, Turkey

131 132 118 42 105 135 136 137 138 139


bromoallene obtusallene (168),135 10-bromo-obtusallene (169) and kasallene (170) were reported,136,137 170 also exhibiting a dioxane moiety in its structure. Simultaneously, compounds 171 and 172 were obtained from the same Turkish red alga L. obtusa,138 in which the dioxane ring is replaced by an oxolane. The presence of three hydroxyl groups in 171 was a peculiarity among Cl5 Laurencia metabolites. Discovery of compound 173, whose NMR spectrum showed resonances

dodecene skeleton and a bromoallene moiety (Figure 8). Structures of 164 and 165 were determined by spectroscopic means and X-ray diffraction analysis, and confirmed by MM2 force-field calculations.133 The asymmetric total synthesis of 164 was completed by Crimmins et al., confirming the assigned stereochemistry.134 The C15 bromoallenes are uncommon in nature, and those with a macro ring are even less. Following the first C15 M


Chemical Reviews

Review

subunit ring. Faster conformational motions occurred too, which resulted in mediated vicinal J couplings.139 2.2.3. Polycyclic C15 Acetylenes. C-15 acetylenes with more than two rings were also encountered. Their structures are usually composed of rings in different sizes and substituted with halogen, especially with bromine. Although the members of this class of metabolites are few, their structures are diverse and complex. Because of the structural complexity, their structure determination often turned out to be a challenge. In fact, many structures of the compounds isolated in the early 1980s were incorrect, and were later reassigned. Three polycyclic acetylenes, okamurallene (174, Figure 9),140 deoxyokamurallene (175), and isookamurallene (176),141 all isolated from the Bikuni’s L. okamurai and their structures were featured by containing a common bromoallene and cyclopropane moiety. Actually, the structures of 174−176 initially were wrongly assigned and were later revised to be 177−179, respectively, by extensive interpretation of 2D-NMR spectra.117 The analogue 180 was also isolated. The absolute configuration of the bromoallene moiety in each of these compounds was assigned as S by application of Lowe’s rule. The absolute configurations for the remaining stereocenters of 180 were determined by X-ray crystallographic analysis, as well as based on chemical and spectral evidence.142 A unique bromine-containing ketal, obtusin (181), was obtained from the Mediterranean alga L. obtusa.143 The structure, assigned by spectroscopic means, was secured by X-ray crystallographic analysis of obtusinol, its 3-hydroxy derivative. Obtusin (181) was reisolated from the same alga but collected from the Canary Islands, and the structure was confirmed by its own X-ray crystallographic data.144


attributable to equilibrating conformers, in contrast to previous single-conformer descriptions for compounds of this class in solution, prompted a reinvestigation of the conformational behavior of the known compounds 168−169 and 171−172. The results indicated that trans olefin bonds undergo 180° flipping, by which conformers are intercoverted. These equilibria are controlled by enthalpic factors and are only slightly dependent on the solvent nature. Activation barriers depend on the ring size, being larger for compounds with a 10membered (168−169) than an 11-membered (171−173)

Figure 9. Structures of compounds 174−190. N


Chemical Reviews

Review



compounds

174/177c

okamurallene

175/178c

deoxyokamurallene

176/179c

isookamurallene

180

−a

181

obtusin

182 183 184 185 186 187 188 189 190 191 192−194 195 196

cis-maneonene A cis-maneonene B trans-maneonene B cis-maneonene C iso-maneonene-A iso-maneonene-B lembyne-A lembyne-B −a poitediene −a peyssonenyne A peyssonenyne B

sources

distribution

ref

L. okamurai L. intricata L. okamurai L. intricata L. okamurai L. intricata L. intricata L. intricata L. obtusa L. obtusa L. nidifica L. nidifica L. nidifica L. nidifica L. nidifica L. nidifica L. majuscula L. majuscula L. implicata L. poitei Liagora farinose Peyssonnelia caulifera P. caulifera

Bikuni and Takahama, Japan Bikuni, Hokkaido, Japan Bikuni, Hokkaido, Japan Bikuni, Hokkaido, Japan Bikuni, Hokkaido, Japan Bikuni, Hokkaido, Japan Bikuni, Hokkaido, Japan −b Tossa de Mar, Spain Canary Island, Spain south coast of Oahu, Hawaii south coast of Oahu, Hawaii south coast of Oahu, Hawaii south coast of Oahu, Hawaii south coast of Oahu, Hawaii Ssouth coast of Oahu, Hawaii Malaysian Waters, Malaysia Malaysian Waters, Malaysia The Great Barrier Reef, Australia Boca Grande Key, FL Carrie Bow Cay, Belize; Los Frailes Bay, Baja California, Mexico Yanuca Island, Fiji Yanuca Island, Fiji

140 117 141 117 141 117 117 142 143 144 145 145 145 146 146 146 148 148 118 151 210 233 233

a


chemical study of L. poitei collected at Boca Grande Key, Florida, yielded poitediene (191) featuring a 12-member ring system and a dibromo olefin functionality.151 Its structure was confirmed by X-ray analysis.

Chemical investigation of L. nidifica collected off the south coast of Oahu, Hawaii, a rich source of interesting C15 compounds, led to the isolation of three unusual C15halogenated compounds, cis-maneonenes A and B (182 and 183), and trans-maneonene B (184).145 The cis-maneonene C (185) was also isolated from the same species along with two further components, isomaneonenes A and B (186 and 187).146 The structures of these compounds were secured by comparison to the structure of isomaneonene B (187), whose chemical characterization, including absolute configuration, was confirmed by X-ray diffraction analysis.147 Recently, lembyne B (189), a stereoisomer of isomaneonene A (186), was isolated from an undescribed Laurencia species collected off Malaysian waters, together with a new halogenated C15 acetogenin, lembyne A (188).148 In antibacterial bioassay, 188 showed weak antibacterial activity with MIC values in the range of 20− 60 mg/disc. The total synthesis of 182 and 183 was achieved, employing a developed partial catalytic hydrogenation of a silylated butadiyne derivative.149 Also, trans-maneonene B (184) was synthesized in four steps.150 L. implicate from the Great Barrier Reef, Australia, was the source of the tricyclic molecule 190, whose structure was determined by extensive 2D NMR spectroscopy,118 whereas

2.3. Long-Chain (More than C15) Acetylenes/Polyacetylenes from Algae

Polyacetylenes with more than 15 carbons isolated from the algae are rare. Hitherto, only five compounds were isolated from two kinds of red algae, Liagora farinosa and Peyssonnelia caulifera. The monoglyceride 194 (Figure 10) was found in L. farinosa from both the Pacific Ocean and the Caribbean Sea together with the two acetylenic acids 192 and 193; compound 193 was lethal, at 5 μg/mL, to the reef-dwelling fish, Eupomacentrus leucostictus. 152 From Fijian red alga P. caulifera, two monoglycerides, peyssonenynes A and B (195 and 196), were isolated as DNA methyl transferase inhibitors (Table 9).153 However, the stereochemistry of the two compounds was not determined due to their instability and the scarcity of diagnostic protons around the double bond until the solution NMR methods and long-range 1H−13C heteronuclear scalar couplings, nJCH, measured with the 2D excitation sculptured indirect detection experiment (EXSIDE) were used.154 O


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sponges (i.e., Petrosia, Xestospongia, Callyspongia), belonging to the order Haplosclerida, or sponges phylogenetically related to Petrosia genus seem to be the main sources of these polyacetylenic molecules. Generally, sponge-derived polyacetylenes are widely recognized to exhibit various bioactivities ranging from cytotoxicity to antimicrobial activity.

Chart 1 displays the geographical distribution of algal collection sources. As shown, the algae collected from Japan Chart 1. Geographic Distribution of Collection Sources for Algae

3.1. Short-Chain (Less than C15) Acetylenes/Polyacetylenes from Sponges

Hitherto, less than 30 polyacetylenes with short carbon chains are reported from marine source. In particular, most of them were found in sponges. The shortest polyacetylene was xestospongiene Z13 (197, Figure 11), isolated from the Chinese marine sponge Xestospongia testudinaria,155 which may be an artifact derived during the separation process. Compound 197 showed weak cytotoxicity against the tumor cell lines HL-60 (human promyelocytic leukemia), BGC-823 (human gastric cancer), Bel-7402 (human hepatic carcinoma), and KB (human oral epithelium carcinoma). Three polyacetylenes, petrynol (198), petroraspailyne A1 (199), and petroraspailyne B1 (200),156 were all isolated from the sponge Petrosia sp. of Korean origin. The absolute configuration at C-3 of petrynol (198) was determined by the modified Mosher method.156 Compound 199, belonging to the yne-diene series, showed weak cytotoxicity against the human leukemia cell-line K-562 (LC50 9.2 μg/mL), while compounds 198 and 200 possessing the similar yne−ene moiety were inactive. Raspailyne B2 (201), from sponges Raspailia pumila and R. ramose from the North-East Atlantic,157 and petroraspailyne A2, B2, and B3 (202−204), from an undescribed Petrosia sponge collected from Keomun Island, Korea,156 are linear glyceryl enol ethers with the same 13 carbons and an yne-diene group (201, 202), or an yne-ene moiety (203, 204). The stereochemistry at C-10 in 203 or at C-11 in 204 was not determined. Bioactivity evaluation showed that 202 was weakly cytotoxic against human leukemia cell-line K-562 (LC50 57 μg/mL), whereas compounds 203 and 204 were inactive.

are most studied. Particularly, algae from Hokkaido, Okinawa prefecture, and Mie prefecture are the three major sources. Apart from Japan, the research on the algae from other regions like Greece, Spain, Italy, and U.S. makes no difference. Further, the compounds from the algae collected from the other waters including South China Sea, Bahamas, France, Malaysia, Ecuador, etc., account for a large proportion of the C15 acetylenes.

3. SPONGES While C15 acetogenins have been isolated exclusively from algae, long-chain linear polyacetylenic compounds largely dominate the wide set of polyacetylenes isolated from sponges, with few examples of short-chain and C15 acetylenes. Some C15 acetylenic metabolites have been found both in algae and in sponges, thus raising the issue of a possible sponge/macrophyte interaction; the real producer of C-15 acetogenins found in the sponges may be a Laurencia alga on which the sponge preferentially grows and engulfs it entirely. Selected genera of

Figure 11. Structures of compounds 197−213. P


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A diastereomeric mixture of petrosynes Ia and Ib (210 and 211) in a ratio of about 1:1 was isolated as their corresponding acetates 212 and 213 from Okinawan marine sponge Petrosia sp.159 The absolute chemistry at C-2′ was determined by Mosher’s method, whereas the configuration of C-7 was established by enantioselective total synthesis of all possible stereoisomers. Petrosyne Ia (210) showed a moderate antimicrobial activity at a concentration of 1 mg/mL toward Trichophyton mentagrophytes and S. aureus.159

A C14 acetylenic acid 205 was isolated from a marine sponge Oceanapia sp. in Kamagi Bay on the Sada Peninsula by Fusetani et al., and its structure was established by analysis of spectral data. The geometry of two double bonds at Δ7 and Δ11 was assigned on the basis of the coupling constants.158 Compound 205 exhibited a selective antimicrobial activity. It was moderately active against four mutants of Saccharomyces cerevisiae and Candida albicans, but was inactive against Penicillium chrysogenum and Mortierella ramanniana. Four acetylenic enol ethers of glycerol, raspailyne B1 (206), isoraspailynes B1a, B1b, and B1 (207−209), were isolated from R. pumila and R. ramose;157 their structures, except for the configuration at C-2′ in glycerol, were established by extensive spectroscopic analysis (Table 10).

3.2. C15 Acetylenes/Polyacetylenes from Sponges

The long-chain acetylenic enol ethers of glycerol are ubiquitous in marine organisms. From both sponges R. pumila and R. ramose, three long-chain acetylenic enol ethers of glycerol, raspailyne B (214), isoraspailynes B and Ba (215 and 216), were isolated (Figure 12); unfortunately, like the abovementioned compounds 206−213, also the configuration at C2′ in the glycerol part of these molecules remained undetermined.157 A diastereomeric mixture of petrosynes IIa and IIb (217 and 218) was isolated from an unidentified sponge of the genus Petrosia collected from Ishigaki Island, Japan, as their acetates 219 and 220.159 Although they were obtained in a very limited amount, the absolute stereochemistry of the chiral centers at C-7 was established by Mosher’s method and confirmed by enantioselective total synthesis.159 Petroraspailyne A3 (221), bearing an yne-diene moiety, was isolated from Korean sponge Petrosia sp.;156 it exhibited weak cytotoxicity against the human leukemia cell-line K-562 (LC50 29 μg/mL). Two polybrominated C15 acetogenins, 222 and 223 (Figure 12), were isolated from Mycale rotalis.160 Their structures and absolute stereochemistry were confirmed by a single-crystal Xray analysis. From the same sponge, compound 224 was also isolated,161 whose complex bicyclic structure was also determined by X-ray diffraction analysis. The sponge Spongia zimocca collected off the torrent II Rogiolo, south of Livorno, Italy, was the source of rogiolenynes B and C (50 and 225), both featuring a seven-member ring.113 The rogiolenyne B (50), as described above, was also obtained from a Laurencia species growing in the same area. It is interesting to note that the structures of 222−225 are strongly reminiscent of C-15 acetylenes from Laurencia algae, and this finding suggested the possibility of a sponge/macrophyte interaction (Table 11).52 Bearing in mind the fact that most of the acetylenes with 15


compounds

197

xestospongiene Z13

198 199 200 201

petrynol petroraspailyne A1 petroraspailyne B1 raspailyne B2

202 203 204

petroraspailyne A2 petroraspailyne B2 petroraspailyne B3

205

−a

206 207 208 209 210 211

raspailyne B1 isoraspailyne B1a isoraspailyne B1b isoraspailyne B1 petrosyne Ia petrosyne Ib

sources Xestospongia testudinaria Petrosia sp. Petrosia sp. Petrosia sp. Raspailia pumila; R. ramosa Petrosia sp. Petrosia sp. Montipora sp., M. mollis, Pectinia lactuca Oceanapia sp. R. pumila, R. ramosa

Petrosia sp.

distribution

ref

South China Sea, China Keomun Island, Korea

155

−b Keomun Island, Korea −b Sada Peninsula, Japan −b

Ishigaki Island, Okinawa, Japan

156 156 156 157 156 156 156 185 158 157 157 157 157 159 159

a


Figure 12. Structures of compounds 214−225. Q


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carbons were obtained from the algae, mainly Laurencia genus, one acceptable explanation is that some sponges could preferentially grow on a Laurencia species and engulf it entirely.


compounds

sources R. pumila and R. ramosa R. pumila and R. ramosa R. pumila and R. ramosa Petrosia sp.

214

raspailyne B

215

isoraspailyne B

216

isoraspailyne Ba

217 218 221

petrosyne IIa petrosyne IIb petroraspailyne A3

222−223 224

−a −a

M. rotalis M. rotalis

225

rogiolenyne C

S. zimocca

Petrosia sp.

distribution −

b

ref 157

3.3. Long-Chain (More than C15) Polyacetylenes from Sponges

157

3.3.1. Symmetric Polyacetylenes. Symmetry is a common phenomenon in nature, and, interestingly, many polyacetylenes from marine sponges possess highly symmetric structures, which are either axisymmetric or have central symmetry. Callydiyne (226, Figure 13), from a collection of Callyspongia flammea on reefs off Madang, Papua, New Guinea, Indonesia, is the shortest polyacetylene possessing 2-fold element of symmetry.162 From an Indonesian marine sponge of the same family Callyspongiidae, the symmetric polyacetylene (227) was isolated.163 The absolute configurations of the hydroxyl groups at C-3 and C-18 of 227 were established using the modified Mosher’s method. Petrosia sponges are a characteristic source of hydroxylated polyacetylenic compounds. For example, an antimicobial C30 polyacetylene alcohol, petrosynol (228), was isolated from an unidentified Petrosia species from Hachijo-jima Island, Japan, along with its

157

Ishigaki Island, Okinawa, Japan Keomun Island, Korea −b Stagnone di Marsala lagoon, Italy torrent II Rogiolo, south of Livorno, Italy

159 159 156 160 161 113

a


Figure 13. Structures of compounds 226−237. R


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a

compounds

226 227 228

callydiyne −a petrosynol

229

petrosynone

230−232 232

−a −a

233

−a

233−236 237

−a −a

238 239 240 241 242 243 244 245 246 247

petrosiacetylenes A petrosiacetylenes C petrosiacetylenes D dideoxypetrosynols A dideoxypetrosynols D −a (+)-duryne (−)-duryne duryne E fulvinol

sources

distribution

ref

Callyspongia flammea Callyspongia pseudoreticulata Petrosia sp. Petrosia sp. Petrosia sp. undescribed Adocia sp. Petrosia sp. undescribed Petrosia sp. Petrosia sp. Adocia sp. undescribed Adocia sp. undescribed undescribed Adocia sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Tetrosia sp. Cribrochalina dura Petrosia sp. Petrosia sp. Reniera fulva

Papua, New Guinea, Indonesia Spermonde Archipelago, Indonesia Hachijo-jima Island, Japan −b Sukumo Bay, Japan Okinawan waters, Japan Canary Island, Spain Hachijo-jima Island, Japan Okinawan waters, Japan Sukumo Bay, Japan Sukumo Bay, Japan Canary Island, Spain Okinawan waters, Japan Canary Island, Spain Okinawan waters, Japan Okinawan waters, Japan Canary Island, Spain Keomun Island, South Sea, Korea Keomun Island, South Sea, Korea Keomun Island, South Sea, Korea Komun Island, Korea Komun Island, Korea Hachijojima Island, Japan Staniel Cay, Bahamas Miyako Sea-knoll, Japan Miyako Sea-knoll, Japan Algeciras Bay, Spain

162 163 164 165 166 167 195 164 167 166 166 168 167 168 167 167 168 169 169 169 170 170 175 176 177 177 181


tetraketo analogue, petrosynone (229).164 Their structures including absolute configuration were determined by spectral and chemical methods. Petrosynol (228) was not only inhibitory against Mortierella ramannianus but also was active in the starfish egg assay, while petrosynone (229) showed antimicrobial activity against Bacillus subtilis. Later, 228 was found to inhibit the DNA polymerase functions of HIV-l RT

without affecting the RT-associated RNase H activity.165 From another Petrosia sponge in Sukumo Bay, Japan, three new polyacetylenes 230−232, with C2 symmetry, were isolated, together with petrosynol (228).166 Compounds 231 and 232 inhibited the cell division of fertilized ascidian eggs with IC50 values of 30 and 0.5 μg/mL, and compounds 230−232 displayed toxicity in the brine shrimp lethality bioassay. From a S


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respectively.175,176 The absolute configuration of (+)-duryne (244) was determined by synthesis of both enantiomers, whereas the configuration of the carbinol centers and the geometry of the central olefin in compound 243 are still unclear. Compound 243 inhibits mitotic cell division in sea urchin eggs, while 244 inhibits the growth of both mouse and human tumor cell lines in vitro. The enantiomer of 244, (−)-duryne (245), was also recently isolated from a Petrosia sp. collected at Miyako Sea-knoll, Japan,177 along with its derivative, duryne E (246). The stereochemistry of (−)-duryne (245) was established by the modified Mosher’s analysis. (−)-Duryne (245) and duryne E (246) were cytotoxic against HeLa cells with IC50 values of 0.50 and 0.08 μM, respectively. The first total synthesis of (±)-duryne (244 and 245) was finished in 1989.178 Chattopadhyay and his colleagues synthesized (15E,R,R)-duryne by application of the chiron, 1tert-butyldimethylsilylpenta-1,4-diyn-3-ol.179 Recently, the total synthesis of (±)-duryne (244 and 245) was completed, employing the autoxidation/Wittig coupling reaction to synthesize the central (Z)-olefin and using Burgess’ enzymatic resolution procedure with Pseudomonas AK lipase to establish the absolute configurations of the chiral centers.180 From the sponge Reniera fulva collected at Algeciras Bay, Spain, which is closely related to the Petrosia genus by phylogenetic study, fulvinol (247), a long-chain polyacetylene with a highly symmetric structure, was isolated (Table 12).181 Its absolute configuration was elucidated by Mosher’s method. Fulvinol (247) showed in vitro cytotoxicity against P-388 mouse lymphoma, A-549 human lung carcinoma, HT-29

new sponge species of the family Niphatidae from Okinawan waters, other than petrosynol (228) and petrosynone (229), previously found in a Petrosia sponge, five new polyacetylenes 233−237 as minor constituents were obtained.167 All of the isolated compounds 228−229 and 234−237, except for 233, were highly cytotoxic against P388, A-549, HT-29, and MEL-28 melanoma cells. Compounds 232−233 and 237 were also isolated from an Okinawan marine sponge of Adocia sp. along with petrosynol (228), even though to these compounds new names were given.168 Three highly symmetric C30 linear polyacetylenes, petrosiacetylenes A, C, and D (238−240) and dideoxypetrosynols A and D (241 and 242), were isolated from the sponge Petrosia sp. from Korean waters (Figure 14).169,170 The absolute configuration at C-3 and C-28 of 242 was later corrected as 3R,28R.171 Compounds 239−240 were isolated as unseparable mixtures of diastereomers, and their absolute stereochemistry was determined by the modified Mosher’s method. Compounds 238−240 exhibited a wide range of bioactivities, including brine-shrimp lethality, RNA-cleaving, and moderately inhibitory against PLA2 and Na+/K+ ATPase activities. Deoxypetrosynols A and D (241 and 242) were found to be cytotoxic against human tumor cell lines (A549, SK-OV-3, SKMEL-2, XF498, and HCTl5) and to inhibit DNA replication at the level of initiation.169,172 Recently, the mechanism of 241 inhibiting DNA replication and its antiproliferative action in cultured human leukemia U937 cells was studied.173,174 Compounds 243 and (+)-duryne (244) were obtained from the sponges Tetrosia sp. and Cribrochalina dura from Hachijojima Island, Japan and Staniel Cay, Bahamas, T


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human colon carcinoma, and MEL-28 human melanoma (ED50 = 1 μg/mL). As shown, symmetric polyacetylenes were almost isolated from Petrosia sponges or from sponges phylogenetically related to Petrosia genus. Although further research should be conducted to prove this conclusion, on the basis of the reported studies, symmetric polyacetylenes can be considered charactheristic chemical makers of Petrosia sponges. 3.3.2. Asymmetric Polyacetylenes. Asymmetric polyacetylenes with long chains ranging from n = 16 to n = 48 are ubiquitous in marine sponges, and they are believed to play a crucial role in the sponge metabolism. As for asymmetric polyacetylenes, some genera of sponges (i.e., Petrosia, Xestospongia, Callyspongia) belonging to the order Haplosclerida seem to be the main sources of these typical molecules; thus, long-chain asymmetric polyacetylenes are considered as chemotaxonomic markers for these sponge genera.182 A few reports of this kind of polyacetylenes from marine organisms belonging to different plants and animal groups, such as red algae,24,27,152 nudibranch mollusks,183,184 and stony corals,185 also have appeared in the literature. Acetylenic compound biogenesis is a highly speculative field, with an almost total lack of experimentation. Still, there is enough evidence to hypothesize a likely biosynthesis de novo of most of the compounds by sponge themselves even though a bacterial symbiont origin in the different organisms also could be possible. Notable biological activities including antifungal properties,186 HIV protease inhibition,5 and cytotoxicity have been reported for several members of this class of compounds.187 Two novel diyne enol ethers of glycerol, raspailyne A1 (248) and 249, were obtained from the marine sponges R. pumila and R. ramosa,157 and New Zealand sponge Petrosia hebes,188 respectively (Figure 15). The S-configuration at C-2′ for raspailyne A1 (248) was derived from chemical correlations. Chemical investigation of Haliclona lunisimilis from Point Loma, CA, led to the isolation of nine chlorinated polyacetylenes, compounds 250−254, 255, and 256−258 (Table 13).189 The sponges belonging to Xestospongia genus are a prolific source of long-chain, often brominated polyacetylenes. Because they always feature the carboxylic function, usually the extract is methylated with CH2N2. From X. testudinaria in the straits of the Gulf of Eilat, compounds 259−261 were isolated;190 some of them, compounds 259−260, were later found also in a collection of an unidentified sponge in Papua New Guinea.191 Compound 259 was also found in X. muta collected in Columbus Island, Bahamas, along with 262, and was shown to inhibit HIV protease, a critical enzyme in the replication of human immunodeficiency virus.5 Five brominated polyacetylenic diols, diplynes A−E (263− 267), and the three sulfated analogues 268−270 were isolated from the Philippines sponge Diplastrella sp. by employing bioassay-guided fractionation using the HIV-1 integrase inhibition assay.192 However, the pure compounds 263−267 did not significantly inhibit the integrase (IC50 > 50 μg/mL), while the sulfated compounds 268−270 exhibited mild inhibition of HIV-1 integrase (∼30−90 μg/mL). Compounds 268−270 degraded rapidly, so at the time of the assay, these compounds had partially degraded, and it is possible that compounds produced by the degradation process are responsible for the observed activity. Recently, diplynes A, C, and E (263, 265, and 267) were reisolated from the same


compounds

248

raspailyne A1

249

−

250−254

−a

255

−a

256−258 259

−a −a

a

sources R. pumila and R. ramosa Petrosia hebes

D. sandiegensis Haliclona lunisimilis D. sandiegensis H. lunisimilis H. lunisimilis X. testudinaria Xestospongia sp. X. muta

260

−a

X. testudinaria Xestospongia sp.

261

−a

X. testudinaria

262

−a

X. muta

263

diplyne A

Diplastrella sp. Diplastrella sp.

264

diplyne B

Diplastrella sp.

265

diplyne C

Diplastrella sp. undescribed

266

diplyne D

Diplastrella sp.

267

diplyne E


268−270

−a


271

faulknerynes A

Diplastrella sp.

272

faulknerynes B

Diplastrella sp.

273

faulknerynes C

Diplastrella sp.

distribution

ref

−

157

Poor Knights Islands, New Zealand Point Loma, CA Point Loma, CA

188

Point Loma, CA Point Loma, CA Point Loma, CA The Gulf of Eilat, Red Sea, Isreal The Gulf of Eilat, Red Sea, Isreal Columbus Island, Bahamas The Gulf of Eilat, Red Sea, Isreal The Gulf of Eilat, Red Sea, Isreal The Gulf of Eilat, Red Sea, Isreal Columbus Island, Bahamas Boracay Island, Philippines Sweetings Cay, Bahamas Boracay Island, Philippines Boracay Island, Philippines Sweetings Cay, Bahamas Boracay Island, Philippines Boracay Island, Philippines Sweetings Cay, Bahamas Boracay Island, Philippines Sweetings Cay, Bahamas Sweetings Cay, Bahamas Sweetings Cay, Bahamas Sweetings Cay, Bahamas

184 189 189 190

b

184 189

191 5 190 191 190 5 192 193 192 192 193 192 192 193 192 193 193 193 193

a


sponge Diplastrella sp. but collected from Bahamas, together with faulknerynes A−C (271−273).193 The absolute configuration of diplyne C (265) and faulkneryne A (271) was established by two microscale methods based on exciton coupling circular dichroism (ECCD) in allylic benzoates/ naphthoates. Faulknerynes B and C (272 and 273) were assumed to have the same configuration as that of faulkneryne A (271) because they were produced by the same source. Diplyne C (265) was cytotoxic against cultured human colon tumor cells (HCT-116; LD50 3.6 μg/mL); unfortunately, insufficient amounts of faulknerynes A−C (271−273) were available for biological evaluation. The total synthesis of (+)-diplynes C and E (265 and 267) was completed.194 (+)-Diplyne C (265) was produced in an overall yield of ca. U


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and KB (human oral epithelium carcinoma). From the sponge Strongylophora durissima collected at Lan-Yu, China, durissimol A (288) was isolated,198 and compound 289 was found from the Okinawan sponge of Petrosia (Strongylophora) genus.199 Nitrogen-containing cyclic and polycyclic marine natural compounds are well-known and commonly encountered,200 while less familiar are the acyclic, long-chain, nitrogencontaining compounds. Clathculins A and B (290 and 291) containing a 1,2-diaminoethane moiety were isolated from the sponge Clathrina aff. Reticulum in Sodwana Bay, South Africa,201 and represent the first two examples of the acyclic, long-chain, nitrogen-containing compounds. From the Egyptian marine sponge Callyspongia fistularis, callyspongamide A (292), an amide derivative of a C17-polyacetylenic acid and phenethylamine, was found (Table 14).202 Compound 293, unique for the presence of an isolated thiophene ring, was isolated from the Okinawan calcareous sponge Paragrantia cf. waguensis.203 It showed a weak cytotoxic effect against NBT-T2 rat bladder epithelial cells (IC50 > 20 mg/mL), and antimicrobial activity with MIC values of 64 and 128 mg/mL against S. aureus and Escherichia coli, respectively. From the sponge R. pumila from the North-East Atlantic, two acetylenic enol ethers of glycerol, raspailyne-A (294) and isoraspailyne A (295), were isolated.157,204 Chemical investigation of an Australian marine sponge, Spongia sp. (Heterofibria), led to the isolation of fatty acids heterofibrins A1 and B1 (296 and 297), along with the relevant monolactyl

22% using Brown’s hydroboration−bromination procedure to establish the (E)-vinyl bromide stereochemistry. (+)-Diplyne E (267) was synthesized stereoselectively by means of a Takai olefination and Pd-catalyzed cross-coupling reactions in an overall yield of ca. 10%.194 Di- and tribromocarboxylic acids are not frequently encountered in marine organisms. From the sponge X. muta collected near Summerland Key, FL, the polyacetylene with dibrominated terminus 274 was found, which showed a slight degree of cytotoxicity.195 Compound 274 was later obtained from the Indonesian sponge Oceanapia sp., along with two new bromo-substituted polyunsaturated C16 fatty acids, 275 and 276.196 Compounds 274 and 276 (Figure 16) were again isolated from the Bahamian sponge X. muta,197 and found to be active against Cryptococcus neoformans. Because of their instability, the mixture cytotoxicity of the three comounds 274−276 was tested for its cytotoxicity against KB cells and displayed only a weak effect. Compound 276 showed mild antimicrobial activity against Gram-positive bacteria. Xestospongienes T−Z (277− 283) and xestospongienes Z1−Z4 (284−287) were isolated from the Chinese marine sponge X. testudinaria.155 The stereochemistry of the secondary alcohol at C-8 was determined by the modified Mosher’s method. All of these compounds showed weak cytotoxicity against the tumor cell lines HL-60 (human promyelocytic leukemia), BGC-823 (human gastric cancer), Bel-7402 (human hepatic carcinoma), V


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From the Australian marine sponge X. testudinaria, a brominated bisacetylenic acid (302, Figure 17) was isolated,206 which was later found in the sponge of the genus Xestospongia collected in the straits of the Gulf of Eilat, Israel.190 The methyl ester of compound 302 was isolated from the sponge X. testudinaria collected from Queensland, Australia, together with another two methyl esters 304 and 305.207 It seems that 303 and 304 were not present in the sponge in this form but are artifacts from the separation method, which involved warming the crude extract with MeOH. From the sponge X. testudinaria but collected at Mayotte, xestospongic acid (306) and its ethyl ester (308) were isolated.208 Both compounds showed antimicrobial activity, and compound 308 is a Na+/K+ ATPase inhibitor. Chemical study of the Japanese sponge Petrosia volcano resulted in the isolation of compound 305 as the free carboxylic acid, xestospongic acid (306) and its methyl ester 307, and C18 acetylenic acids and methyl esters 309−318.3 Both acetylenic acids and their methyl esters exhibited antifungal activity against the fungus Mortierella ramannianus. The xestospongic acid 306 and its 17Z isomer 309 were recently isolated as methyl esters from the sponge X. testudinaria collected at Weizhou Island, China.155 From the Bahamian sponge X. muta, the inhibitors of HIV protease 319− 323 were obtained,5 which showed inhibitory activity against HIV-1 protease with an IC50 of 6−12 μM. The proposed structure for compound 323 is tentative because the methyl ester of 321 could not be prepared due to its instability. Compounds 302 and 304 were also found in the sponge belonging to the genus of Xestospongia collected in Papua New Guinea with another four brominated polyacetylenes 324− 327,191 and a polyacetylene with two bromides substituted 328, which was previously isolated from this sponge collected in the straits of the gulf of Eilat.190 From the Australian sponge X. testudinaria, two unprecedented polyacetylenes with the steroid moiety, 329 and 330, were isolated, together with the known acid 302 (Table 15).209 Polyacetylenic hydrocarbons with 19 carbons are very rare; hitherto, only one was identified, aikupikanyne (331), from Red Sea sponge Callyspongia sp. (Figure 18).210 From the Korean sponge Stelletta species, four acetylenic acids were isolated, stellettic acid A (332), (Z)-stellettic acid A (333) and its derivative 334, (E)-stellettic acid B (335), and (Z)-stellettic acid C (336) and its derivative 337.211 Their stereochemistry was defined by combined use of CD spectroscopy and a chiral anisotropic reagent, phenylglycine methyl ester (PGME). Interestingly, (Z)-stellettic acid C (336) induces apoptosis in human leukemic U937 cells and affects telomerase activity.212 From a sponge of the same genus collected from GaguDo, Korea, stellettic acid A (332) was isolated, along with its analogue 338 and the dimer 339.213 Compounds 332, 338, and 339 exhibited weak cytotoxicity against a human leukemia cellline (K562). Further investigation of the Korean Stelletta sponge resulted in the isolation of the polyacetylenics monoglyceride and lysophosphatidylcholine 340 and 341, respectively.214 These compounds were evaluated for cytotoxicity against a small panel of five human tumor cell lines (A549, SK-OV-3, SK-MEL-2, XF498, HCT15). Only 341 showed moderate cytotoxicity, whereas 340 was virtually inactive. The terminal mono acetylenic compound 342 was first obtained from the sponge Cribrochalina vasculum collected in Belize.215 However, its absolute configuration at C-3 was not determined until it was isolated again from the same sponge but collected in different waters, when the configuration of C-3 was

Table 14. Summary Information for Compounds 274−301 no. 274

compounds −a

sources X. muta Oceanapia sp.

a

275

−a

X. muta Oceanapia sp.

276

−a

Oceanapia sp.

277

xestospongiene T

X. muta X. testudinaria

278

xestospongiene U

X. testudinaria

279

xestospongiene V

X. testudinaria

280

xestospongiene W

X. testudinaria

281

xestospongiene X

X. testudinaria

282

xestospongiene Y

X. testudinaria

283

xestospongiene Z

X. testudinaria

284

xestospongiene Z1

X. testudinaria

285

xestospongiene Z2

X. testudinaria

286

xestospongiene Z3

X. testudinaria

287

xestospongiene Z4

X. testudinaria

288

durissimol A

289

−a

Strongylophora durissima Petrosia sp.

290

clathculin A

291

clathculin B

292

callyspongamide A

293

−a

294

raspailyne-A

Clathrina aff. Reticulum Clathrina aff. Reticulum Callyspongia fistularis Paragrantia cf. waguensis R. pumila

295

isoraspailyne A

R. pumila

296

heterofibrins A1

Spongia sp.

297

heterofibrins B1

Spongia sp.

298

heterofibrins A2

Spongia sp.

299

heterofibrins B2

Spongia sp.

300

heterofibrins A3

Spongia sp.

301

heterofibrins B3

Spongia sp.

distribution

ref

Summerland Key, L Manado, Sulawesi, Indonesia Bahamas Manado, Sulawesi, Indonesia Manado, Sulawesi, Indonesia Bahamas Weizhou Island, China Weizhou Island, China Weizhou Island, China Weizhou Island, China Weizhou Island, China Weizhou Island, China Weizhou Island, China Weizhou Island, China Weizhou Island, China Weizhou Island, China Weizhou Island, China Lan-Yu, China

195

Ishigaki Island, Okinawa Prefecture, Japan Sodwana Bay, South Africa Sodwana Bay, South Africa Hurghada, Red Sea, Egypt Onna village, Okinawa, Japan Baie de Morlaix, Brittany, France Baie de Morlaix, Brittany, France Great Australian Bight, Australia Great Australian Bight, Australia Great Australian Bight, Australia Great Australian Bight, Australia Great Australian Bight, Australia Great Australian Bight, Australia

196 197 196 196 197 155 155 155 155 155 155 155 155 155 155 155 198 199

201 201 202 203 204 205 205 205 205 205 205 205


and dilactyl esters, heterofibrin A2, B2, A3, and B3 (298− 301).205 These compounds were not cytotoxic, but the two carboxylic acids 296 and 299 inhibit lipid droplet formation in A431 fibroblast cell lines. W


Chemical Reviews

Review


established as S by the modified Mosher’s method.216 The stereoselective synthesis of the two enantiomers of 342 was achieved from D-gluconolactone and D-xylose, respectively, using acetylenic technology.217 A pair of enantiomers of compound 342 was later prepared using sugars as chiral pool starting materials.218 Compound 342 was also synthesized without use of the protecting groups, the key step being an enzymatic resolution of a racemic mixture of the compound.219 From an undescribed Callyspongia sponge at Sharm El Sheikh, Egypt, a hydroxylated C20 polyacetylene, aikupikanyne D (343), was obtained.210 Two common acetylenic acids (344 and 345) were isolated from the demosponge Ecbinochalina mollis around Noumea;220 the polyacetylenes with rare cyclopropane ring, cladocroic acid (346), were found in the New Caledonian sponge Cladocroce incutvata.221 The polyunsaturated brominated fatty acid 347, from an Indonesian sponge, showed moderate cytotoxicity against NBT-T2 rat bladder epithelial cells.222 These kinds of compounds were also found in Xestospongia sponges, such as compound 348 isolated from the Vietnamese sponge X. testudinaria,223 compounds 349 and 350 from an Indian Xestospongia sponge,224 and compound 351 from a Xestospongia sp. collected in Papua New Guinea, which also contained compound 350 (Table 16).191 An unusual optically active chlorodibromohydrin, mollenyne A (352), was obtained from the Bahamian marine sponge Spirastrella mollis, and its complete stereostructure was solved

by an integrated approach employing NMR, MS, CD, and chemical synthesis.225 Mollenyne A (352) exhibited significant cytotoxicity against human colon tumor cells (HCT-116; IC50 = 1.3 μg/mL; etoposide = 0.55 μg/mL). Brominated polyunsaturated fatty acids (BPUFAs) are hallmark metabolites of X. muta, a common sponge found throughout the Caribbean, and X. testudinaria, which is found in the Indo-Pacific; however, polyacetylenes like mutafurans A−G (353−359), from Bahamian sponge X. muta, featuring a brominated ene-yne THF moiety, are quite uncommon (Figure 19).197 The absolute configuration of compounds 353−359 was assigned by interpretation of the Cotton effect arising from weak perturbation of an ene−yne chromophore by a propargylic THF ring. Moreover, they were found to be active against Cryptococcus neoformans, an opportunistic fungus commonly linked to the pathologies of HIV patients. The Callyspongia sponge is a rich source of C21 polyacetylenes, often endowed with significant bioactivities. Callytetrayne (formerly called callyberyne C) and callypentayne (formerly callyberyne A) (360 and 361), from C. truncata collected in Sagami Bay, Japan showed potent metamorphosisinducing activity in the ascidian Halocynthia roretzi, with ED100 values at 0.25 μg/mL.8 From the Japanese and Red Sea Callyspongia sponges, callyberynes A−C (361, 362, and 360) and aikupikanyne B (363), respectively,210,226 were isolated but they were inactive. Callyberynes A, B (361, 362) were X


Chemical Reviews

Review

376) were obtained from another Red Sea sponge Callyspongia sp.,210 and compound 377 from the Caribbean sponge C. vasculum.229 Aside from compounds 370−374, two hydroxylated polyacetylenes, siphonochalynol and dehydrosiphonochalynol (378 and 379), were found in Siphonochalina sponge in the Gulf of Eilat.232 However, the double bond geometry in 379 was not determined. From a Red Sea Callyspongia sponge, aikupikanyne E (380) was isolated.210 Dehydrosiphonochalynol (379) was reisolated from a Red Sea sponge Callyspongia sp., together with callyspongenols A−C (381−383).233 The double bond geometry of Δ5 and Δ20 in dehydrosiphonochalynol (379) was established as cis using 1H NMR data. The four compounds (379−383) showed moderate cytotoxicity against P388 and HeLa cells. Compound 384 was first isolated from the sponge C. vasculum in Belize, and its R absolute configuration at C-3 was determined by application of the exciton chirality method.215,229 Later, it was isolated from the Mediterranean sponge P. ficiformis and its absolute configuration confirmed by applying advanced Mosher’s method.234 Similarly, from the sponge C. vasculum collected in the Bahamas, the polyacetylene 385 with S configuration at C-3 was obtained, the stereochemistry of which was established by using the modified Mosher’s method.216 The stereochemistry of compounds 384, 385 was further confirmed applying the chemoenzymatic synthesis by lipase-catalyzed biotransformations.235 Compounds 384 and 385 were first synthesized without the stereoselectivity.230 The stereoselective synthesis of compound 384 was also achieved in highly enantiomerically pure form by lipase-catalyzed transesterification with Novozym 435 (Candida antarctica).236 A polyacetylene diol, callyspongidiol (386), exhibiting antiproliferative activity against HL-60 with the IC50 value of 6.5 μg/mL, was isolated from the Japanese sponge Callyspongia sp.237 It was recently found to regulate human dendritic cell (DC) function in a fashion that favors Th1/Th2 cell polarization or IL-10 producing T cells, and might have implication in tumor or in autoimmune diseases.238 From the sponge Reniera fulva in the bay of Naples, debrorenierin-1 (387), renierin-1 (388), and l8-dihydrorenierin-1 (389) were obtained.239 Chemical investigation of the sponge X. testudinaria led to the isolation of the brominated acid 390 (Table 17).223 Polyacetylenes with a cyclic peroxide function are less abundant; because they are very unstable, they were usually isolated as their methyl esters. Compounds 391 and 392 (Figure 20) were isolated from the Red Sea marine sponge Acarnus cf. bergquistae, the corresponding free carboxylic acids being the natural metabolites of the sponge.240 From an Indian sponge A. bicladotylota, compound 391 was reisolated, together with two new compounds, 393 and 394, also obtained as their methyl esters.241 The absolute configurations of these compounds at C-3 and C-6 were determined by chemical conversion combined with the Mosher’s method of their derivatives. The first syntheses of peroxyacarnoates A and D (391 and 394) were achieved on the basis of chemoselective ozonolysis within a polyunsaturated framework and Pdmediated cross-couplings of a functionalized 1,2-dioxane.242 A C23 polyacetylene (395) was isolated from the unidentified Palauan Haliclona sponge.243 Renierin 2 (396) was first identified from the sponge R. fulva collected in the bay of Naples, Italy,239 and also found in a Taiwanese sponge S. durissima.198 From a Okinawan Petrosia sponge, compound 397 was isolated.199 Two related compounds (398 and 399) were

Table 15. Summary Information for Compounds 302−330 no. 302

compounds −

a

sources X. testudinaria Xestospongia sp. X. testudinaria Xestospongia sp. X. testudinaria

304

−a

X. testudinaria

305

−a

Xestospongia sp. X. testudinaria Petrosia volcano

a

306

−a

307

−a

X. testudinaria P. volcano

308 309

−a −a


310−318

−a


319−323

−a

X. muta

324−327 328

− −a

Xestospongia sp. Xestospongia sp.

329−330

−a

X. testudinaria

a


distribution

ref

Pandora Reef, Queensland, Australia The Gulf of Eilat, Red Sea, Israel Pandora Reef, Queensland, Australia Papua New Guinea Bird Island, Wreck Reef, Coral Sea, Australia Pandora Reef, Queensland, Australia Papua New Guinea Pandora Reef, Queensland, Australia Hachijo-jima Island, Japan Mayotte, France Hachijo-jima Island, Japan Weizhou Island, China Hachijo-jima Island, Japan Mayotte, France Hachijo-jima Island, Japan Weizhou Island, China Hachijo-jima Island, Japan Columbus Island, Bahamas Papua New Guinea The Gulf of Eilat, Red Sea, Israel Bird Island, Wreck Reef, Coral Sea, Australia

206 290 207 191 209

207 191 207 3 208 3 30 3 208 3 30 3 5 191 190 209


synthesized for the first time using highly convergent approaches based on optimized Cadiot−Chodkiewicz (Alami, Vasella) and sequential Sonogashira cross-coupling reactions.227 Transition-metal-catalyzed cross-coupling reactions to sp centers have been applied to the total syntheses of 360−362.228 From the sponge C. vasculum in Belize, two C21 hydroxylated polyacetylenes (364 and 365) were obtained,215 whose stereochemistry at C-3 was later determined by applying the circular dichroic excitation method.229 Their enantiomers, compounds 366 and 367, were also isolated from the same sponge but collected in Bahamas, together with compounds 368 and 369,216 and their stereochemistry of C-3 was determined by Mosher’s method. The total synthesis of 365 was completed.230 The first enantioselective synthesis of 364 was achieved, which confirmed the absolute configuration of 364.231 Four C22 polyacetylenic hydrocarbons with a long unsaturated alkyl chain were isolated from the sponge Siphonochalina sp.232 The double bond configuration in Δ15docos-1-yne (370) and siphonochalyne (372) was established as cis by spectroscopic data. The exact location of the central triple bond of octahydrosiphonochalyn (371) could not yet be determined; similarly, two general formulas 373 and 374 were suggested for the dihydrosiphonochalyne.232 The analogues octahydrosiphonochalyne (371) and aikupikanyne C (375− Y


Chemical Reviews

Review



a

compounds

331 332

aikupikanyne stellettic acid A

333 334 335 336 337 338−339 340 341 342

(Z)-stellettic acid A −a (E)-stellettic acid B (Z)-stellettic acid C −a −a −a stellettacholine A −a

343 344 345 346 347 348 349 350

aikupikanyne D −a −a cladocroic acid −a −a −a −a

351 352

−a mollenyne A

sources

distribution

ref

Callyspongia sp. Stelletta sp. Stelletta sp. Stelletta sp. Stelletta sp. Stelletta sp. Stelletta sp. Stelletta sp. Stelletta sp. Stelletta sp. Stelletta sp. Cribrochalina vasculum C. vasculum Callyspongia sp. Ecbinochalina mollis E. mollis Cladocroce incutvata Haliclona sp. X. testudinaria Xestospongia sp. Xestospongia sp. Xestospongia sp. Xestospongia sp. Spirastrella mollis

Sharm El Sheikh, Egypt Ullung Island, Korea GaguDo, Korea Ullung Island, Korea Ullung Island, Korea Ullung Island, Korea Ullung Island, Korea Ullung Island, Korea GaguDo, Korea Ullung Island, Korea Ullung Island, Korea Glover reef, Belize Caribbean near Egg Island, Bahamas Sharm El Sheikh, Egypt Noumea, France Noumea, France South of New Caledonia, France Alor Island, Indonesia Nam Yet, Truong Sa archipelago, Vietnam Bennett Shoal, Exmouth Gulf, Australia Bennett Shoal, Exmouth Gulf, Australia The Gulf of Eilat, Red Sea, Israel The Gulf of Eilat, Red Sea, Israel Plana Cays, Bahamas

210 211 213 211 211 211 211 211 213 214 214 215 216 210 220 220 221 222 223 224 224 191 191 225


Z


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Review


obtained from C. vasculum in the Bahamas,216 and in the same species, collected in Belize, the derivative 401 was also found.215 The epimer of 398 (compound 400) was also found in the Bahamian sponge C. vasculum, together with compound 401.229 The total synthesis of compound 401 was completed without controlling the stereochemistry of the carbinol center.230 Several polyacetylene diols were reported; among them, 18hydroxyrenierin-2 (402) was obtained from the Italian R. fulva,239 and siphonodiol, dihydrosiphonodiol, and tetrahydrosiphonodiol (403−405) were isolated as H, K-ATPase inhibitors.244 Compound 404 was reported to show weak

activity against Trichophyton asteroides and medium activity against S. aureus and Streptococcus pyogenes C-203.245 However, the structure represented by 406 can not be eliminated. Compound 403 was also found in a Japanese Callyspongia sponge;226 it was shown to possess antiproliferative activity against HL-60 with IC50 values of 2.8 and 6.5 μg/mL as with compound 404, which was also found to regulate the function of human monocyte-derived dendritic cells.237,238 Highly convergent approaches based on optimized Cadiot−Chodkiewicz and sequential Sonogashira cross-coupling reactions were applied to the stereoselective total syntheses of siphonodiol and tetrahydrosiphonodiol (403 and 405).246 AA


Chemical Reviews

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a

compounds

sources

collection of sources

ref

353 354 355 356 357 358 359 360c

mutafuran A mutafuran B mutafuran C mutafuran D mutafuran E mutafuran F mutafuran G callytetrayne; callyberyne C

361c

callypentayne; callyberyne A

362 363 364−365

callyberyne B aikupikanyne B −a

366−369 370 371 372 373/374b 375 376 377 378 379

−a Δ15-docos-1-yne octahydrosiphonochalyn siphonochalyne dihydrosiphonochalyne octahydrosiphonochalyne aikupikanyne C −a siphonochalynol dehydrosiphonochalyno

380 381 382 383 384

aikupikanyne E callyspongenol A callyspongenol B callyspongenol C −a

385 386 387 388 389 390

−a callyspongidiol debrorenierin-1 renierin-1 18-dihydrorenierin-1 −a

X. muta X. muta X. muta X. muta X. muta X. muta X. muta Callyspongia truncata Callyspongia sp. C. truncata Callyspongia sp. Callyspongia sp. Callyspongia sp. C. vasculum C. vasculum C. vasculum Siphonochalina sp. Siphonochalina sp. Siphonochalina sp. Siphonochalina sp. Callyspongia sp. Callyspongia sp. C. vasculum Siphonochalina sp. Siphonochalina sp. Callyspongia sp. Callyspongia sp. Callyspongia sp. Callyspongia sp. Callyspongia sp. C. vasculum C. vasculum P. ficiformis C. vasculum Callyspongia sp. Reniera fulva R. fulva R. fulva X. testudinaria

Bahamas Bahamas Bahamas Bahamas Bahamas Bahamas Bahamas Atami, Sagami Bay, Japan Tokushima prefecture, Japan Atami, Sagami Bay, Japan Tokushima prefecture, Japan Tokushima prefecture, Japan Sharm El Sheikh, Egypt Glover reef, Belize San Salvador Island, Bahamas Caribbean near Egg Island, Bahamas The Gulf of Eilat, the Red Sea, Israel The Gulf of Eilat, the Red Sea, Israel The Gulf of Eilat, the Red Sea, Israel The Gulf of Eilat, the Red Sea, Israel Sharm El Sheikh, Egypt Sharm El Sheikh, Egypt San Salvador Island, Bahamas The Gulf of Eilat, the Red Sea The Gulf of Eilat, the Red Sea, Israel Hurghada, Egypt Sharm El Sheikh, Egypt Hurghada, Egypt Hurghada, Egypt Hurghada, Egypt Glover reef, Belize San Salvador Island, Bahamas Naples, Italy Caribbean near Egg Island, Bahamas Tokushima prefecture, Japan Naples, Italy Naples, Italy Naples, Italy Nam Yet, Truong Sa archipelago, Vietnam

197 197 197 197 197 197 197 8 226 8 226 226 210 215 229 210 232 232 232 232 210 210 229 232 232 233 210 233 233 233 215 229 234 216 237 239 239 239 223

The name of the compound was not given. bTwo different structures for the same compound. cTwo different names for the same compound.

Chemical investigation of the Japanese sponge C. truncata resulted in the isolation of the C23 triols 407−411 (Table 18), which showed both a potent metamorphosis-inducing activity in the ascidian Halocynthia roretzi larvae, with ED100 values of 0.13−1.3 μg/mL, and antifouling activity against the barnacle Balanus amphitrite larvae, with ED50 values of 0.24−4.5 μg/ mL.8 The study of Australian marine sponge Phakellia carduus yielded a series of new C23 acetylenic acids, carduusynes A−E (412−416), isolated and characterized as their ethyl esters (417−421).247 The synthesis of carduusyne A (412) was completed, by using organometallic addition to pyrylium salts followed by Wittig homologation and dehydrohalogenation.248 Again the Japanese sponge C. truncata is the source of the polyacetylene sulfates callyspongins A and B (422 and 423, Figure 21), isolated as inhibitors against fertilization of starfish gametes.249 Both compounds inhibited fertilization of starfish gametes with minimum inhibitory concentrations of 6.3 and 50 μM, respectively, but affected neither the maturation of oocytes nor cell division of embryos. These findings indicate that the

sulfate group plays an important role in specific inhibition of starfish fertilization. Callyspongins A and B (422 and 423) were later reisolated from the same sponge collected in different waters (Table 19).8 Sponges belonging to Petrosia and Callyspongia genera are the main source of C24 polyacetylenes. Both compounds 424 and 425 were isolated from the Japanese Petrosia sponges,199,250 and aikupikanyne F (426) was isolated from a Callyspongia sponge collected on the Red Sea.210 The sponge C. truncate collected at Hako Island off the Kii Peninsula, Japan, was the source of callysponginol sulfate A (427), which inhibited membrane type 1 matrix metalloproteinase (MT1MMP) with an IC50 value of 15.0 μg/mL.251 Hitherto, just a few bromine-containing amides were isolated from marine organisms; examples are clathrynamides A−C (428−430), from the Japanese Clathria sponge.9 Clathrynamide A (428) inhibited mitotic cell division of starfish eggs at an extraordinarily low concentration (IC50 = 6 ng/mL); the remaining clathrynamides (429 and 430) were much less AB


Chemical Reviews

Review



a

compounds

391

peroxyacarnoate A

392 393 394 395 396

peroxyacarnoate B peroxyacarnoate C peroxyacarnoate D −a renierin-2

397 398 399 400 401

−a −a −a −a −a

402 403

18-hydroxyrenierin-2 siphonodiol

404 405 407−411 412−416

dihydrosiphonodiol tetrahydrosiphonodiol callytriols A−E carduusynes A−E

sources


ref

Acarnus cf. bergquistae A. bicladotylota A. cf. bergquistae A. bicladotylota A. bicladotylota Haliclona sp. R. fulva S. durissima Petrosia sp. C. vasculum C. vasculum C. vasculum C. vasculum C. vasculum R. fulva Siphonochalina truncata Callyspongia sp. S. truncata S. truncata C. truncata Phakellia carduus

Dahlak Island, Eritrea Muttom, Kerala, India Dahlak Island, Eritrea Muttom, Kerala, India Muttom, Kerala, India Palau Naples, Italy Lan-Yu, China Ishigaki Island, Okinawa Prefecture, Japan Caribbean near Egg Island, Bahamas Caribbean near Egg Island, Bahamas San Salvador Island, Bahamas Glover reef, Belize San Salvador Island, Bahamas Naples, Italy The Gulf of Suruga, Japan Tokushima prefecture, Japan The Gulf of Suruga, Japan The Gulf of Suruga, Japan Atami, Sagami Bay, Japan Great Australian Bight, Australia

240 241 240 241 241 243 239 198 199 216 216 229 245 229 239 244 226 244 244 8 247


AC


Chemical Reviews

Review



a

compounds

422−423

callyspongins A and B

424 425 426 427 428

−a strongylodiol G aikupikanyne F callysponginol sulfate A clathrynamides A

429−430 431 432 433 434−435 436, 437 438, 439 440 441 442 443 444 445−446 447 448−449 450 451 452 453 454

clathrynamides A−C debromoclathrynamide A (4E,6E)-debromoclathrynamide A (6E)-clathrynamide A −a strongylodiol A strongylodiol B strongylodiol H taurospongin A −a strongylodiol D strongylodiol I strongylodiol C −a −a polyacetylenetriol miyakosyne B −a petrosiacetylene B dideoxypetrosynol C

sources

distribution

ref

C. truncata C. truncata Petrosia sp. Petrosia sp. Callyspongia sp. C. truncata Clathria sp. Psammoclemma sp. Clathria sp. Psammoclemma sp. Psammoclemma sp. Psammoclemma sp. Petrosia sp. Strongylophora sp. Strongylophora sp. Petrosia sp. Hippospongia sp. Petrosia sp. Petrosia sp. Petrosia sp. Strongylophora sp. Petrosia sp. Haliclona sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp.

Sada-misaki, Ehime Prefecture, Japan Atami, Sagami Bay, Japan Ishigaki Island, Okinawa Prefecture, Japan Ishigaki Island, Okinawa Prefecture, Japan Sharm El Sheikh, Egypt Hako Island off the Kii Peninsula, Japan Sada-misaki, Ehime Prefecture, Japan Aka-jima Island, Okinawa, Japan Sada-misaki, Ehime Prefecture, Japan Aka-jima Island, Okinawa, Japan Aka-jima Island, Okinawa, Japan Aka-jima Island, Okinawa, Japan Ishigaki Island, Okinawa Prefecture, Japan −b −b Ishigaki Island, Okinawa Prefecture, Japan Okinawa Island Ishigaki Island, Okinawa Prefecture, Japan Ishigaki Island, Okinawa Prefecture, Japan Ishigaki Island, Okinawa Prefecture, Japan −b Ishigaki Island, Okinawa Prefecture, Japan Palau Mediterranean Sea Miyako Sea-knoll, Japan Sukumo Bay, Japan Keomun Island, South Sea, Korea Komun Island, Korea

249 8 199 250 210 251 9 252 9 252 252 252 199 7 7 250 256 199 250 250 7 199 243 257 258 166 169 170


active, the IC50 values of 429 and 430 being 0.2 and 1 μg/mL, respectively. It is noteworthy that the difference of the structure of the amide moiety strongly affected the bioactivity. Clathrynamide A (428) was reisolated from the Okinawan Psammoclemma sponge, along with three related metabolites, debromoclathrynamide A (431), (4E,6E)-debromoclathrynamide A (432), and (6E)-clathrynamide A (433).252 Within this

study, the absolute stereochemistry of 428 was determined to be 3R,12R by the modified Mosher’s method, and the antifungal activity of the metabolites was evaluated against the phytopathogenic fungus, Phytopathora capsici.252 The structure−activity relationship studies indicate that (i) the bromine atom at C11 slightly decreased the activity and (ii) the AD


Chemical Reviews

Review


was reported by Yadav et al.253 Carreira completed the syntheses of both strongylodiols (436 and 438) via the asymmetric alkynylation of aldehydes.254 Carreira’s synthesis is succinct; however, the ee of their asymmetric addition products was only approximately 80%. Thus, Lee et al. modified the synthesis using a minimum protection strategy.255 The analogue strongylodiol H (440) was obtained from a Petrosia sponge collected from a coral reef off Ishigaki Island, Okinawa Prefecture, Japan;250 the presence of similar hydroxylated longchain acetylenes both in Strongylophora and in Petrosia species confirms the close relationships between the two genera. The

conversion from 6Z to 6E geometry markedly reduced the activity. Two C25 hydroxylated polyacetylenes, 434 and 435 (Figure 22), were obtained from an Okinawan Petrosia sponge,199 whereas strongylodiols A and B (436 and 439) were found in the sponge Strongylophora sp., closely related to the genus Petrosia.7 The absolute chemistry of C-6 was determined by Mosher’s method. Strongylodiols, which were shown to be enantiomer mixtures with a different ratio (91:9 for 436 and 97:3 for 439), showed cytotoxic activity against tumor cells (MOLT-4). The first total synthesis of strongylodiol A (436) AE


Chemical Reviews

Review


are compounds 442−444, from the Japanese Petrosia sponge,199,250 and the cytotoxic strongylodiol C, isolated as an enantiomer mixture (445 and 446) in a ratio of 84:16 from the Okinawan sponge of Strongylophora genus.7 From a Japanese Petrosia sponge, a C27 polyacetylene (447) was also obtained.199 Compounds 448 and 449 were isolated from the sponge Haliclona sp. collected at Palau; compound 449 possessed two identical terminal enyne systems and a single methyl substituent at an unknown location along with the methylene chain joining the two terminal enyne units.243

structure of taurospongin A (441), which was isolated from an Okinawan Hippospongia sp., consists of a taurine and two fatty acid residues; its absolute configuration was established to be 3R, 7S, and 9R by analysis of the MTPA esters NMR spectra on a degradation product.256 Taurospongin A (441) exhibited potent inhibitory activity against DNA polymerase β and HIV reverse transcriptase with IC50 values of 7.0 and 6.5 μM, respectively. Sponges belonging to both Petrosia and Strongylophora genera also contain C26 hydroxylated polyacetylenes. Examples AF


Chemical Reviews

Review

compounds. Corticatic acids A−C (469−471) exihibed antifungal activity against Mortieralla ramanniana, and corticatic acids A, D, and E (469, 472, and 473) were identified as geranylgeranyltransferase type I (GGTase I) inhibitors. Corticatic acids A, D, and E (469, 472, and 473) inhibited Candida albicans GGTase I with IC50 values of 1.9, 3.3, and 7.3 μM, respectively (Table 20).

Polyacetylenetriol (450), a general potent inhibitor of DNA polymerases, was also isolated from Petrosia sponge in the Mediterranean Sea; it inhibits equally well the RNA- and DNAdependent DNA polymerase activities of retroviral reverse transcriptases.257 A Petrosia sponge collected at Miyako Seaknoll, Japan, was also the source of the cytotoxic compound 451.258 Again Petrosia sponges were the source of compound 452, petrosiacetylene B (453), and dideoxypetrosynol C (454). Compound 452, the absolute configuration at C-3 of which was determined by the modified Mosher’s method, was toxic in the brine shrimp lethality bioassay with an IC50 value of 30 μg/ mL;166 compound 453 displayed a wide range of bioactivities, such as brine-shrimp lethality, RNA-cleaving activity, and/or moderate inhibitory activity against PLA2 and Na + /K + ATPase.170 Dideoxypetrosynol C (454) was found as a racemic mixture of (3S,28S) and (3R,28R) or a single enantiomer of (3S,28R) or (3R,28S).169 Dideoxypetrosynols E and F (455 and 456), from the Korean sponge Petrosia sp., exhibited cytotoxicity against human solid-tumor cells (Figure 23).187 The absolute stereochemistry of 455 at C-3 and C-28 could not be determined due to degradation during the esterification reaction. The Petrosia sponge collected from Miyako Sea-knoll yielded the C30 polyacetylene, miyakosyne B (457).258 Unusually, the chemical investigation of an Okinawan Adocia sponge resulted in the isolation of a C30 polyacetylene, adociacetylene A (458).168 Adociacetylene A (458) showed weak antibiotic activity and moderate cytotoxicity against KB cells (IC50 0.8 μg/mL) and inhibited neutrophil leukocyte adhesion to tumor necrosis factor-α (5-JRU/mL)-stimulated endothenial cells at the concentration of 1 μg/mL.168 Chemical investigation of P. solida collected off the coast of Amami-Oshima, Kagoshima Prefecture, Japan, yielded petroacetylene (459), which inhibited blastulation of starfish embryos at a concentration of 3.1 μg/mL or greater.259 The sponges belonging to the genus Petrosia are the main source for the C31 and C32 polyacetylenes, which usually exhibited siginificant activities. It was worthy to note that the C31 and C32 polyacetylenes isolated by Matsunaga’s group from the sponges collected from the Japanese waters showed obvious inhibitory activity against HeLa cells with micromolar IC50 values.177,258 In addition, Matsunaga’s discovery of the polyacetylenic acid with α-glucosidase inhibition revealed that carboxylic acid and the allylic alcohol linked to an acetylene are important for the inhibitory activity agaist α-glucosidase.260 From an Okinawan sponge of Petrosia genus, the C31 polyacetylenes strongylodiols E, F, and J (460−462) were obtained as diastereomeric mixtures in ratios of 61:39, 80:20, and 96:4, respectively.250 Their configuration at C-6 was determined as R by the modified Mosher’s method. Later, a similar derivative 463 was isolated from the same sponge.199 Miyakosynes C, E, and F (464−466) were found in the Japanese sponge Petrosia sp. as inhibitors against Hela cells.258 Triangulyne C (467) was isolated from Pellina triangulata collected at Kuop Atoll, Truk Island, Micronesia, through cytotoxicity-guided fractionation, demonstrating in vitro cytotoxicity against NCI human tumor cell line panel.261 Petroformynic acid (468) was isolated from two varieties (red and white) of the sponge P. ficiformis collected off Naples, Italy, and off Tarifa, Spain, respectively.262 The corticatic acids A−E (469−473) were isolated from the Japanese sponge P. corticata;186,263 several bioactivities were recognized for these


compounds

455 456 457 458

dideoxypetrosynol E dideoxypetrosynol F miyakosyne B adociacetylene A

Petrosia sp. Petrosia sp. Petrosia sp. Adocia sp.

sources

459

petroacetylene

P. solida

460

strongylodiol E

Petrosia sp.

461

strongylodiol F

Petrosia sp.

462

strongylodiol J

Petrosia sp.

463

−a

Petrosia sp.

464 465 466 467

miyakosyne C miyakosyne E miyakosyne F triangulyne C

468

petroformynic acid

Petrosia sp. Petrosia sp. Petrosia sp. Pellina triangulate P. ficiformis

469

corticatic acid A

P. corticata P. corticata

a

470

corticatic acid B

P. corticata

471

corticatic acid C

P. corticata

472

corticatic acid D

P. corticata

473

corticatic acid E

P. corticata

474 475 476

petrosynoic acid A duryne B duryne C

Petrosia sp. Petrosia sp. Petrosia sp.

distribution

ref

Komun Island, Korea Komun Island, Korea Miyako Sea-knoll, Japan Aragusuku Island, Okinawa Prefecture, Japan Amami-Oshima, Kagoshima Prefecture, Japan Ishigaki Island, Okinawa Prefecture, Japan Ishigaki Island, Okinawa Prefecture, Japan Ishigaki Island, Okinawa Prefecture, Japan Ishigaki Island, Okinawa Prefecture, Japan Miyako Sea-knoll, Japan Miyako Sea-knoll, Japan Miyako Sea-knoll, Japan Kuop Atoll, Micronesia

187 187 258 168

Bay of Naples, Italy and Tarifa, Spain Shikine-jima Island, Japan Hachijo-jima Island, Japan Hachijo-jima Island, Japan Hachijo-jima Island, Japan Shikine-jima Island, Japan Shikine-jima Island, Japan Tutuila, American Samoa Miyako Sea-knoll, Japan Miyako Sea-knoll, Japan

259

250 250 250 199 258 258 258 261 262 263 186 186 186 263 263 264 177 177


From a Petrosia sponge collected in American Samoa, petrosynoic acid A (474) was isolated, and its absolute configuration was provisionally assigned on the basis of a correlation pattern of specific rotation values.264 Petrosynoic acid A (474) was found to be broadly cytotoxic with limited selectivity for cancer cells. From an undescribed Japanese Petrosia sponge, (−)-durynes B and C (475 and 476) were obtained, exhibiting the cytotoxic activity against HeLa cells with IC50 values of 0.26 and 0.26 μM, respectively.177 Miyakosyne D (477, Figure 24) was also isolated from the Japanese Petrosia sponge as an inhibitor against HeLa cell with IC50 of 0.15 μg/mL.258 Triangulynes A and E (478 and 479), found in the sponge P. triangulate growing in Kuop Atoll, Micronesia, demonstrated in vitro cytotoxicity profiles.261 From the same sponge P. triangulate obtained from Chuuk Atoll, pellynol B (480) was isolated.265 This compound was also AG


Chemical Reviews

Review


The first class of C-branched polyacetylene acids, aztèquynols A and B (484 and 485), were isolated from the French Petrosia sponge;269 their structure elucidation was based on high-energy collisionally activated decomposition tandem mass spectrometry of lithium adducts. Callyspongynic acid (486) was obtained from the marine sponge C. truncata collected off the Kii Peninsula, Tokyo, Japan, as a α-glucosidase inhibitor with an IC50 value of 0.25 μg/mL; it was indeed inactive against β-glucosidase, β-galactosidase, thrombin, and trypsin at 100 μg/ mL.260

found in a Pellina sponge collected in Tonga, along with pellynol I (481).266 Pellynol I (481), recently isolated also from a sponge of Petrosia genus collected from America Samoa,264 exhibited cytotoxicity against the LOX (melanoma) and OVCAR-3 (ovarian) human tumor cell lines with IC50 values of 0.41 and 2.0 μg/mL.266 Pellynol E (482) was obtained from an undescribed Micronesian sponge of Theonella, along with pellynol B (480).267 The triol polyeneyne analogue melyne B (483) was isolated from a Vanuatuan sponge belonging to the genus Xestospongia.268 AH


Chemical Reviews

Review

Phytochemical investigation of a Southern Australian sponge of Callyspongia genus and Okinawan Petrosia sponge resulted in the isolation of callyspongyne A (487) and compound 488.199,270 Similar bioactive compounds were also isolated from other marine sponges, such as melyne A (489) from the Vanuatuan Xestospongia sponge,268 the cytotoxic triangulyne B (490) from the Micronesian sponge P. triangulata,261 pellynols A and C (491 and 492), and pellynone (493) isolated from P. triangulata collected from Kuop Atoll, Micronesia,265 and pellynols F−H (494−496) from an undescribed species of Theonella sponge also obtained in Chuuk Atoll, Micronesia, together with melyne A (489) and pellynol C (492) (Table 21).267

C33 polyacetylenic acids found in the marine sponges usually show potent bioactivity. Triangulynic acid (497) from P. triangulata exhibits cytotoxicity, and pellynic acid (498) from P. triangulata inhibits inosine monophosphate dehydrogenase (IMPDH) in vitro with an IC50 value of 1.03 μM.261,265 (−)-Petrosynoic acids B−D (499−501, Figure 25), from a Petrosia sponge collected in American Samoa, were found to be cytotoxic with limited selectivity for cancer cells, being moderately active against A2058 (melanoma), H522-T1 (lung), and H460 (lung) human cancer cell lines as well as IMR-90 quiescent human fibroblast cells.264 From the same sponge, pellynols A, C, and F (491, 492, and 494) were also obtained.264 Melyne C (502) was isolated from the Vanuatuan sponge of Xestospongia genus,268 and later found in the Taiwanese sponge S. durissima, along with durissimol B (503).198 Durissimol B (503) showed potent cytotoxicity against human gastric tumor (NUGC) cells. The absolute configurations of compounds 502 and 503 were not determined. The cytotoxic compounds triangulynes F and G (504 and 505) and (−)-duryne D (506) were found in P. triangulata and a Petrosia sponge from Kuop Atoll, Micronesia, and Miyako Sea-knoll, Japan,177,261 respectively. The C35 polyacetylene 507 was isolated, both from the Micronesian sponge P. triangulata and from an undescribed species of Theonella sponge also obtained from Micronesia.265,267 Chemical investigation of a southern Australian Callyspongia sponge led to the isolation of callyspongyne B (508).270 An uncommon neuritogenic activity was reported for lembehyne A (509); this compound induced neuritogenesis in pheochromocytoma PC12 cells and neuroblastoma Neuro 2A cells at 2 and 0.1 μg/mL.271 Lembehyne A (509) was synthesized by using alkyne formation with dimethyl-1-diazo-2oxopropylphosphonate and asymmetric reduction with Alpineborane as the key steps.272 The analogues embehynes B and C (510 and 513) also exhibited neuritogenic activity against a neuroblastoma cell line, Neuro 2A.273 Structure−activity relationship studies indicated that the stereochemistry of the hydroxyl group at C-3 in lembehynes is important for the neuritogenic activity. The C37 and C38 polyacetylenes were almost all isolated in recent years, which may be due to the advanced technology of sample collection. From a tropical Reniochalina sponge collected in Chuuk Atoll, Micronesia, two new acetylenic alcohols 511 and 514 were obtained (Table 22).274 Among them, compound 511 showed significant growth inhibition against ACHN, NCI-H23, and HCT 15 with GI50 values of 0.156, 0.117, and 0.345 μg/mL, respectively. Triangulyne H (512) from the marine sponge P. triangulata collected at Kuop Atoll, Micronesia, demonstrates in vitro cytotoxicity profile.261 A high number of polyacetylenes with more than 40 carbons, among which the C46 polyacetylenes are very interesting, were isolated. There are seven polyacetylenes bearing more than 40 carbons and less than 46 carbons. The shortest one is triangulyne D (515, Figure 26) obtained from the Micronesian sponge P. triangulate.261 From the Italian sponge P. ficiformis, the acetylene 516 was obtained as its methyl ester.275 Reinvestigation of the latter sponge resulted in the isolation of petroformynes A and B (517 and 519),276 whose absolute configuration at C-3 was later established by Mosher’s method.234


compounds

sources

477

miyakosyne D

Petrosia sp.

478 479 480

triangulyne A triangulyne E pellynol B

P. triangulata P. triangulata P. triangulata Pellina sp. Theonella sp.

481

pellynol I

Pellina sp. Petrosia sp.

482

pellynol E

Theonella sp.

483 484

melyne B aztèquynol A

Xestospongia sp. Petrosia sp.

485

aztèquynol B

Petrosia sp.

486

callyspongynic acid

C. truncata

487

callyspongynes A

Callyspongia sp.

488

−a

Petrosia sp.

489

melyne A

Xestospongia sp. Theonella sp.

490 491

triangulynes B pellynol A

P. triangulata P. triangulata Petrosia sp.

492

pellynol C

P. triangulata Theonella sp. Petrosia sp.

493 494

pellynone pellynol F

P. triangulata Theonella sp. Petrosia sp.

a

495

pellynol G

Theonella sp.

496

pellynol H

Theonella sp.

497 498

triangulynic acid pellynic acid

P. triangulata P. triangulata

distribution

ref

Miyako Sea-knoll, Japan Kuop Atoll, Micronesia Kuop Atoll, Micronesia Kuop Atoll, Micronesia Tonga Chuuk Atoll, Micronesia Tonga Tutuila, American Samoa Chuuk Atoll, Micronesia Mele Bay, Vanuatu the Banc Aztèque off New Caledonia, France the Banc Aztèque off New Caledonia, France Kii Peninsula, Tokoyo, Japan Barwon Heads, Australia Ishigaki Island, Okinawa Prefecture, Japan Mele Bay, Vanuatu Chuuk Atoll, Micronesia Kuop Atoll, Micronesia Kuop Atoll, Micronesia Tutuila, American Samoa Kuop Atoll, Micronesia Chuuk Atoll, Micronesia Tutuila, American Samoa Kuop Atoll, Micronesia Chuuk Atoll, Micronesia Tutuila, American Samoa Chuuk Atoll, Micronesia Chuuk Atoll, Micronesia Kuop Atoll, Micronesia Kuop Atoll, Micronesia

258 260 260 265 266 267 266 264 267 268 269

269

260 270 199

268 267 261 265 264 265 267 264 265 267 264 267 267 261 265

The name of the compound was not given. AI


Chemical Reviews

Review


fraction of the extract.183 The finding of the unusual compound stimulated further research on the polyacetylenic metabolites present in the red variety of P. ficifomis collected in the bay of Naples, Italy, which resulted in the isolation of compound 524.275 To obtain both further structural details and a preliminary understanding of their biological properties, a reinvestigation of the sponge P. ficifomis was conducted, resulting in the isolation of petroformynes 1−4 (525− 528).281 The four high molecular weight polyacetylenes 525−528 were tested in the Artemia salina bioassay and were found to be the most potent substances ever reported for this assay. Moreover, these compounds inhibited the development of sea urchin fertilized eggs at concentrations ranging from 1 to 50 μg/mL. To gain a preliminary understanding of the structural prerequisites necessary for this type of activity, six polyacetylenes were obtained from this sponge from Naples, Italy, petroformynes 5−9 (529−536).276 Two alternative structures 529 and 530 were proposed for petroformyne-5, two structures (533−534) for petroformyne-8, and 535−536 for petroformyne-9 (Table 23). All compounds tested with

Vasculyne (518) was obtained from the Caribbean sponge C. vasculum, exhibiting cytotoxicity with mean average GI50, TGI, and LC50 values of 0.2, 0.7, and 6.7 μg/mL, respectively.277 Nor-3S,14S-petrocortyne A (520) was found in a Korean Petrosia sponge,278,279 and its absolute stereochemistry at C-3 and C-14 was determined by the modified Mosher’s method. The % inhibitions of 520 on the DNA replication at various concentrations were 12 (125 μM), 47 (250 μM), and 70 (500 μM).278 A Petrosia sponge collected at Hachijo Island, Japan, was the source of two C45 polyacetylenes, neopetroformynes B and D (521 and 522).280 One of the most intriguing classes of sponge metabolites is the C46-linear polyacetylenes, representing a unique class of natural products. Usually, they have an unbranched chain and vary due to the oxidization positions. All of these C46-linear polyacetylenes are mainly isolated from the sponges belonging to Petrosia genus collected in the Bay of Naples, Italy, and Keomun Island, Korea, and scarcely present in the sponges from South China Sea and Japanese waters. The first polyacetylene with 46 carbons (523) was isolated from the sponge P. ficifomis after hydrogenation of the first AJ


Chemical Reviews

Review

(562) displayed an unusual γ-pyrone ring formed by an oxidative cyclization of a diacetylenic carbinol functionality. The absolute configuration of hydroxyl groups in 560−561 was determined by Mosher’s method; however, the stereochemistry of petroeortyne C (562) at C-3 was not established because treatment of 562 with (S)- and (R)-MTPA chloride under various conditions resulted in rapid decomposition of the reactant. These compounds exhibited significant brine-shrimp lethality, RNA-cleaving activity, and/or moderate inhibitory activity against PLA2 and Na+/K+ ATPase. Investigation of an undescribed Petrosia sponge collected from Keomun Island, Korea, resulted in the isolation of petroeortynes D−H (563− 567).283 The absolute configurations of most of the asymmetric carbon centers were determined by the modified Mosher’s method because limitations on the application of Mosher’s method to allylic alcohols did not allow establishing all of the stereochemistries. Petrocortynes D−H (563−567) exhibited moderate cytotoxicity and inhibitory activity against PLA2. Guided by the P-388 cytotoxicity assay, three C46 analogues, (3S,14S)-petrocortyne A (568), petrotetrayndiol A (569), and petrotetrayndiol B (570), were obtained.187 In the antiinflammatory bioasssy, (3S,14S)-petrocortyne A (568) was found to be a novel anti-inflammatory agent, which may inhibit cellular inflammatory process and immune cell migration to inflamed tissue.284 The NMR spectra of petroeortyne A (560) and (3S,14S)-petrocortyne A (568) were identical, but Mosher’s analysis of these samples suggested they were enantiomers; the finding that enantiomers of the same natural products were isolated from the similar Petrosia collected from the same locations in different years is questionable. In 2010, the four stereoisomers of petroeortyne A were synthesized, and comparison of data between synthetic and natural samples indicated that the two natural samples were the same stereoisomer, assigned as 3S,14S.285 The possible mechanisms of antiproliferative activity in cultured SK-MEL-2 human melanoma cells by petrotetrayndiol A (569) were investigated, which was ascribed to inducing cell cycle arrest and apoptosis in SK-MEL-2 human melanoma cells through cytochrome cmediated activation of caspases.286 The cytotoxic polyacetylenes, petrotetrayndiol C (571) and (3S,14R)-petrocortynes F−H (572−574), were isolated from a Petrosia sponge collected from Komun Island, Korea,278,287 and their absolute stereochemistry at C-3 and C-14 was determined by the modified Mosher’s method (Table 25). Additional cytotoxic C46 polyacetylenes (575−582, Figure 29) together with petroeortyne C (562) were isolated from a Korean Petrosia sponge and displayed considerable cytotoxicity against a small panel of human solid tumor cell lines. These compounds were further evaluated for in vitro inhibitory activity on DNA replication.279 Recently, from a Japanese Petrosia sponge, two cytotoxic polyacetylenes related to petroformynes were obtained, neopetroformynes A and C (583 and 584), exhibiting cytotoxic activity against P388 murine leukemia cells.280 Their structures were determined on the basis of spectroscopic data and the modified Mosher’s analysis. The homo-(3S,14S)-petrocortyne A (585) and petrotetrayndiol F (586),279,287 with an unprecedented C47 skeleton, were isolated from the Korean sponges belonging to Petrosia genus. Petrotetrayndiol F (586) is unique for having unconjugated acetylenic groups at both termini. The C47-polyacetylene carboxylic acids petroformynic acids B and C (587 and 588), also obtained from a Petrosia


compounds

sources


ref

499

petrosynoic acid B

Petrosia sp.

264

500

petrosynoic acid C

Petrosia sp.

501

petrosynoic acid D

Petrosia sp.

502

melyne C

503 504

durissimol B triangulyne F

Xestospongia sp. S. durissima S. durissima P. triangulata

505

triangulyne G

P. triangulata

506

(−)-duryne D

Petrosia sp.

507

pellynol D

P. triangulata

Tutuila, American Samoa Tutuila, American Samoa Tutuila, American Samoa Mele Bay, Vanuatu Lan-Yu, China Lan-Yu, China Kuop Atoll, Micronesia Kuop Atoll, Micronesia Miyako Sea-knoll, Japan Kuop Atoll, Micronesia Nama Island, Chuuk Atoll, Micronesia Barwon Heads, Australia Lembeh Island, Bitung, Indonesia Indonesia Chuuk Atoll, Micronesia Kuop Atoll, Micronesia Indonesia Chuuk Atoll, Micronesia

Theonella sp.

a

508

callyspongyne B

Callyspongia sp.

509

lembehyne A

Haliclona sp.

510 511

lembehynes B −a

Haliclona sp. Reniochalina sp.

512

triangulyne H

P. triangulata

513 514

lembehynes C −a

Haliclona sp. Reniochalina sp.

264 264 268 198 198 261 261 204 265 267 270 271 273 274 261 273 274


brine shrimp (A. salina) assays were found to be extremely toxic at concentrations ranging from 0.002 to 0.12 ppm. The structure of petroformyne-8 was later revised to bear Δ8,9 double bond as shown in the structure of 537 (Figure 27).234 However, the configuration at the chiral centers (C-20 and C-44) remained undetermined. Thus, the Italian sponge P. ficifomis was reinvestigated, resulting in the isolation of the polyacetylenes, petroformynes 1−5 (538−542). Moreover, their structures (538−542) were unambiguously assigned with the stereochemistry of hydroxyl groups established by application of the Mosher’s method.234 In 1995, Cimino et al. restudied the two varieties of the Mediterranean P. ficiformis (red variety from sunlit waters, white variety from dark caves); this study resulted in the isolation of 12 minor petroformynes (543−555).282 Two structures (552 and 553) were suggested for petroformyne-10. Because of the scarcity of the material, the stereochemistry of these compounds could not be established by chemical method. Most of these polyacetylenes were tested for their toxic potential by means of the A. salina bioassay and showed LD50 values ranging from 0.04 to 6.8 ppm. Four polyacetylenes 556− 559 were obtained from the sponge P. ficiformis collected in the Mediterranean Sea and the Atlantic Ocean (Table 24).262 The stereochemistry of 556 was determined by the advanced Mosher’s method. As described above, most of the C46 polyacetylenes were isolated from the sponge P. ficiformis collected in the Mediterranean Sea, and this work was pioneered by Cimino’s group. Subsequently, the investigation of P. ficiformis collected from Komun Island, Korea led to the isolation of petroeortynes A−C (560−562, Figure 28).170 Interestingly, petroeortyne C AK


Chemical Reviews

Review

Figure 26. Structures of compounds 515−536. AL


Chemical Reviews

Review


a

compounds

515 516 517

triangulyne D −a petroformyne A

518 519

vasculyne petroformyne B

520

nor-3S,14S-petrocortyne A

521 522 523 524 525/538c 526/539c 527/540c 528/541c 529−530/542c 531 532 533−534/537c 535−536

neopetroformyne B neopetroformyne D −a −a petroformyne-1 petroformyne-2 petroformyne-3 petroformyne-4 petroformyne-5 petroformyne-6 petroformyne-7 petroformyne-8 petroformyne-9

sources

distribution

P. triangulata P. ficiformis P. ficiformis undescribed Cribrochalina vasculum P. ficiformis undescribed Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. P. ficifomis P. ficifomis P. ficifomis P. ficifomis P. ficifomis P. ficifomis P. ficifomis P. ficifomis P. ficifomis P. ficifomis P. ficifomis

Kuop Atoll, Micronesia Naples, Italy Naples, Italy Naples, Italy Egg Island, Bahamas Naples, Italy Naples, Italy Komun Island, Korea Komun Island, Korea Hachijo Island, Japan Hachijo Island, Japan −b Naples, Italy −b −b −b −b Naples, Italy Naples, Italy Naples, Italy Naples, Italy Naples, Italy

ref 261 275 276 234 277 276 234 278 279 280 280 183 275 234, 234, 234, 234, 234, 276 276 276 276

281 281 281 281 276

The name of the compound was not given. bThe place of the sample collection was not mentioned. cDifferent structures for the same compound.

resulting in the dramatical increase of the numbers of polyacetylenes. Generally, almost two-thirds of acetylenes are identified and characterized from sponges.

sponge collected at Katsuo-jima Island, Japan, inhibited the growth of P388 cells each with an IC50 value of 0.4 μg/mL.288 C47 compounds possessing a diacetylenic carbinol and an αacetylenic carboxylic acid are not frequently encountered. The molecules usually differed in the functional groups as well as their locations in the carbon framework. Nepheliosyne A (589), isolated from an Okinawan sponge of Xestospongia genus, was the first polyacetylene belonging to this class; it was shown to be weakly cytotoxic.289 From the sponge Haliclona osiris obtained at Sponge Mound, Guam, six highly oxygenated polyacetylenes, osirisynes A−F (590−595, Figure 30), were found. These compounds exhibited moderate cytotoxicity against a human leukemia cell-line (KS62) with LC50 values of 25, 48, 52, 25, 20, and 22 μM, respectively.6 In addition, 592, 594, and 595 exhibited inhibitory activities against Na+/K+ATPase and reverse transcriptase (RT) at the concentration of l00 μg/mL. Similarly, chemical investigation of the Mediterranean sponge H. fulva led to the isolation of eight antimicrobial polyoxygenated acetylenes (596−603), which were found to be active against a chloramphenicol-resistant strain of Bacillus subtilis.4 From another Israeli Haliclona sponge, haliclonyne (604) was isolated, featuring a C47 oxooctahydroxy-dienetetrayne carboxylic acid structure.290 Hitherto, the naturally occurring acetylenes with more than 47 carbons are scarce. The first report is the isolation of compounds 605−608 from the sponges P. ficiformis and Peltodoris atromaculata.183 Further examples were dihomo(3S,14S)-petrocortyne A (609) from a Korean Petrosia sponge and fulvyne H (610) from the Mediterranean sponge H. fulva (Table 26).4,287 In summary, as showed in Chart 2, most polyacetylenes from the sponges are isoalted and reported by the Japanese scientists, whereas the research on the secondary metabolites of sponges from Korea, Bahamas, and Australia also accounted for a considerable proportion. Actually, phytochemical studies have been conducted on various collections of sponges worldwide,

4. CORALS A relative few acetylenic compounds have been isolated from corals, mainly from Montipora species, and most polyacetylenes possess less than 15 carbons, usually bearing two triple bonds. A large proportion of the compounds isolated from corals showed important bioactivities such as ichthyotoxicity and antimicrobial activity, implying that the compounds play defensive role in the corals. Often, the same compound or similar derivatives were isolated from different coral genera, suggesting they could be metabolites of common symbiotic organisms, such as zooxanthellae algae that commonly lived in coral tissues. 4.1. Short-Chain (Less than C15) Polyacetylenes from Corals

Chemical investigation of a hermaphroditic coral Montipora digitata collected from Magnetic Island and Orpheus Island, respectively, resulted in the isolation of dodeca-2,4-diynol (611, Figure 29) as an active compound for sperm chemotaxis and montiporic acid A (612).291,292 Dodeca-2,4-diynol (611) was also synthesized from simple precursors by known reactions (Figure 31).291 Montiporic acid A (612) showed antibacterial activity against Escherichia coli and also cytotoxicity against P-388 murine leukemia cells with IC50 values of 5.0 and 12.0 μg/mL, respectively. In 2001, Jung et al. isolated compounds 611 and 612 again from the same coral but collected from a different geographical area; this study yielded seven further diacetylene derivatives, montiporynes G and H (613 and 614), the sodium salts of montiporic acids A and C (615, 616), methyl montiporates A and C (617 and 618), and compound 619.185,293,294 Bioactivity evaluation against a small panel of AM


Chemical Reviews

Review


human cancer cell lines, A549, SK-OV-3, SK-MEL-2, and XF498, showed that most of these compounds were cytotoxic.293,294 Compound 619 exhibited ichthyotoxicity against guppies at concentration level of 1−5 ppm, but was inactive against Bacillus subtilis, S. aureus, Aspergillus sp., and Cladosporium sp. at 10−100 μg/disc.185 A further ichthyotoxic acetylenic metabolite, 2,4-tridecadiynyl methoxyacetate (620), was found in the corals Montipora sp. and M. mollis.185

The C14 polyacetylene alcohol 621 was isolated from the coral of Montipora genus, and also found in M. mollis and Pectinia lactuca, together with compounds 619 and 204.185 It was later found in the Australian and Korean Montipora corals.291,293 Ichthyotoxicity assays showed that it had the same activity as that of 619 and 204, but it was also active at 10 μg/ disc against Bacillus subtilis, S. aureus, Aspergillus sp., and Cladosporium sp.185 Montiporic acid B (622) was isolated from AN


Chemical Reviews

Review


a

no.

compounds

543 544 545 546 547 548 549 550 551 552−553 554 555 556−559

isopetroformyne-3 4,5-dihydroisopetroformyne-3 isopetroformyne-6 23,24-dihydropetroformyne-6 20-oxo-petroformyne-3 23,24-dihydro-20-oxo-petroformyne-3 isopetroformyne-4 isopetroformyne-7 23,24-dihydropetroformyne-7 petroformyne-10 3,44-dioxo-petroformyne-1 3,44-dioxo-petroformyne-2 −a

sources P. P. P. P. P. P. P. P. P. P. P. P. P.

ficifomis ficifomis ficifomis ficifomis ficifomis ficifomis ficifomis ficifomis ficifomis ficifomis ficifomis ficifomis f icifomis

Naples, Naples, Naples, Naples, Naples, Naples, Naples, Naples, Naples, Naples, Naples, Naples, Naples,

distribution

ref

Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy Italy; Tarifa, Spain

282 282 282 282 282 282 282 282 282 282 282 282 261



AO


Chemical Reviews

Review

4.3. Long-Chain (More than C15) Polyacetylenes from Corals

Table 25. Summary Information for Compounds 560−574 sources

distribution

ref

560

no.

petroeortyne A

compounds

P. ficifomis

169

561

petroeortyne B

P. ficifomis

562

petroeortynes C

P. ficifomis

Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea

Petrosia sp. 563

petroeortyne D

Petrosia sp.

564

petroeortyne E

Petrosia sp.

565

petroeortyne F

Petrosia sp.

566

petroeortyne G

Petrosia sp.

567

petroeortyne H

Petrosia sp.

568

(3S,14S)-petrocortyne A

Petrosia sp.

569

petrotetrayndiol A

Petrosia sp.

570

petrotetrayndiol B

Petrosia sp.

571

petrotetrayndiol C

Petrosia sp.

572

(3S,14R)-petrocortyne F

Petrosia sp.

573

(3S,15R)-petrocortyne G

Petrosia sp.

574

(3S,14R)-petrocortyne H

Petrosia sp.

The only examples of polyacetylenes with more than 15 carbons from corals are the four polyacetylenes, 634 and montiporyne K (635), obtained from the productive stony coral Montipora sp. obtained from Magnetic Island, Australia and Cheju Island, Korea, respectively,291,293 and butenolides 632 and 633, isolated from the Israeli soft corals Sarcophyton trocheliophorum and Lithophyton arboretum.296 It was worthy to note that montiporyne K (635) was present as racemate in nature. Both compounds 632 and 633 gave positive results in a brine shrimp toxicity assay (Table 28).

169 169 279 283 283 283

5. MOLLUSKS Most C15 acetogenins isolated from the mollusks, mainly from species belonging to the genus Aplysia, appear to be from dietary sources. Generally, the mollusks feed on red and brown algae from which they sequester selected bioactive secondary metabolites. Unlike the coral, which is probably used for defensive purposes, the mollusks usually make use of the compounds elaborated by algae and/or sponges, in two main fashions. The metabolites of the algae/sponges are directly accumulated by the mollusks; this is the case of compounds 16 and 17 obtained from the sea hare A. fasciata feeding on algae, usually on Laurencia species. In addition, mollusks engulf the algae/sponges entirely, and, to increase their defensive properties (antiparasitism and antifouling), the active compounds are modified by the mollusks from the corresponding metabolites in the algae/sponges. Ths is the case of the ketones 654 and 656 (see below), which are synthesized by the nudibranch D. sandiegensis from the corresponding alcohols 250 and 251 produced by the sponge H. lunisimilis.184

283 283 187 187 187 278 287 287 287

M. digitata obtained from Orpheus Island, Australia,292 and its methyl ester (623) and sodium salt (624) were isolated from the same species by Jung et al. in 2001.293 Compound 623 was reisolated from the same coral in Cheju Island, Korea, together with dihomomontiporyne H (625).294 Montiporic acid B (622) was not only antibacterial against Escherichia coli, but also cytotoxic against P-388 murine leukemia cells with an IC50 value of 12.0 μg/mL. In addition, a bioassay against a small panel of human cancer cell lines A549, SK-OV-3, SK-MEL-2, and XF498 demonstrated that 623 and its sodium salt 624 were cytotoxic, whereas dihomomontiporyne H (625) was only moderately active (Table 27). The ichthyotoxicity and antimicrobial activity exhibited by most of the above-mentioned molecules imply that these compounds may play a defensive role in the corals.

5.1. C15 Acetylenes from Mollusks

Compounds 16 or 17, and 636 (Figure 33), found in the Laurencia algae, were isolated from the Spanish sea hare Aplysia fasciata feeding on algae, usually on Laurencia species;297 they may be one of the accumulated metabolites by the sea hare from the Laurencia algae. From Aplysia mollusks, momocyclic polyacetylenes were also obtained, which usually bear a skeleton similar to that from the Laurencia algae, further supporting the above-mentioned hypothesis that the mollusks sequester selected bioactive secondary metabolites from the algae. Chemical investigation of the sea hare A. oculifera collected at Duwa, Sri Lanka and A. dactylomela obtained in the environs of Bimini, Bahamas led to the isolation of srilankenyne (637),298 dactylyne (46),299 and isodactylyne (638).300 They are characterized structurally by a tetrahydropyran and exhibited central nervous system depressant activity.301 Attracted by the unusual chemical structure and promising biological property, the total syntheses of dactylyne (46) and isodactylyne (638) were completed; it involved 25 steps, and the overall yields amounted to 9.7% for dactylyne (46) and 10.9% for isodactylyne (638), respectively (Table 29).301 The antifeedant metabolites, cis-dihydrorhodophytin (72) and cis-isodihydrorhodophytin (639), were isolated from the sea hare A. brasiliana, and the structure of compound (72) was established on the basis of the spectroscopic data and X-ray diffraction study.302 cis-Isodihydrorhodophytin (639) appeared to be the stereoisomer of 72, but it was uncertain whether it was different in configuration at C-12 or C-13. Phytochemical studies of A. dactylomela collected from South China Sea led to

4.2. C15 Polyacetylenes from Corals

Montiporyne A (626, Figure 32) and its geometric isomer montiporyne B (628) as well as montiporynes L and M (627 and 629) were isolated from the Korean soft coral Montipora species.293,295 All of these compounds showed moderate to marginal cytotoxicity against human ovarian cancer (SK-OV-3), human skin cancer (SK-MEL-2), human CNS cancer (XF498), and human colon cancer (HCT15) with a rather selective cytotoxicity against SK-MEL-2. The trans-isomer of the linear chain congener was most active, while the cis-isomer was nearly inactive; interestingly, the cytotoxicity of compound 626 was comparable to that of cisplatin. Montiporynes I and J (630 and 631), isolated from the same genus Montipora,293,294 and featuring a β-hydroxy ketone functionality, were found to be more active than montiporyne A (626) against the same cell lines. AP


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from red algae, aplysiallene (646) is the first bromoallene metabolite with a branched C16 skeleton. Because of its unusual structure, aplysiallene (646) was totally synthesized in 16 steps and features a key sequential Mukaiyama aerobic oxidative cyclization to prepare the fused bis-THF core.306 (E)-Ocellenyne (647) and (Z)-ocellenyne (648) possessing a rare 2,5-dioxabicyclo[2.2.1]heptane system were found in the American mollusk A. oculifera.307 The structures of 647 and 648 were elucidated by chemical degradation and spectral analysis. The zinc debromination reaction resulted in the formation of a cis olefin between C-12 and C-13; thus the stereochemistry of the 12,13-dibromo moiety was assigned as 12(S), 13(S) or 12(R), 13(R). From a Caribbean sample of A. dactylomela, (3E)- and (3Z)-dactomelynes (649 and 650), possessing two fused pyran rings, were isolated.304 The

the isolation of compound 76 along with the enantiomer 640 by Manzo et al.76 Doliculols A and B (641 and 642) were isolated from the Japanese sea hare Dolabella auricularia,303 both of which possess the common eight-numbered skeleton. In 1970s, brasilenyne (643) was isolated from a sea hare as a ninemembered acetogenin.302 Its structure was elucidated on the basis of an X-ray diffraction study. The mollusk A. dactylomela has the same metabolites as the Laurencia algae, such as (3E)12-epi-obtusenyne (97) and (3Z)-12-epi-obtusenyne (98),304 and also the peculiar compounds, compounds 644 and 645.76 Aplysiallene (646) was isolated as an Na, K-ATPase inhibitor from the Japanese sea hare, A. kurodai, together with the two metabolites 109 and 110.305 Although a number of C15 acetogenins with bromoallene functionality have been isolated AQ


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concise, highly stereoselective synthesis of panacene (652) has been accomplished starting from commercially available 2methoxy-6-methylbenzoic acid in 15 steps and 8.3% overall yield; this synthesis allowed the author to unambiguously establish the relative and absolute configuration of panacene (652).313 From another Japanese sea hare, A. parvula, the novel ichthyotoxic C15 acetogenin aplyparvunin (653) was isolated.314 Its structure was established by spectroscopic evidence and a single-crystal X-ray analysis. Aplyparvunin (653) showed ichthyotoxicity against mosquito fishes, and its lethal concentration within 24 h is 3 ppm.

structure of 649 was determined by analysis of its X-ray, while that of 650 was elucidated by comparison of its spectral data with that of its geometric isomer 649. Total syntheses of 3Zand 3E-dactomelynes (649 and 650) were accomplished; it featured a stereoselective introduction of alkyl and halogen substituents around the pyranopyran ring system.308 Laurefucin (145), previously obtained from a Laurencia alga, was recently isolated from a sea hare, and chlorofucin (153) and its geometric isomer (3Z)-bromofucin (651) were isolated from the South African sea hare A. parvula.309 An unprecedented aromatic bromoallene, panacene (652), was isolated from the mollusk A. brasiliana obtained in coastal waters near Panacea, Florida; this compound possesses an unusual tetrahydrofurobenzofuran core and is believed to serve as a feeding deterrent to sharks and other predatory fish.310 It is closely related to the large group of halogenated acetylenic natural products of marine origin, all of which are based on an unbranched C15 skeleton. Panacene (652) was totally synthesized, allowing its relative configuration to be determined.311 Panacene (652) was also synthesized by a biomimetic brominative cyclization.312 A

5.2. Long-Chain (More than C15) Polyacetylenes from Mollusks

The chlorinated acetylenes are usually believed to be involved in the chemical defensive mechanism of the marine organisms. Compounds 250−255 and 654−656 (Figure 34) isolated from the nudibranch mollusk Diaulula sandiegensis collected at Point Loma, San Diego, are related to the chemical defensive mechanism of the nudibranch.184 Also, these compounds are AR


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a

no.

compounds

sources

distribution

ref

575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596−603 604 605−608 609 610

petrotetrayndiol C petrotetrayntriol A (3S,14R)-petrocortyne E petrotetrayndiol D (3S,14S)-petrocortyne B petrotetrayndiol E petrotriyndiol A petrotetraynol A neopetroformyne A neopetroformyne C homo-(3S,14S)-petrocortyne A petrotetrayndiol F petroformynic acids B petroformynic acids C nepheliosyne A osirisyne A osirisyne B osirisyne C osirisyne D osirisyne E osirisyne F −a haliclonyne −a dihomo-(3S,4S)-petrocortyne A fulvyne H

Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Petrosia sp. Xestospongia sp. H. osiris H. osiris H. osiris H. osiris H. osiris H. osiris H. fulva Haliclona sp. P. atromaculata; P. ficifomis Petrosia sp. H. fulva

Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Komun Island, Korea Hachijo Island, Japan Hachijo Island, Japan Keomun Island, Korea Keomun Island, Korea Katsuo-jima Island, Japan Katsuo-jima Island, Japan Ishigaki Island, Okinawa Sponge Mound, Guam Sponge Mound, Guam Sponge Mound, Guam Sponge Mound, Guam Sponge Mound, Guam Sponge Mound, Guam Punta Pizzaco, Procida Island, Italy the Gulf of Eilat, Israel −b Keomun Island, Korea Punta Pizzaco, Procida Island, Italy

279 279 279 279 279 279 279 279 280 280 279 287 288 288 289 6 6 6 6 6 6 4 290 183 287 4


Chart 2. Geographic Distribution of Collection Sources for Sponges


6. MISCELLANEOUS The four hydroxylated polyacetylenes 657−660, featuring an uncommon dienyne group, are acetylenic lipids first and only reported from a marine ascidian collected off Vigo, Spain.315 The absolute stereochemistry at chiral centers remained undetermined due to their high instability in solution.

supposed to be obtained from the dietary source and concentrated by the nudibranch for use in a defensive secretion. In fact, compounds 250−255 were also found in the sponge H. lunisimilis collected approximately from the same location where the nudibrach was found.189 Interestingly, ketones 654 and 655, the major metabolites of D. sandiegensis, were not found in the sponge H. lunisimilis, suggesting that these compounds are synthesized by the nudibranch from the corresponding alcohols 250 and 251 found in the sponge. Two polyacetylenes with long chains (523 and 605−608) were found in the nudibranch Peltodoris atromaculata and its prey P. ficifomis.183 These findings provide the proof to further understand some basic biological problems linked to symbiosis, including chemical defense mechanisms.

7. CONCLUSIONS The ocean has proven to be a rich source for polyacetylenes. Numerous different types of polyacetylenes have been and continue to be isolated and identified from diverse marine organisms, especially from algae and sponges. The structural variety of these secondary metabolites, their wide distribution among marine life, and the broad selection of biological AS


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a

compounds

sources

611

dodeca-2,4-diynol

612

montiporic acid A

613 614 615 616 617 618 619

montiporyne G montiporyne H −a montiporic acid C methyl montiporate A methyl montiporate C 11-dodecene-2,4-diynyl methoxyacetate

620 621

2,4-tridecadiynyl methoxyacetate 13-tetradecene-2,4-diyn-1-ol

622 623 624 625

montiporic acid B −a −a dihomomontiporyne H


ref

Montipora digitata M. digitata M. digitata M. digitata Montipora sp.

Geoffrey Bay, Magnetic Island, Australia Cheju Island, Korea Orpheus Island, Australia Cheju Island, Korea Cheju Island, Korea

Montipora sp. Montipora sp. Montipora sp., M. mollis, Pectinia lactuca Montipora sp.; Montipora mollis Montipora sp., M. mollis, Pectinia lactuca M. digitata Montipora sp. M. digitata Montipora sp. Montipora sp. Montipora sp.

Cheju Island, Korea −b −b −b −b Geoffrey Bay, Magnetic Island, Australia Cheju Island, Korea Orpheus Island, Australia Cheju Island, Korea Cheju Island, Korea Cheju Island, Korea

291 293 292 293 293 293 293 293 293 294 185 185 185 185 291 293 292 293, 294 293 294



Table 28. Summary Information for Compounds 626−635 no. 626 627 628 629 630 631 632−633 634 635 a

compounds montiporyne montiporyne montiporyne montiporyne montiporyne montiporyne −a −a montiporyne

A L B M I J

K

sources

distribution

ref

Montipora sp. Montipora sp. Montipora sp. Montipora sp. Montipora sp. Montipora sp. Sarcophyton trocheliophorum, Lithophyton arboretum M. digitata Montipora sp.

Cheju Island, Korea Cheju Island, Korea Cheju Island, Korea Cheju Island, Korea Cheju Island, Korea Cheju Island, Korea the gulf of Aqaba, Eilat, Israel Geoffrey Bay, Magnetic Island Cheju Island, Korea

293, 295 293 295 293 293 293, 294 296 291 293


Laurencia algae. Thus, C15 acetylenes could play an important role as chemotaxonomic markers in morphologically similar red algae, although the use of nominal secondary metabolites to define a chemotaxonomy is now somewhat problematic as a significant number of compounds are now known to be produced by “commensal” microbes (see below). In contrast, polyacetylenes from sponges, mainly those belonging to

activities reported provide the opportunity to make some general remarks. 7.1. Differences and Distribution of Polyacetylene Structures among the Species of Algae and Invertebrates

The polyacetylenes isolated from the algae are mainly C15 nonterpenoid cyclic acetogenins, usually composed by rings of different sizes, and seem to be characteristic metabolites of the AT


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a

no.

compounds

sources


ref

636 637 638 639 640 641 642 643 644−645 646 647 648 649 650 651 652 653 654−655 656 657−660

(3Z,9Z)-7-chloro-6-hydroxy-12-oxo-pentadeca-3,9-dien-1-yne srilankenyne isodactylyne cis-isodihydrorhodophytin −a doliculol A doliculol B brasilenyne −a aplysiallene (E)-ocellenyne (Z)-ocellenyne (3E)-dactomelyne (3Z)-dactomelyne (3Z)-bromofucin panacene aplyparvunin −a −a −a

A. fasciata Aplysia oculifera A. dactylomela A. brasiliana A. dactylomela Dolabella auricularia D. auricularia A. brasiliana A. dactylomela A. kurodai A. oculifera A. oculifera A. dactylomela A. dactylomela A. parvula Aplysia brasiliana Aplysia parvula Diaulula sandiegensis D. sandiegensis undescribed

Alfacs Bay, Delta de l’Ebre, Spain Duwa, Sri Lanka Environs of Bimini, Bahamas −b Hainan Island, China Mie Prefecture, Japan Mie Prefecture, Japan −b Hainan Island, China Echizen Coast of Fukui, Japan Hawaii Hawaii Bimini, Bahamas Bimini, Bahamas Tsitsikamma National Park, South Africa Panacea, Florida Koinoura, Fukuoka Prefecture, Japan Point Loma, San Diego, CA Point Loma, San Diego, CA Vigo, Spain

293 298 300 302 76 303 303 302 76 305 307 307 304 304 154 310 314 184 184 315


Petrosia, Xestospongia, Callyspongia, and Spongia, often bear a long straight chain. Both the C15 acetogenin and the long straight polyacetylenes, however, share the presence of halogen atoms in the molecule, particularly bromine and chlorine, which may account for the high content of halogen in the seawater. In the light of the distribution of the collection sources of algae and sponges, it is concluded that the research on the algae and sponges is pioneered by the chemists in Japan, and followed by Italy, U.S., and Australia. The algae are the most studied organism from Greece and Turkey, whereas studies on the sponges are concentrated on samples from Korea,

Micronesia, Indonesia, and Red Sea. Although the discovery of new compounds from South China Sea grows significantly,316 the polyacetylenes from Chinese algae and sponges are out of proportion to the new compounds (Chart 3). 7.2. Bioactivity and Microelectronic Properties of Polyacetylenes

Polyacetylenes of marine origin usually showed a wide range of biological activities, including antifungal activity,3 antimicrobial activity,4 HIV reverse transcriptase inhibition,5 and cytotoxicity.6,7 As an example, (−)-durynes B and C (475 and 476) isolated by Matsunaga’s group exhibit the cytotoxic activity AU


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an interesting and rapidly developing field in the area of novel electronic and optoelectronic materials and devices.

Chart 3. Geographic Distribution of Collection Sources for Sponges and Algae

7.3. The Biosynthesis of Polyacetylenes: A Potential Microbial Link

The great chemical diversity generating in the family of polyacetylenes isolated from marine invertebrates and their wide range of biological activities could represent a useful tool for the development of new therapeutics. Yet the biomedical potential of these compounds could be greatly enhanced by a comprehensive understanding of their biosynthetic origin combined with the recent progress in molecular biology. Generally, the occurrence of different but biosynthetically related compounds in different organisms, in terrestrial sources, and/or in collections of the same organism from distinct geographical locations, strongly supports the possibility of their microbial origin. Further evidence could be indicative of the involvement of associated microorganisms in the biosynthesis of such compounds when the structures of the metabolites are reminiscent of fungal and/or bacterial biogenetic pathways. For example, the isolation of callyspongamide A (292) from the sponge C. fistularis suggested its microbial origin,202 because it was structurally similar to hermitamides A−B, recently isolated from a marine cyanobacterium Lyngbya majuscula.320 Actually, the chemical diversity observed within the class of acetylenic compounds might be largely explained by considering the possibility that polyacetylenes are the product of interactions between macroorganism (algae, sponges) and microorganism (bacteria, fungi) in salt-water environments, but the real biosynthetic origin of polyacetylenes is still unclear. It is expected that the mutualistic relationships between marine animals and microorganisms will become increasingly apparent as natural product isolation and genomics provide an overall vision of microbial and marine secondary metabolic pathways. During the past decade, research into the metabolism of polyacetylenes has swiftly advanced, driven by the cloning of the first genes responsible for polyacetylene biosynthesis in plants, moss, fungi, and actinomycetes and the initial characterization of the gene products. A likely PK biogenesis of the highly oxygenated marine polyacetylenes has been proposed. The dominance of polycistronic operons in microbial PK biosynthesis should lead to the cloning of entire pathways for bacterially produced marine polyacetylenes and the heterologous production of phamacologically useful compounds in pure bacterial cultures.2 This is a direction with shining prospects, because a huge number of marine derived metabolites, including the polyacetylenes, could represent new lead structures in drug discovery.

against HeLa cells with IC50 values of 0.26 and 0.26 μM, respectively,177 and petroformynes A1, A2, C5, E2, E3, and F5 (529−536) were found to be extremely toxic against brine shrimp (A. salina) assays at very low concentrations ranging from 0.002 to 0.12 ppm.276 Thus, polyacetylenes have the potential for leads or drug candidates; however, the intractability of high molecular weight polyacetylenes, limited sample availability, and the unstable nature of these metabolites are still long-term challenges for chemists. The polyacetylenes not only possess a series of biological activities but also provide the prototypical polymer for the organic material. The polyacetylenes that were usually processed to form thin, coherent film can be used as the active layers in semiconductor device structures.317 The polymer of polyacetylene was prepared by two main routes, the Shirakawa route and the Durham precursor route.317 It is worthy to note that the iodine-doping polyacetylene exhibits substantially high electrical conductivity.318 Despite the considerable advances in the understanding of the electronic properties of conjugated polymers, and in the control and handling of these materials, there has been relatively little work reported on their use as the active component in semiconductor device structures, because the most conjugated polymers cannot be conveniently processed to the forms required in these semiconductor devices, and in the use of p- or n-type doped polymer. Moreover, the dopants are able to diffuse through the sample at room temperature.319 In particular, the natural polyacetylenes are scarcely used for designing the semiconductor devices. The different electro-optical properties of these organic devices from those of devices based on inorganic semiconductors indicate that the organic devices based on polyacetylenes promise to be AV


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AUTHOR INFORMATION Corresponding Author

*Tel.: (86-21) 5080-5813. Fax: (86-21) 5080-5813. E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

You-Sheng Cai was born in Hubei province, China, in 1981. He obtained his Bachelor’s degree in Pharmaceutical Engineering from Central South University, China, in 2005. In 2007, he joined Prof. Yue-wei Guo’s research group at the Shanghai Institute of Materia Medica, CAS, as a graduate student and performed his Ph.D. work in marine natural products chemistry. Following the successful completion of his Ph.D. study, he first worked as a lecturer at Wuhan Institute of Bioengineering and is now a lecturer at the Wuhan University. His research interests focus on the discovery of novel secondary metabolites with biomedical functions from terrestrial and marine organisms.

Zhen-Fang Zhou was born in Anhui Province, China. She received her Bachelor’s degree from School of Traditional Chinese Pharmacy, China Pharmaceutical University. In 2009, she joined the research group of Professor Yue-Wei Guo as a Ph.D. student at Shanghai Institute of Materia Medica, Chinese Academy of Sciences, where she is carrying out research on isolation and structural elucidation of biologically active natural products from Chinese marine organisms, mangroves, and endophytic fungi from Chinese mangroves. She now works at Shanghai Institute of Materia Medica.

Yue-Wei Guo received his Ph.D. degree in 1997 at University of Naples Italy. From 1997 to 2000 he worked as postdoctoral fellow in the Istituto di Chimica Biomoleculare-CNR, Italy, and Hokkaido University, Japan. He has been a Professor at Shanghai Institute of Materia Medica, CAS, since 1999. His field of research interests concerns natural bioactive compounds from marine and terrestrial fauna and flora. He is an author of over 300 scientific papers and also one of the inventors of 7 patents. He received several awards including the 2010 “Paul Scheuer Prize”. He is a member of several editorial boards of chemical or pharmaceutical journals.

Prof. Marialuisa Menna received her Ph.D. in “Pharmacologically Active Natural Substances” at the University of Naples Federico II in 1992. She was a Ph.D. exchange student in 1989 at the institute of “Pharmacognosie et phytochimie”, University of Lausanne (Suisse), and during 1992−1994 she got at a postdoctoral position at the University of Venice. In 1995 she attained a researcher position at the Department of Chemistry of Natural Substances of the University of Naples Federico II, and since 2003 she has been associate professor in Organic Chemistry at the Pharmacy Department of the same University. The major scientific and research interests of Prof. Menna are in the field of the chemistry of natural products; she is a component of the NeaNAT multidisciplinary research group, founded by Professor Ernesto Fattorusso, which has been active for over 40 years in the isolation and identification of bioactive natural products of marine origin.

ACKNOWLEDGMENTS This research work was financially supported by the National Marine “863” Projects (nos. 2012AA092105 and 2013AA090202), the Natural Science Foundation of China (nos. 81273430, 41306130, and 41476063), and was partially funded by the EU seventh Framework Programme-IRSES Project (no. 246987). REFERENCES (1) Jiang, C.-S.; Muller, W. E. G.; Schroder, H. C.; Guo, Y.-W. Chem. Rev. 2012, 112, 2179. AW


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