Research Progress of Polycyclic Polyprenylated Acylphloroglucinols

Review Cite This: Chem. Rev. 2018, 118, 3508−3558

pubs.acs.org/CR

Research Progress of Polycyclic Polyprenylated Acylphloroglucinols Xing-Wei Yang,† Robert B. Grossman,‡ and Gang Xu*,† †

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming 650201, People’s Republic of China ‡ Department of Chemistry, University of Kentucky, Lexington, Kentucky 40506-0055, United States S Supporting Information *

ABSTRACT: Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of hybrid natural products sharing the mevalonate/methylerythritol phosphate and polyketide biosynthetic pathways and showing considerable structure and bioactivity diversity. This review discusses the progress of research into the chemistry and biological activity of 421 natural PPAPs in the past 11 years as well as in-depth studies of biological activities and total synthesis of some PPAPs isolated before 2006. We created an online database of all PPAPs known to date at http://www.chem.uky.edu/research/grossman/PPAPs. Two subclasses of biosynthetically related metabolites, spirocyclic PPAPs with octahydrospiro[cyclohexan-1,5′-indene]-2,4,6-trione core and complicated PPAPs produced by intramolecular [4 + 2] cycloadditions of MPAPs, are brought into the PPAP family. Some PPAPs’ relative or absolute configurations are reassigned or critically discussed, and the confusing trivial names in PPAPs investigations are clarified. Pharmacologic studies have revealed a new molecular mechanism whereby hyperforin and its derivatives regulate neurotransmitter levels by activating TRPC6 as well as the antitumor mechanism of garcinol and its analogues. The antineoplastic potential of some type B PPAPs such as oblongifolin C and guttiferone K has increased significantly. As a result of the recent appearances of innovative synthetic methods and strategies, the total syntheses of 22 natural PPAPs including hyperforin, garcinol, and plukenetione A have been accomplished.

CONTENTS 1. Introduction 2. Classification of Diverse PPAPs 2.1. Bicyclic Polyprenylated Acylphloroglucinols (BPAPs) 2.1.1. Type A BPAPs 2.1.2. Type B BPAPs 2.1.3. seco-BPAPs 2.2. Caged PPAPs with Adamantane and Homoadamantane Skeletons 2.2.1. Adamantane-Type PPAPs 2.2.2. Homoadamantane-Type PPAPs 2.3. Other PPAPs 2.3.1. Spirocyclic PPAPs with Octahydrospiro[cyclohexan-1,5′-indene] Core 2.3.2. Complicated PPAPs via Intramolecular [4 + 2] Cycloadditions from MPAPs 3. Investigation of Certain PPAPs’ Configurations 3.1. Relative Configuration of C-7 for Certain BPAPs 3.2. Reassignment of Some PPAPs’ Relative Configuration on Other Locations 3.3. Investigation of the Absolute Configurations of Certain PPAPs 4. Consolidation of Some PPAPs’ Trivial Names 5. Living Database of PPAPs 6. Biological Activities of PPAPs 6.1. Biological Activities of Type A BPAPs © 2018 American Chemical Society

6.1.1. Hyperforin and Its Synthetic Derivatives 6.1.2. Nemorosone and 7-epi-Nemorosone 6.1.3. Garcinielliptone FC 6.2. Biological Activities of Type B BPAPs 6.2.1. Garcinol and Its Derivatives 6.2.2. Clusianone and 7-epi-Clusianone 6.2.3. Guttiferone A and Its Derivatives 6.2.4. Oblongifolin C and Guttiferone K 6.3. Biological Activities of Other PPAPs 7. Synthetic Chemistry of PPAPs 7.1. Shibasaki’s Total Syntheses of ent-Hyperforin and Garsubellin A 7.2. Shair’s Enantioselective Total Syntheses of (+)-Hyperforin and (−)-Nemorosone 7.3. Barriault’s Total Syntheses of Hyperforin and Papuaforins A−C 7.4. Maimone’s Total Synthesis of Hyperforin 7.5. Nakada’s Syntheses of Hyperforin, Nemorosone, Garsubellin A, and Clusianone 7.6. Danishefsky’s Total Syntheses of Nemorosone, Clusianone, and Garsubellin A 7.7. Simpkins’s Total Syntheses of Nemorosone and Clusianone 7.8. Plietker’s Total Syntheses of a Series of Type B PPAPs

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Received: September 12, 2017 Published: February 20, 2018 3508

DOI: 10.1021/acs.chemrev.7b00551 Chem. Rev. 2018, 118, 3508−3558

Chemical Reviews 7.8.1. Oblongifolin A, 7-epi-Clusianone, Hyperibone L, and Hyperpapuanone 7.8.2. Hyperibone I, Sampsonione P, (+)-Clusianone, Garcinol, and Isogarcinol 7.8.3. Guttiferone A 7.9. Porco’s Total Syntheses of PPAPs Using Alkylative Dearomatization Strategy 7.9.1. (−)-Hyperibone K and Clusianone 7.9.2. Plukenetione A and 7-epi-Nemorosone 7.9.3. Asymmetric Syntheses of (−)-Clusianone and Non-natural PPAPs 7.10. Biomimetic Syntheses of PPAPs Using Radical Cyclization 8. Summary and Future Directions Associated Content Supporting Information Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References Note Added after ASAP Publication

Review

one core and complicated PPAPs via intramolecular [4 + 2] cycloadditions of MPAPs, emerged in large numbers. Meanwhile, the structures of all of the type C PPAPs were revised to the corresponding type A structures,9 and several other PPAPs’ skeletons and configurations were also clarified. Furthermore, pharmacologic studies revealed a new molecular mechanism of hyperforin and its derivatives whereby they regulate neurotransmitters by activating transient receptor potential channel 6 (TRPC6)10 as well as the antitumor mechanism of garcinol and its analogues. The antineoplastic potential of some recently isolated type B PPAPs such as oblongifolin C and guttiferone K is increasing significantly. In addition, as a result of the recent appearances of innovative synthetic methods and strategies, the total syntheses of 22 complex natural molecules, such as hyperforin, clusianone, and plukenetione A, have been achieved. In particular, the remarkable contributions from the research groups of Plietker, Porco, Jr., and Maimone et al. ushered in the peak period of PPAPs synthesis. Some minireviews related to partial aspects of PPAPs have been presented. Prenylated acylphloroglucinols and their bioactivities from genera Hypericum and Garcinia, respectively, have been summarized in different years.11−14 It is noteworthy that some reviews emphasized the well-known hyperforin and garcinol and aspects of their chemistry and bioactivities, including antidepressant and antitumor activities.10,15−22 The organic synthesis progress of PPAPs has also been reviewed before 2013.23−25 In addition, some reviews about the chemistry and bioactivities of natural phloroglucinol derivatives and benzophenones, which involved some of the PPAPs, have been published.26−28 However, none of them gave general insight into the chemistry and biological activities of PPAPs. During our investigations on the biologically active PPAPs from Guttiferae, we noticed confusion and ambiguity about PPAPs in the literature. (i) Some PPAPs’ relative configurations were assigned incorrectly, perhaps because the key NOE signals were deficient or overlapped in their NOESY spectra. (ii) Certain PPAPs’ absolute configurations as assigned by their optical rotations or determined by comparison of their experimental and calculated ECDs were not reliable. (iii) Some PPAPs were given the same nomenclature but had different structures, while some PPAPs had the same structure but different names. This review summarizes the progress of research into the chemistry and biological activity of 421 natural PPAPs in the past 11 years (from 2006 to June 30, 2017) as well as the in-depth studies of biological activities and total synthesis of some promising PPAPs reported before 2006. Some PPAPs’ relative or absolute configurations are reassigned or critically commented upon. Furthermore, we try to clarify the confusing trivial names in PPAPs investigations. In addition, we created a freely accessible Web site at http://www.chem.uky.edu/research/grossman/ PPAPs that shows structures, names, plant sources, specific rotations, and hyperlinked references to the original literature for all PPAPs known to date. We will continue to add new PPAPs to the database as they are discovered and to modify the entries as new information comes to light.

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1. INTRODUCTION Polycyclic polyprenylated acylphloroglucinols (PPAPs), possessing highly oxygenated acylphloroglucinol-derived cores decorated with isoprenyl or geranyl side chains, are a group of structurally fascinating and synthetically challenging natural products that collectively exhibit a broad range of biological activities. Biogenetically, PPAPs are derived from a “mixed” mevalonate/ methylerythritol phosphate and polyketide biosynthetic pathway.1 Their acylphloroglucinol cores are produced by a characteristic polyketide-type biosynthesis involving the condensation of one acyl-CoA and three malonyl-CoA units.2−5 Prenylation of this core moiety affords monocyclic polyprenylated acylphloroglucinols (MPAPs), which may be further cyclized to PPAPtype metabolites with diverse carbon skeletons.2−5 The type of acyl groups, the number and position of isoprenyl substituents, the degree of oxidation of isoprenyl side chains and corresponding locations of ether rings, and different types of secondary cyclization (such as aldol, Diels−Alder, etc.) create PPAPs’ structural diversity and complexity. Interestingly, this special class of hybrid natural products has been exclusively isolated from the plants of family Guttiferae (Clusiaceae) and mainly from the genera Hypericum and Garcinia with only a few exceptions, discussed later. The first PPAP to be identified, hyperforin, was isolated in 1971 from H. perforatum (St. John’s wort) and is now considered to be the main constituent of the medicinal herb responsible for its antidepressant activity.6,7 The separation and structural identification of PPAPs were difficult because their physical and chemical properties were similar to each other, which hindered the progress of comprehensive research into this type of metabolite. Up to 2005, only 119 members belong to the PPAP family had been reported according to Ciochina and Grossman’s review in 2006.8 With the development of techniques of separation and structural identification, a total of 421 natural PPAPs with various skeletons were reported in the past decade. Two new classes of biosynthetically related metabolites, spirocyclic PPAPs with octahydrospiro[cyclohexan-1,5′-indene]-2,4,6-tri-

2. CLASSIFICATION OF DIVERSE PPAPS Previously, the various PPAPs have been divided into types A, B, and C depending on the relative position of the acyl group on the phloroglucinol core.8,29 However, the structural assignments of type C PPAPs were problematic and doubtful. In fact, the investigations before 2003 involved the structural revisions of three type C PPAPs, nemorosone, hydroxynemorosone, and 7-epi-nemoro3509


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sone.8,29,30 In 2017, the structures of all of the remaining type C PPAPs, garcinielliptones K−M,31 were revised to corresponding type A structures (24, 23, and 18) by our team via NMR spectroscopic and quantum computational chemistry methods (Scheme 1).9 The positions of the bridgehead substituents (the

skeletons, derived via the enolic C-3 cyclizing onto C-27 and C-28 of normal endo-BPAPs, respectively, are included in group II and consist of 82 members. Other biosynthetically related metabolites, derived from direct cyclizations of MPAPs rather than via formation of the BPAPs, are also brought into the PPAP family and assigned to group III. This group contains two subclasses: spirocyclic PPAPs with an octahydrospiro[cyclohexan-1,5′indene]-2,4,6-trione core (346−391, Table 6) and complicated PPAPs (392−421, Table 7) derived from intramolecular [2 + 4] cycloadditions of MPAPs. Interestingly, 18 BPAPs, hyperibine J (2) from H. perforatum and H. triquetrifolium,32,33 hypermongones A−J (21, 28, 20, 27, 44, 54, 43, 53, 45, 46) from H. monogynum,34 hyperscabrones C (110), D (111), and G (98) from H. scabrum,35 and ascyronones A−D (259, 260, 255, 100) from H. ascyron36 as well as some spirocyclic PPAPs from genus Hypericum37−42 feature a methyl substituent at C-5 rather than a prenyl or geranyl group in most of other PPAPs. It suggests that not only prenylation but also methylation may occur in the acylphloroglucinol cores to form the MPAP intermediates in these plants, which enriches the structural diversity of PPAPs. In literature surveys, many PPAPs have been classified into the benzophenone family.28 However, the benzoyl or hydroxylated benzoyl group in many PPAPs is just a substituent acyl group rather than part of the PPAPs’ basic phloroglucinol architecture. The acyl group in PPAPs can also be an isobutyryl, 2-methylpentanoyl, or 3-methylpentanoyl (isovaleryl) group. To date, this special class of hybrid natural products has been almost exclusively isolated from the plants of family Guttiferae. However, there are two exceptions in recent years. Two BPAPs (101 and 134) have been isolated from Spiranthera odoratissima (Rutaceae),43 and five spirocyclic PPAPs (353, 354, 376−378) obtained from Harrisonia perforate (Simaroubaceae) have been reported.44 These findings expand plant resources for diverse PPAPs.

Scheme 1. Skeleton Reassignment of Type C PPAPs

acyl and isoprenyl groups) in these compounds and the enolic βdiketone system in 18, 23, and 24 were all switched from their originally assigned positions. Therefore, only type A and B PPAPs are likely present in plants of the family Guttiferae.9 In this review, we provide a new classification of PPAPs; and Cuesta-Rubio and Grossman’s classification into types A and B will continue to be used as subclassification.29 Biogenetically, PPAPs are all derived from a common biosynthetic pathway via different cyclizations of the less complex monocyclic polyprenylated acylphloroglucinols (MPAPs).1−5,8 All of the PPAP profiles are generated via three major biosynthetic pathways and may be divided into three groups (I−III) according to their different scaffolds (Scheme 2).1 The bicyclic polyprenylated acylphloroglucinols (BPAPs) with major bicyclo[3.3.1]nonane2,4,9-trione core (1−243, Tables 1 and 2) and related secoBPAPs (244−263, Table 3) are classified as group I and comprise approximate 60% of PPAPs. The caged PPAPs with adamantane (tricyclo[3.3.1.1]decane) (264−296, Table 4) and homoadamantane (tricyclo[4.3.1.1]undecane) (297−345, Table 5)

Scheme 2. Proposed Biosynthetic Pathways to the PPAPs: from Polyketides to Acylphloroglucinols to Diverse PPAP-Type Derivatives

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Table 1. Type A BPAPs

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a

C. = Clusia, G. = Garcinia, H. = Hypericum. bThe values in parentheses are the concentration and the solvent (c = CHCl3, e = EtOH, m = MeOH). The absolute configuration is known to be as shown. dThe C-7 relative configuration was reassigned according to the method of Grossman and Jacobs. eThe absolute configurations of C-1 and C-5 are assigned by comparison of its experimental and calculated ECD. fNot all of the stereocenters’ configurations have been assigned. gThe original structures were incorrectly drawn by mistake and reassigned as shown. hTwo compounds with identical NMR data were reported almost simultaneously (The other name, hypersampsone S, has been used previously88), but opposite configurations were assigned in the cyclohexane substituent. iThe original assignment of the C-7 relative configuration is probably incorrect according to the rule of Grossman and Jacobs. c

2.1.2. Type B BPAPs. This subclass, whose acyl groups are located at the C-3 position, comprises 129 members (Table 2).95,96,111,112,120,122,124−128,132,134,135 Most of the type B BPAPs are obtained from the genus Garcinia, and the majority of them share a characteristic hydroxylated benzoyl group. It has been found that the enolic β-diketone system and 3, 4-dihydroxybenzoyl substituents in the structures of type B BPAPs are important for their anticancer activities.89,90 Compounds 115−236 possess the same bicyclo[3.3.1]nonane-2,4, 9-trione core, whereas 241−243 feature a rare bicyclo[4.3.1]decane-2,4,9-trione core. Yezo’otogirins E (237) and F (238), isolated from H. yezoense and takaneones A (239) and B (240) obtained from H. sikokumontanum, share a basic bicyclo[3.2.1]octane-2,4,8-trione core; further cyclization of the C-1 and C-7 side chains gives them a more complicated tricyclic carbon system.46,91 It is noteworthy that in only three BPAPs, oblongifolin M (170),92 garciesculentone A (191),93 and paucinone C (207),94 an oxygen atom is inserted between C-3 and the acyl group to form an ester moiety. Type B BPAPs that possess a 3, 4-dihydroxybenzoyl substituent are prone to be oxidized (C-6 position of benzene) and further cyclized with O-2 or O-4 to form a fused tetracyclic system, as shown in 218−236. 2.1.3. seco-BPAPs. Twenty seco-BPAPs are listed in Table 3.139 Among them, compounds 244−261 are type A derivatives, whereas 262 and 263 are type B derivatives. Compounds 244−260 are suggested to be 1,9-seco-BPAPs, which are derived from 3,9-hemiketal precursors such as 97, and 261−263 are considered to be 1,2-seco-BPAPs. In fact, 244 was isolated from H. perforatumin and named perforatumone early in 2004138 but assigned an incorrect skeleton with a seven-membered carbon

In order to facilitate the following analysis and discussion, we unified the numbering of the bicyclo[3.3.1]nonane core for both type A and type B BPAPs, as shown in Scheme 2. 2.1. Bicyclic Polyprenylated Acylphloroglucinols (BPAPs)

2.1.1. Type A BPAPs. As shown in Table 1, this subclass includes 114 BPAPs in which the acyl group is located at the C-1 position. Interestingly, the majority of the type A BPAPs (102 members) are obtained from the genus Hypericum.62,69,70,73,75,79,80,82 The vast majority, compounds 1−112, share a common bicyclo[3.3.1]nonane-2,4,9-trione core. By contrast, hypercohin A (113) possesses an unusual bicyclo[5.3.1]hendecane core. Compound 113, isolated from H. cohaerens, is the first PPAP featured with an eight-membered ring B, and its absolute configuration was determined by single-crystal X-ray diffractions of its p-bromobenzoate ester.45 Takaneone C (114), reported by Tanaka et al.,46 is the first type A BPAP that possesses a basic bicyclo[3.2.1]octane-2,4,8-trione core, and further cyclization of the C-5 and C-6 side chains makes it bear a more complicated tricyclic carbon system. It is noteworthy that the BPAPs that keep an enolic β-diketone system in their structures, such as 1−5, are usually obtained as keto−enol tautomeric mixtures, doubling the signals present in their 1H and 13 C NMR spectra.33,47−49 The prenyl or geranyl side chains at C-3 and C-5 as well as the prenylmethyl group at C-8 are prone to be oxidized and further cyclized with O-2 or O-4 to form furan, pyran, etc., substructures in 6−96 and 105−113, which thereby hinders keto−enol tautomerism of these BPAPs. In addition, C-3 of type A structures are also easily oxidized and further generate 3,9-hemiketal form, as exemplified by 97−104. 3515


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Table 2. Type B BPAPs

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a C. = Clusia, G. = Garcinia, H. = Hypericum, M. = Moronobea, S. = Symphonia. bThe values in parentheses are the concentration and the solvent (a = acetone, c = CHCl3, e = EtOH, m = MeOH). cNot all of the stereocenters’ configurations have been assigned. dThe absolute configuration is known to be as shown. eThe C-7 configuration was reassigned (see text). fThe original assignment of the C-7 relative configuration is probably incorrect according to the rule of Grossman and Jacobs. gThe original name, guttiferone I, has been used previously, and we rename as 13-deoxyguttiferone J. hThe absolute configurations of C-1 and C-5 are assigned by comparison of its experimental and calculated ECD. iPairs of isolates with positive and negative optical values, respectively, may be enantiomers. jIt may be an enantiomer of (+)-cycloxanthochymol according to its negative optical value. kThe original absolute configuration was reassigned. lIts C-4 stereocenter was not assigned, and the C-7 relative configuration was incorrectly drawn by mistake in the original paper; hence, it may be enantiomeric to symphonone I. mThe original name, guttiferone O, has been used previously, and we rename as oxy-oblongifolin A.

C and I (256 and 257), featuring a 5/8/5 fused ring system, and hyphenrone D (258), with an unprecedented 6/6/5/8/5 fused ring system, are suggested to be derived from the less complicated 1,9-seco-BPAP precursors 244−246 via aldol condensation and intermolecular Diels−Alder cycloaddition, respectively.1,85

core. In 2015, the structure was revised to hyphenrone A (244) by NMR spectroscopic analysis and biomimetic synthesis from 3-hydroxyhyperforin-3,9-hemiketal via 244 into hyphenrone F (254) (Scheme 3).1 The final single-crystal X-ray diffraction analysis of 254 suggested that the structure of perforatumone was identical or enantiomeric to that of hyphenrone A (244). Also, the structure of its derivative, attenuatumione B (249),60 was revised to share the same eight-membered carbon core fused by a γ-lactone ring as that of 244.87 The structures of hyphenrone

2.2. Caged PPAPs with Adamantane and Homoadamantane Skeletons

2.2.1. Adamantane-Type PPAPs. It was once assumed that living organisms could not synthesize adamantane derivatives, 3521


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Table 3. seco-BPAPs

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H. = Hypericum. bThe values in parentheses are the concentration and the solvent (a = acetone, c = CHCl3, e = EtOH, m = MeOH). cThe absolute configuration is known to be as shown. dNot all of the stereocenters’ configurations have been assigned.

whose synthesis was considered purely abiotic.141 However, this view was finally refuted in 1996 when plukenetione A, the first adamantane-type PPAP, was isolated from the Clusia plukenetii.142 As shown in Table 4,146 this subclass includes 33 PPAPs with a “diamond-like” caged core (264−282 and 288−295) or related seco-scaffolds (283−287 and 296). Among them, compounds 264−287 and 288−296 are derived from corresponding type A and B BPAP precursors, respectively. Two secondary skeletons with tetracyclo[7.3.1.13,11.03,8]tetradecane (276 and 277) and tetracyclo[6.3.1.13,10.03,7]tridecane (278−282) cores are derived by the further cyclization of C-18/C-29 and C-18/C-28, respectively, from the normal adamantane-type PPAP precursors.1 2.2.2. Homoadamantane-Type PPAPs. As shown in Table 5,152,154,157,162 49 members of the homoadamantane-type

PPAPs, which share a common tricyclo[4.3.1.1]undecane core (except for 345 with its tricyclo[4.2.1.1]decane skeleton), all have type A structures. Compounds with a tetracyclo[7.3.1.13,11.03,7]tetradecane core (320−344) are secondarily derived from C-18/C-29 cyclization in the homoadamantanetype PPAPs. Lathrophytoic acid A (345), isolated from Kielmeyera lathrophyton, is the first 4-nor-homoadamantane PPAP with loss of C-4 carbonyl and followed by the formation of a C-3/C-5 carbon−carbon bond.66 It is noteworthy that H. sampsonii, a traditional Chinese medicine to treat blood stasis and swelling reduction, is the richest source of caged PPAPs, and over 50 adamantane- and homoadamantane-type derivatives have been reported from this plant thus far. In 2017, the relative configurations of cowabenzophenone B (344) and an unnamed 3522


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Table 4. Caged PPAPs with Adamantane Skeleton

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a

G. = Garcinia, H. = Hypericum. bThe values in parentheses are the concentration and the solvent (c = CHCl3, m = MeOH). cThe absolute configuration is known to be as shown. dThe original name, garcimultiflorone D, has been used previously, and we rename as isosampsonione J. e The configuration of the oxirane unit was reassigned according to the rule established by Xu et al.144 fPairs of isolates with positive and negative optical value, respectively, may be enantiomers.

this subclass reported early in 1988.165 Compounds 392−399, which have a fused hexacyclic system, represent the most complex PPAPs thus far and are likely derived from tetraprenylated MPAPs (such as weddellianone A) via successive intramolecular [4 + 2] radical cycloadditions (Scheme 4).166 Interestingly, racemic mixtures such as (±)-garmultin A (406 and 407) and optically pure analogues such as garmultin B (408) have been coisolated from G. multif lora.167 The authors presume that different MPAP precursors (with chiral or achiral center) before the biosynthetic Diels−Alder reactions may be the main reason for this special phenomenon.167 Hypatulin A (421), obtained from H. patulum, is also presumed to be generated from an MPAP with four isoprene units via [3 + 2] intramolecular cyclization, oxidative ring cleavage, and further cyclization.168 It is noteworthy that the previous C-5 configurations of doitunggarcinone A (393) and doitunggarcinone B (402) were incorrectly drawn by mistake, even though the authors had provided correct NOE correlations.133 In 2012, George’s team accomplished the synthesis of 393 and suggested the structural revision for 393 and its biosynthetic precursor 402.166,169

one were revised to the same as those of hyperattenin H and pseudohenone E (343), respectively.143 2.3. Other PPAPs

2.3.1. Spirocyclic PPAPs with Octahydrospiro[cyclohexan-1,5′-indene] Core. This subclass comprises 46 PPAPs (Table 6164) that are considered to be the further intramolecular cyclization products of the less complicated MPAPs, such as hypercalin C (Scheme 4). Interestingly, these spirocyclic PPAPs are all isolated from the genus Hypericum, except for five compounds (353, 354, 376−378), sharing a distinct acetyl group, that are obtained from H. perforate, a plant of family Simaroubaceae. Oxidative ring opening of the phloroglucinol core of these PPAPs affords derivatives with a bicyclo[4.3.0]nonane skeleton (385−391), which might recyclize to a spiroskeleton metabolite with a cyclopentane-1,3-dione moiety (384). This type of PPAP was first reported in 2008, when tomoeones A−H (348, 350−352, 370, 372, 374, and 375) were isolated from the leaves of H. ascyron by Hashida and co-workers.160 In 2015, Zhu et al. revised the hydroxyl substituent of C-13 in tomoeones C, D, G, and H (372, 350, 375, and 352) to a hydroperoxyl group as well as the relative configuration of C-13 by analysis of their MS and NMR spectroscopic data.161 2.3.2. Complicated PPAPs via Intramolecular [4 + 2] Cycloadditions from MPAPs. As mentioned above, the complicated PPAPs are derived from intramolecular [4 + 2] cycloadditions of MPAPs rather than via formation of the BPAPs (Scheme 4) and have been neglected in all of the previous reviews about PPAPs. As shown in Table 7,171 this subclass includes 30 PPAPs with complicated ring systems that share a basic tricyclo[4.3.1.03,7]decane-2,9-dione moiety (except for 421), as exemplified by (+)-nemorosonol (400), the first member of

3. INVESTIGATION OF CERTAIN PPAPS’ CONFIGURATIONS 3.1. Relative Configuration of C-7 for Certain BPAPs

In the structural determination of BPAPs, the assignment of the C-7 relative configuration by NOE experiments is problematic and sometimes leads to an erroneous conclusion, because the key signals, such as the two H-6 protons and H-7, usually overlap in the upfield region of the 1H NMR spectrum. Furthermore, the NOE correlations of the protons of adjacent carbons are 3524


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Table 5. Caged PPAPs with Homoadamantane Skeleton

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Table 5. continued

a

C. = Clusia, G. = Garcinia, H. = Hypericum. bOMe indicates the rotation was measured for its methylated derivative. The values in parentheses are the concentration and the solvent (c = CHCl3, m = MeOH). cThe absolute configuration is known to be as shown. dPairs of isolates with positive and negative optical value, respectively, may be enantiomers. eThe C-8 configuration was reassigned, see text.

assignment. Rastrelli et al. have shown that the coupling constant of H-7/H-6ax is 6−8 Hz when the C-7 substituent is in the axial position (endo), while the coupling constant of H-7/H-6ax is 10−13 Hz when the C-7 substituent is equatorial (exo).174 After survey of all of the NMR data of BPAPs reported in this period, some PPAPs’ C-7 relative configurations need reevaluation. • In 2012, Kaur et al. reported an unnamed BPAP (231),121 and they used the method of Grossman and Jacobs to assign C-7 an exo configuration, but they drew the structure with the endo configuration. On the basis of the NMR data in the paper, the exo configuration appears to be correct. • Hyperscabrone K (8) was reported to have a C-7 endo substituent, but the chemical shifts of C-7 (δ 43.0) and H-6 (δ 1.98 and 1.48) match those of exo BPAPs.55 Analysis of the process of configuration assignment indicates that the authors misused the Grossman and Jacobs’ rule, and the meaning of endo/exo was mistaken for α/β.55

not reliable for the determination of the corresponding stereochemistry, especially in conformationally variable molecules. Fortunately, Grossman and Jacobs formulated a rule for easily determining the orientation of the C-7 substituent in BPAPs (endo or exo) by examining the 1H and 13C NMR spectroscopic data.8,173 When the C-7 substituent is exo, the difference in chemical shifts of the two H-6 atoms is 0.3−1.2 ppm and the chemical shift of C-7 is 41−44 ppm, whereas when the C-7 substituent is endo, either the difference in chemical shifts of the two H-6 atoms is 0.0−0.2 ppm or the chemical shift of C-7 is 45−49 ppm.8,173 Since this rule was formulated in the early 2000s, dozens more BPAPs have been isolated and characterized. Remarkably, the rule holds very consistently across all of these newly discovered BPAPs, regardless of NMR solvent and BPAP type. Hence, we strongly suggest that researchers use Grossman and Jacobs’ rule to determine the C-7 configuration of BPAPs in the future. Meanwhile, the conformational analysis of the B ring of the bicyclo[3.3.1]nonane system and the coupling constant of H-7/H-6ax can also be used to make the 3526


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Table 6. Spirocyclic PPAPs with Octahydrospiro[cyclohexan-1,5′-indene] Core

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Table 6. continued

a H. = Hypericum. bThe values in parentheses are the concentration and the solvent (c = CHCl3, m = MeOH). cThe absolute configuration is known to be as shown. dThe original assignment of the C-4 relative configuration is probably incorrect according to its NMR data, and it may be a C-6 or C-18 epimer of sampsonol A. eThe absolute configuration is known and is opposite to what is shown.

• Similarly, the structures of hypersampsone H (7)54 and oblongifolin T (149)119 were reassigned to be 7-endo BPAPs, according to their chemical shifts of H-6 (Δ = 0.12 and 0.09) and C-7 (48.7 and 47.7). The authors did not recognize that a 7-endo substituent could cause the H-7 to have a NOESY interaction with either methyl group on C-8.119 According to the rules mentioned above, the original assignments of the C-7 relative configuration of the following 14 BPAPs are questionable (their C-7 configuration is not assigned in Tables 1 and 2) and need to be further investigated. Spiranthenone A (101),43 spiranthenone B (134),43 semsinone A (135),104 oblongifolins M−O, Q−S, and Z (170, 166, 169, 167, 203, 190, and 168, respectively),92,119 13,14-didehydroxyisogarcinol (187),77 and garcinialone (232)130 are all reported to have C-7 endo substituents; however, their C-7 δ values (40.2−44.3 ppm, 37.5 for 169) are not consistent with those of other endo BPAPs but match those of exo BPAPs. Also, the C-7 δ values (47.0−47.5 ppm) of exo BPAPs 32-hydroxy-entguttiferone M (148)110 and garciesculentone A (191)93 suggest that they are endo BPAPs. It is important to note that Grossman and Jacobs’ rule can be widely used for determination of the C-7 relative configuration of those BPAPs with two methyl groups at C-8, but caution should be exercised when a prenylmethyl group is present at

Hence, we reassign the C-7 relative configuration of hyperscabrone K, and it should share the same relative structure with scrobiculatone B.56 • The exo BPAP hyperibrin D,61 reported by the same team, possesses identical 1H and 13C NMR spectroscopic data to those of endo BPAP hyperattenin E (199),71 indicating the original assignment of C-7 relative configuration for hyperibrin D was incorrect. Their C-7 (δ 46.4) value and coupling constant of H-7/H-6ax (6.0 Hz) are consistent with those of other endo BPAPs. Therefore, we reassign the C-7 configuration of hyperibrin D to be the same as that of hyperattenin E (199). • We also reassign the C-7 configuration of a pair of C-7 epimers, oblongifolins L (161) and AA (164),92,119 according to their chemical shifts of C-7 (δ 42.4 for 161 and 45.5 for 164) and two H-6 protons (δ 2.02, 1.47 for 161 and δ 2.21, 2.18 for 164). The original assignment of one H-6 proton (δ 1.99, m) in 161 was incorrect; it should be located at 1.47 ppm (t, J = 12.9 Hz) after examining its HSQC spectrum.92 Therefore, both the difference in chemical shifts of two H-6 atoms (0.55 ppm) and the large coupling constant of H-7/H-6ax (12.9 Hz) support the equatorial (exo) substituent of C-7 in 161. 3528


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Table 7. Complicated PPAPs via Intramolecular [4 + 2] Cycloadditions of MPAPs

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Table 7. continued

a

C. = Clusia, G. = Garcinia, H. = Hypericum, T. = Triadenum. bThe values in parentheses are the concentration and the solvent (c = CHCl3, m = MeOH). cThe absolute configuration is known to be as shown. dThe absolute configuration is known and is opposite to what is shown.

avoid steric hindrance, when cationic C-8 cyclized to the phloroglucinol core).8

Scheme 3. Biomimetic Transformation of 3-Hydroxyhyperforin-3,9-hemiketal to 254

3.2. Reassignment of Some PPAPs’ Relative Configuration on Other Locations

We suggest that some PPAPs’ relative configurations on other locations (beside C-7) should be reassigned after detailed investigation of their NMR data. • The Z configuration of the geranyl group (should be E-configuration) in androforin A (36)68 as well as the structures of furohyperforin isomer 1 (40), 18-epifurohyperforin isomer 1 (49), and furoadhyperforin isomers A and B (41 and 50),65,72 were drawn incorrectly by mistake; the correct structures are given in Table 1. • We have revised the C-18 configuration of hypercohin J (57) because of its similar NOE correlations to those of hyperforatin K (59).63,67 • The use of NOE experiments to determine the C-28 configuration of adamantane-type PPAPs with a 28,29epoxide moiety is not reliable due to the rotational freedom about the C-27/C-28 bond. A more reliable solution,144 examining the chemical shifts of C-27 and C-28, that was proposed in 2016 suggests the reassignment of the epoxide moiety’s configuration in hyperandrone A (272).68 • The homoadamantane-type PPAP, attenuatumione A,60 shares identical 1H and 13C NMR spectroscopic data to those of hypercohone A (333)158 but bears different relative configuration at C-18. Examination of their original NOESY spectra suggests that the C-18 relative configuration of attenuatumione A was incorrectly assigned and that it should possess the same relative structure with hypercohone A (333). Interestingly, hypersampsonone A (64) and another compound (its name, hypersampsone S, has been used and reserved for Lin’s isolate, 30288) with identical NMR data were reported almost simultaneously.53,76 However, opposite configurations

Scheme 4. Proposed Biosynthetic Pathways to Representative Spirocyclic and Complicated PPAPs

C-8, as in some endo BPAPs, such as guttiferone A, 2,16oxyguttiferone A (230), and 4,16-oxyguttiferone A (235).129,175 The difference in chemical shifts of the two H-6 atoms for guttiferone A, 230, and 235 indeed conform to the rule, but their chemical shifts of C-7 (39−42 ppm) do not match with endo BPAPs (45−49 ppm), which could be resulted from the prenylmethyl group’s participation ultimately leading to the conformational change of these molecules. Nevertheless, the C-8 prenylmethyl group in BPAPs was proposed to be trans to the C-7 prenyl group, as expected from the postulated mechanism of cyclization of MPAPs to BPAPs (C-8 prenylmethyl may adjust to be trans to the C-7 prenyl group to 3530


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4. CONSOLIDATION OF SOME PPAPS’ TRIVIAL NAMES Some PPAPs were isolated simultaneously by different groups working independently, who then gave the PPAP different names. The structures of adhyperfirin and garcinielliptone K were initially misassigned;31,32 later revision showed them to be identical to the already known hyperibine J (2)33 and propolone C (24).9,64 Furthermore, the structures of hyperibine J (2) and hyperpolyphyllirin,50,51 hypersampson R (88) and hyperattenin B,71,83 hypercohone F (107) and uralione H,57,86 guttiferone J (137) and garciyunnanin A,105,106 oblongifolin C (141) and (+)-guttiferone G,100,108 cowanone (160) and chamuangone,117,118 sampsonione P (196) and hyperscabrone L,55,59 hyperattenin E (199) and hyperibrin D,61,71 pyramidatone A (365) and chipericumin E,40,163 and hypelodin B (394)78 and hyphenrone L1 were reported repeatedly and given two different names. In the tables, we arrange these names according to the order of publication. On the contrary, some PPAPs were given the same name but had different structures. The original name of 136, guttiferone I,176 has been used in 2005 for another PPAP, so we rename 136 as 13-deoxy-guttiferone J.105 Also, the original names of 234 and 271 were reserved for earlier reported isolates, 132 (guttiferone O) and 126 (garcimultiflorone D),102,103 respectively, and new names were given to 234 (oxy-oblongifolin A)131 and 271 (isosampsonione J).148 Hypersampsone S, another name of hypersampsonone A (64),53,76 has been reserved for Lin’s isolate, 302.88 In addition, the names of 7 pairs of PPAPs with uncertain enantiomeric relationship mentioned above are all retained along with their optical rotations in the corresponding tables.

were assigned in the cyclohexane substituent, which remains to be further confirmed. 3.3. Investigation of the Absolute Configurations of Certain PPAPs

In the last 11 years, over 100 PPAPs’ absolute configurations have been determined by X-ray diffraction, comparison of their experimental and calculated ECDs, and synthetic methods. Zhu et al. established a useful method to determine the absolute configuration of C-1 for benzoyl-substituted adamantane/homoadamantane PPAPs by examining the Cotton effect around 330 nm (negative and positive Cotton effects, indicating the R and S configuration of C-1, respectively).149 Although ECD methods have been widely used to determine the absolute configuration of many PPAPs in recent years, especially for the BPAPs and adamantane- and homoadamantane-type PPAPs, this method needs to be used cautiously. The type B BPAPs hyperscabrone L (196) and hyperibrin D (199),55,61 two C-23 epimers isolated from the same plant (H. scabrum), possess identical experimental ECD, but opposite absolute configurations of C-1 and C-5 were assigned by quantum chemical computation. Comparison of the ECD of hyperscabrone L with those of other structures with known absolute configurations (such as oblongifolin X, 201119) and similar chromophores indicated that the computational process of hyperscabrone L must have gone wrong;55 so, we reassigned the absolute configuration of hyperscabrone L. In addition, the authors also used the calculated ECD method to determine the absolute configuration of hyperscabrone J (12),55 which bears a stereocenter (C-23) in a flexible side chain. However, this method may be not fessible to assign the absolute configuration of a stereocenter located far away from the chromophore, such as C-23 in 12. Some PPAPs have been isolated as racemic mixtures (406 and 407,167 409 and 410,167 411 and 412,167 414 and 415,167 417 and 418172), further chiral separations and quantum chemical computation methods revealed their absolute configurations. Moreover, seven pairs of isolatesscrobiculatone B (8)/ hyperscabrone K,55,56 guttiferone Q (160)/cowanone,116,117 garcicowin C (192)/garcinialiptone B,49,101 hyphenrone A (244)/ perforatumone,1,138 hypercohone A (333)/attenuatumione A,60,158 hypercohone C (342)/cowabenzophenone A,159,144 and cowabenzophenone B (344)/hyperattenin H71,159have been found to have the same relative stereochemistry but specific rotations opposite in sign, suggesting that they are enantiomers. However, optical rotations are notoriously sensitive to the presence of impurities, and more reliable evidence, such as X-ray diffraction and ECD data, is not available to support their enantiomeric relationships, so it is too early to judge whether they are enantiomers or homomers, especially for those with small optical values. Nevertheless, when a compound’s absolute configuration is known and the compound is isolated again from a different source, the new isolate’s specific rotation can reveal whether it is enantiomeric or homomeric to the original isolate, so we include each PPAP’s specific rotation in the tables. Kuo’s team has made the remarkable claim that they have successively isolated the enantiomeric PPAPs, (+)-garcinialiptone A (289) in June 2005, and (−)-garcinialiptone A, (+)-cycloxanthochymol, and (−)-cycloxanthochymol (172) in June 2007, from G. subelliptica collected from the same mountain, and that they were able to separate the enantiomers by HPLC without using any chiral HPLC columns.49 It is likely that either one of the plant materials was misidentified or the measured optical rotations of certain compounds were inaccurate.

5. LIVING DATABASE OF PPAPS One of the coauthors of the current paper (RBG) has created an online, freely accessible database of PPAPs that users can find at http://www.chem.uky.edu/research/grossman/PPAPs/. The database groups PPAPs according to the structure and stereochemistry of their cores, much like the tables in this review. Both this review and the database list each PPAP’s name(s), plant origin, reported optical rotation, and hyperlinks to the literature articles describing the determination of the PPAP’s structure, but the database also includes two-dimensional MOL representations, which users can copy and paste into their own structure-drawing programs. Furthermore, the database provides a simple sorting tool, which a user can use to display a subset of PPAPs that have particular structural characteristics. The database will be updated as new compounds are discovered and as the structures of already discovered compounds are revised as new information is acquired. Readers are encouraged to submit additions and corrections to RBG. 6. BIOLOGICAL ACTIVITIES OF PPAPS Significant progress has been made over the past decade in elucidating the biological activities of PPAPs. The pharmacologic activities and corresponding mechanisms of some promising PPAPs isolated before 2006, such as hyperforin, garcinol, nemorosone, 7-epi-clusianone, and guttiferone A, are summarized. Recent studies revealed a new molecular mechanism of hyperforin and its synthetic derivatives for regulating neurotransmitters by activating transient receptor potential channel 6 (TRPC6), and the antitumor mechanism of garcinol and its analogues has been studied in depth. The limitations of the 3531


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stores.18,191−193 Although there have been recent studies in the characterization of cellular responses to hyperforin, it remains unclear what pharmacological aspects of hyperforin functions are relevant in vivo.18 Nevertheless, hyperforin has been shown to have cognition-enhancing and memory-facilitating properties.15 It possesses neuroprotective effects against Alzheimer’s disease (AD) neuropathology, including the ability to disassemble amyloid-β (Aβ) aggregates in vitro, decrease astrogliosis and microglia activation, as well as improve spatial memory in vivo.15,194,195 Besides its antidepressant activity, hyperforin (422) also exerts potent anti-inflammatory effects.196,197 It is shown to be a novel type of 5-lipoxygenase inhibitor, apparently acting by interference with the C2-like domain,198 and induces Ca2+independent arachidonic acid release in human platelets by facilitating cytosolic phospholipase A2 activation through select phospholipid interactions.199 It also blocks several proinflammatory functions of leukocytes in vitro such as chemotaxis and chemoinvasion200,201 and downregulates effector functions of activated T lymphocytes.202 In microglia and macrophages, hyperforin is a modulator of inducible nitric oxide synthase and phagocytosis.203 In addition, it exerts protective effects by inhibiting multiple phosphorylation steps along the STAT1, NF-κB, and MAPK signaling pathways and consequent restriction of inflammatory and apoptotic gene expression in pancreatic β cells.204 In vivo, hyperforin impaired acute neutrophil recruitment and enhanced resolution in a pulmonary bleomycin-induced inflammation model reducing consequent fibrosis,201 and it suppressed carrageenan-induced rat pleurisy when given intraperitoneally.198 In addition, it was shown to inhibit microsomal prostaglandin E2 synthase-1 and suppress prostaglandin E2 formation in vivo.205 Meanwhile, recent studies have shown that hyperforin is a potential anticancer agent,206,207 especially in the treatment of chronic lymphoid leukemia (CLL) and acute myeloid leukemia (AML).16 Hyperforin targets molecules involved in signaling pathways that control leukemic cell proliferation, survival, apoptosis, migration, and angiogenesis.208−210 It can also downregulate the expression of P-glycoprotein, a protein that is involved in the resistance of leukemia cells to chemotherapeutic agents.211 In primary CLL cells, hyperforin stimulates the expression of the pro-apoptotic Noxa, a BH3-only protein of the Bcl-2 family.212,213 In AML cell lines and primary AML cells, it directly inhibits the kinase activity of the serine/threonine protein kinase B/AKT1, leading to activation of the pro-apoptotic Bcl-2 family protein Bad through its nonphosphorylation by AKT1.214 Despite these in vitro observations, further studies in vivo involving the evaluation of hyperforin’s therapeutic potential in CLL or AML are needed. Hyperforin (422) has been also shown to display antibacterial,207,215,216 antioxidant,217 antimalarial,218 larvicidal,219 and estrogenic220 activities in the time range of this review.197 Unfortunately, hyperforin’s chemical instability and poor solubility in aqueous solutions,10,16,17 its ability to increase expression levels of cytochrome P450 enzymes (particularly CYP3A4) by binding to the pregnane X receptor,221−227 and its other side effects228,229 limit its potential clinical application. Nevertheless, synthetic derivatives of hyperforin with increased stability and solubility (Figure 1), such as aristoforin (423), tetrahydrohyperforin (424, IDN5706), and octahydrohyperforin (425), have also recently been studied for their potential antidepressant and antitumor uses both in vitro and in vivo.10,16,17 Among these modified molecules, tetrahydrohyperforin has been shown to be

clinical application of the two most studied molecules (hyperforin and garcinol) are also evaluated. It has become obvious that the antineoplastic potential of type B PPAPs, especially for some recently isolated ones such as oblongifolin C and guttiferone K, is increasing significantly. In addition, many PPAPs have been reported to show anti-HIV, anti-inflammatory, antiplasmodial, and antimicrobial potential in recent years. 6.1. Biological Activities of Type A BPAPs

6.1.1. Hyperforin and Its Synthetic Derivatives. Hyperforin (422), present in great amounts in Hypericum perforatum (St. John’s wort), is the most famous molecule in the PPAP family (Figure 1).6,7 Substantial studies make clear that

Figure 1. Structures of hyperforin and its synthetic derivatives (422−425).

hyperforin is mainly responsible for the antidepressant effects of this medicinal plant.177,178 It has been described as an inhibitor of the reuptake of many neurotransmitters such as serotonin, dopamine, norepinephrine, L-glutamate, and γ-aminobutyric acid (GABA).15,179,180 In addition, it is also an antagonist of many receptors such as the N-methyl-D-aspartate (NMDA) receptor.15 To date, the molecular mechanisms underlying the modulation of neurotransmitter uptake by hyperforin mainly include its protonophoric properties and activation of transient receptor potential channel 6 (TRPC6).10,18 Recently, it has been discovered that hyperforin integrates the inhibition of neurotransmitter uptake and neurotrophism by specifically activating TRPC6, a Ca2+-conducting channel of the plasma membrane, without activating the other isoforms (TRPC1, TRPC3, TRPC4, TRPC5, and TRPC7). Due to this specific property, it is now used as a convenient pharmacological tool to investigate the functions and properties of native TRPC6 in various cell types.18,181−185 Leuner has shown that hyperforin induces neurite outgrowth in PC12 cells and spine morphology changes in CA1 and CA3 hippocampal neurons via activation of TRPC6,186,187 which was further mediated by several mechanisms comprising Ras, ERK, PI3K, and Ca2+/ calmodulin-dependent protein kinase IV (CAMKIV) activation, finally resulting in cAMP-dependent response element binding protein (CREB) phosphorylation.188 The cAMP-dependent protein kinase A and the transcription factor CREB triggered by hyperforin could increase the expression of the brain-derived neurotrophic factor (BDNF) receptor neurotrophic tyrosine kinase (TrkB) and TRPC6.189 However, some other researchers presume that the antidepressant activity is mediated by hyperforin-dependent indirect inhibition of transmitter reuptake and vesicular transmitter loading based on the protonophoric activity of hyperforin without activating TRPC6 channel.190 Further investigations are needed to clarify the interesting discrepancy that the antidepressant activity of hyperforin is dependent or independent of TPRC6.10 In fact, hyperforin (422) is a multitarget drug influencing the cellular homeostatic mechanisms of H+, Na+, Ca2+, and Zn2+ due to its effects on their influx and/or release from internal 3532


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a promising neuroprotective agent against AD.230−237 Further studies about the structure−activity relationship (SAR) of these modified molecules are urgently needed to enhance corresponding antidepressant or antitumor activity with simultaneously eliminating the therapy-limiting pregnane X receptordependent side effects. 6.1.2. Nemorosone and 7-epi-Nemorosone. Nemorosone (426), the major constituent of the floral resin of Clusia species and also present in Cuban propolis,29 has been described as a potent antimicrobial agent (Figure 2).238 In recent years,

Figure 3. Structures of garcinol (428) and its derivatives (429−431).

neck, breast, prostate, colon, hepatocellular, pancreatic, and leukemia.22 The anticarcinogenic properties of garcinol appear to be moderated via its antioxidative, anti-inflammatory, antiangiogenic, proliferation, and proapoptotic activities (Table 8).20,262,263 In addition, garcinol displays an effective epigenetic influence by inhibiting histone acetyltransferases (p300-HAT) and by possible post-transcriptional modulation via miRNA profiles involved in carcinogenesis.20,264,265 Despite its high potential as an antineoplastic modulator of several cancer types, garcinol (428) is still in the preclinical stage due to a lack of a systematic and conclusive evaluation of pharmacological parameters. Meanwhile, recent studies on its effectiveness in ameliorating other chronic diseases, such as cardiovascular diseases, diabetes, allergy, neurodegenerative diseases, etc.,286−289 are promising and require more detailed and in-depth investigations.22,290 Its cyclization product, isogarcinol (429), also exerts antiproliferative and proapoptotic effects on breast cancer cells through modulating different pathways.291,292 Cen’s investigation suggested that it could be a new immunosuppressant that binds directly to calcineurin in vitro, unlike the classical calcineurin inhibitors cyclosporin A and tacrolimus.293 In addition, the enantiomeric forms of garcinol and isogarcinol, guttiferone E (430)294,295 and isoxanthochymol (431),296 also showed promising anticancer activities (Figure 3). 6.2.2. Clusianone and 7-epi-Clusianone. Clusianone (432) and 7-epi-clusianone (433), a pair of C-7 epimers (Figure 4), were first isolated from different Clusia species,174 and recent investigations have shown their wide range of bioactivities. Clusianone induces HepG2 cell death by promoting the dissipation of rat liver mitochondrial membrane potential via a protonophoric uncoupling mechanism.297 In the assay of HIV-1 infection, both (+)- and (−)-clusianone exhibited potent inhibitory activity with IC50 values of 1.5 and 1.1 μM, respectively, in the 3T3 system.298 7-epi-Clusianone (433) showed good antimicrobial activity against Streptococcus mutans at low concentrations (MIC 1.25− 2.5 μg/mL),299,300 and it could be an agent to prevent and control dental caries disease.301 A further mechanistic study showed that it acts by inhibiting glucan synthesis, particularly those synthesized by glucosyltransferases C, and disrupting the development and acidogenicity of S. mutans biofilms.302 Up to 10 μM, 7-epi-clusianone induces an endothelium-dependent vasodilator effect in rat aortic rings, while at higher concentrations (higher than 10 μM) and in conditions where NO synthase was inhibited, it induces a vasocontractile effect.303 7-epi-Clusianone was shown to relax airway smooth muscle through activation of epithelium-, nitric oxide-, and cGMPdependent pathways.304 7-epi-Clusianone also showed potential antitumor,305−308 anti-inflammatory,309,310 antianaphylactic,311 and leishmanicidal312 activities. 6.2.3. Guttiferone A and Its Derivatives. Guttiferone A (434), initially obtained from Symphonia globulifera and

Figure 2. Structures of nemorosone (426) and 7-epi-nemorosone (427).

nemorosone has also been proven to show antitumor potential. It blocks proliferation and induces apoptosis in leukemia cells partly by targeting the Akt/PKB signal transducer, affecting protein levels and cell cycle progression.239 Low concentrations (0.03−1.0 μM) of nemorosone inhibited the cell viability of estrogen receptor positive (ERα+) MCF-7 human breast cancer cells.240 Further mechanistic study has shown that it induced discrete cell cycle arrest in the G1 phase and significant depletion in the G2 phase and altered the expression of genes linked to the cell cycle, apoptosis, and hormone receptors.241 Nemorosone also affects the cell cycle and unfolded protein response (UPR) regulatory pathways in pancreatic cancer cells but not in fibroblasts.242 It exerts antiproliferative activity in neuroblastoma cells possibly via inhibition of upstream kinase MEK1/2 and targeting Akt/PKB kinase.243 In addition, nemorosone was suggested to be a potent protonophoric mitochondrial uncoupler, which is potentially involved in its toxicity on cancer cells.244 Meanwhile, its isomer, 7-epi-nemorosone (427), was also found to be a potent antilentiviral agent in the employed system, inhibiting viral infection at concentrations below 1 μM.245 It also exerts cytotoxicity in an androgen-dependent prostate carcinoma entity by targeting the MEK1/2 signal transducer.246 6.1.3. Garcinielliptone FC. Garcinielliptone FC (5) was obtained from G. subelliptica and Platonia insignis and identified as a type A structure.48,52 It has been shown to be an antitumor,247−249 antioxidant,48,52,250 and antiparasitic247,251 agent. It also decreases the frequency of pilocarpine-induced seizures and increases survival rate in mice,252 and it promotes a vasorelaxant effect on rat mesenteric artery.253 An acute toxicity study indicated that it was well tolerated in animals, suggesting that it is safe for further investigation.254 6.2. Biological Activities of Type B BPAPs

6.2.1. Garcinol and Its Derivatives. Garcinol (428), obtained from Garcinia indica and several other Garcinia plants (Figure 3),255 was shown to be an antibacterial and antioxidant agent in earlier studies.8,19,256 Recent investigations have revealed that garcinol has excellent cytotoxicity and antitumorigenesis activities.20−22,257−261 It has been found to be an effective inhibitor of various key signaling pathways, such as NF-κB and STAT3, in cancer cells (Table 8). In vitro as well as some in vivo studies have shown the potential of garcinol in controlling malignant growth of several cancer types including head and 3533


breast, colon, HCC, leukemia, lung, pancreatic

Figure 4. Structures of clusianone (432) and 7-epi-clusianone (433).

inhibition of proliferation and inflammation; induction of apoptosis; radiosensitization; suppression of oncogenic properties

G. livingstonei in 1992, is a type B structure bearing a prenylmethyl group at C-8 (Figure 5).175 The biologic studies of guttiferone A (434) investigated antitumor,313 antimicrobial,238 antiparasitic,314 and neuroprotective315,316 properties. More importantly, guttiferone A was able to inhibit or increase silent information regulator 1 (SIRT1) catalytic activity, depending on protein concentration and presence of detergent.317 Unfortunately, though, guttiferone A produced genotoxic effects in leukocytes, liver, bone marrow, brain, and testicle cells of mice.318 Its derivatives, guttiferone F (435) and xanthochymol (436) (Figure 5),294,295,319 also showed promising anticancer

upregulation: P21Waf1/Cip1 downregulation: the nicotinic receptor, cyclin D3, NHEJ, PGE2, 5-LO, COX, survivin, Bcl-2, XIAP, cFLIP, Bid, Notch1, Mcl-1, EZH2, ABCG2, Gli-1 upregulation: DR4, DR5, GADD153, Bax, cytosolic cytochrome c, tBid, caspase-3, caspase-8, caspase-9, PARP, DFF-45, miR-200c

Figure 5. Structures of guttiferone A (434), guttiferone F (435), and xanthochymol (436).

activities, and further SAR, toxicological, and metabolic studies of these agents are required. 6.2.4. Oblongifolin C and Guttiferone K. Oblongifolin C (141), also known as (+)-guttiferone G, was first isolated from the bark of Garcinia oblongifolia100 and was later found to be present in a greater amount in the pericarp of G. yunnanensis.106 Oblongifolin C was found to exhibit inhibitory activity against a wide spectrum of cancer cell lines,98,101,106,320,321 with IC50 values less than 1.5 nM in SW620 colon cancer cell line.321 Recent investigations have revealed that oblongifolin C significantly inhibits tumor proliferation and metastasis320,322 and promotes apoptosis320,323,324 by modulating different pathways, indicating its therapeutic potential in several solid tumors. Moreover, oblongifolin C is found to be a novel autophagic flux inhibitor and might be useful in anticancer therapy.323,325 Oblongifolin C not only triggers DNA double-strand breaks and DNA damage response but also inhibits repair of DNA damage, suggesting its use to treat apoptosis-efficient tumors.326 In addition, oblongifolin C is an inhibitor of human silent information regulator 1 and 2 (SIRT1 and SIRT2), with SIRT1 being more greatly affected than SIRT2.108 Therefore, it may be a valuable tool in the area of epigenetics and could also be used to reveal the biological role of sirtuins in processes such as cancer, neurodegenerative diseases, and diabetes.108,327 Oblongifolin C was also shown to inhibit allergic inflammation through the suppression of mast cell activation.328 However, metabolic research of oblongifolin C suggested that it is a broad inhibitor of UDP-glucuronosyltransferase isoforms in human liver and intestine microsomes, indicating a potential side effect of drug−drug interactions.329

others, such as Notch1, p-mTOR, 5-LO, NHEJ279−285

colon, skin lung, skin inhibition of inflammation inhibition of proliferation and inflammation upregulation: E-cadherin, miR-200, let-7s downregulation: cyclin D1, VEGF, iNOS, COX-2 downregulation: iNOS, COX-2

downregulation: vimentin, ZEB-1, ZEB-2, β-catenin, COX-2, cyclin D1, VEGF

inhibition of STAT3 signaling pathway271,276,277 downregulation of Wnt signaling pathway275,278

inhibition of PI3K/Akt267,278 dwonregulation of MAPK signaling260,267

breast, HCC, HNSCC, pancreatic, prostate breast, colon

Review

inhibition of proliferation; induction of apoptosis; inhibition of the invasive capacity of cancer cells reversal of EMT phenotype; inhibition of inflammation

types of cancer function

inhibition of inflammation, proliferation, angiogenesis, cell cycle progression; induction of apoptosis; reversal of EMT phenotype

downstream targets/related molecules

downregulation: vimentin, ZEB-1, ZEB-2, β-catenin, cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1, VEGF, iNOS, COX-2, MMP-9, IL-8, PGE 2, XIAP cIAP, proliferative biomarkers (Ki-67, CD31) upregulation: E-cadherin, miR-200, let-7s, cleaved PARP, cleaved caspases-3 and -9 downregulation: uPA, VEGF, MMP-9, cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1, VEGF

cellular pathways

suppression of NF-κB signaling pathway266−275

Table 8. Summary of Different Cellular Pathways Regulated by Garcinol

breast, HNSCC, oral, pancreatic, prostate, skin

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7.1. Shibasaki’s Total Syntheses of ent-Hyperforin and Garsubellin A

Guttiferone K (138) was first obtained from the fruits of Rheedia calcicola107 and was later coisolated with oblongifolin C from G. yunnanensis and G. cowa.101,106 It shows similar antitumor activities to oblongifolin C by activating apoptosis, arresting the cell cycle, and promoting autophagy.266,324,330,331 Guttiferone K effectively suppresses the motility and metastasis of hepatocellular carcinoma cells mainly by restoration of aberrantly reduced PFN1 protein expression.332

As mentioned above, the first total synthesis of (±)-garsubellin A (446) was achieved by Shibasaki and co-workers in 2005.335 The synthesis began with the preparation of enone 438 from commercially available 437 (Scheme 5). The keys for success are the stereo- and regioselective introduction of the C-5 vinyl group from 439 to 440 via aldol condensation, the stereoselective allylation at C-1 of 441 via Claisen rearrangement to afford 442, and further ring-closing metathesis for construction of the bicyclo[3.3.1]nonane system of 444 in the presence of the Hoveyda−Grubbs catalyst 443. Finally, bridged bicycle 444 was successfully transformed into (±)-garsubellin A (446) in seven steps via a key intermediate 445. The authors further demonstrated that enantiomerically enriched cyclohexenone 438 could be prepared using the asymmetric alkylation method, thus paving the way for an asymmetric synthesis of garsubellin A.335 The first catalytic asymmetric total synthesis of hyperforin (422) was also accomplished by Shibasaki’s research group in 2010,336,337 nearly 30 years after its initial isolation, standing as the most recognizable achievement (Scheme 6). Their synthesis began with an asymmetric Diels−Alder reaction between TIPS enol ether 447 (diene) and the oxazolidinone acrylamide derivative 448 (dienophile), promoted by cationic iron−pybox complex 449, to produce substituted cyclohexane 450 with contiguous C-7 and C-8 stereocenters in excellent yield and isomeric purity (96% ee, dr > 33:1). The thermal Claisen rearrangement of allyl enol ether 451 proceeded with remarkable efficiency (>99% yield) and high diastereoselectivity (dr = 12:1) to afford 452 bearing the bridgehead quaternary carbon (C-1).338 The key bicyclic intermediate 454 was synthesized uneventfully from 452 through a selective hydroboration at the terminal olefin using (Sia)2BH, Dess−Martin oxidation, intramolecular aldol cyclization of resulting aldehyde 453, and oxidation. Under their optimized conditions and using the bulky base 2,6-ditert-butylpyridine, a vinylogous Pummerer rearrangement of allylic sulfoxide 455 took place preferentially to the normal Pummerer rearrangement (4:1) and smoothly provided allylic alcohol 456 in 65% yield. A palladium-promoted Claisen rearrangement of 457 presumably proceeded through the intermediacy of a π-allyl−palladium species, with the resulting enolizable 1,3-diketone temporarily masked as its enol acetate 458 in 50% yield. Finally, cross-metathesis to introduce the prenyl group at C-3 and methanolysis of the acetate under basic conditions completed the total synthesis of ent-hyperforin (422), the antipode of the naturally occurring substance, as confirmed by optical rotation measurements. The authors claim that these basic methods are also applicable to the asymmetric synthesis of other PPAPs and analogues of hyperforin.24,336,337

6.3. Biological Activities of Other PPAPs

Besides garcinielliptone FC (5), oblongifolin C (141), and guttiferone K (138), the biological activities of the other PPAPs reported since 2006 are summarized below. PPAPs possessing cytotoxicities and other activities at the cellular level are listed in Tables 9 and 10, respectively. Hyperibrins C (16) and D (199), hypermongone D (27) and G (43), and hyperscabrones D (111), E (200), F (213), and G (98), isolated from H. scabrum, exhibited neuroprotective effects on glutamate-induced toxicity in SK-N-SH cells at 10 μM.35,61 Uralodins A (68), B (51), and C (42) and uraliones A−E (9, 13, 11, 14, and 78) and H−J (107, 108, and 106) from H. uralum showed potent protective effects against corticosterone-induced injury in PC12 cells within the concentration range tested (0.1−10.0 μM).57 Uralodin A (68), orally administered in doses of 13 and 26 mg/kg, exhibited antidepressant-like activity in tail suspension and forced swimming tests in mice.57 Hyperibrins C (16) and D (199), hypermongone H (53), and hyperscabrones C (110), D (111), G (98), K (8), and M (77) showed moderate hepatoprotective activities against paracetamol-induced HepG2 cell damage at 10 μM.35,55,61 Oblongifolin M (170), isolated from G. oblongifolia, potently inhibits enterovirus 71 reproduction through downregulation of ERp57.333 Dioxasampsone B (308) and hypersampsone N (312), obtained from H. sampsonii, showed mild RXRα transcriptional inhibitory activities in a dose-dependent manner (5−20 μM).83,153 (+)-Garmultin C (409), (−)-garmultin C (410), and (+)-garmultin D (414) from G. multif lora were shown to be capable of inhibiting oncogene (Fli-1) expression and inducing apoptosis in human erythroleukemia cells.167 Garcimultiflorone I (218) exhibited anticancer activity targeting the cell cycle through apoptosis signaling pathways.99 Garcimulin B (419) at 20 μM exhibited strong suppression of lysosomal acidification in HeLa cells.172

7. SYNTHETIC CHEMISTRY OF PPAPS With their fascinating biological profiles and intriguing complex molecular architectures, PPAPs have long provided a fertile playing field for synthetic organic chemists.24 The recent appearances of innovative synthetic methods and strategies together with asymmetric catalysis have vitalized this field tremendously.23−25 Although many synthetic efforts had been made in earlier period, it was not until 2005 that the first synthesis of a PPAP, namely, garsubellin A, was realized.335 Now, a total of 22 natural PPAPs have been successfully synthesized, of which hyperforin, nemorosone, clusianone, and garsubellin A are the most common targets. In particular, the recent remarkable contributions from the research groups of Plietker, Porco, Jr., and Maimone ushered in a peak period of PPAPs synthesis. This review aims to highlight the recent achievements in the total synthesis of PPAPs as well as notable methods developed for construction of the core structures of these molecules.

7.2. Shair’s Enantioselective Total Syntheses of (+)-Hyperforin and (−)-Nemorosone

Shair and co-workers reported a modular, 18-step enantioselective total synthesis of (+)-hyperforin, starting from geraniol.339 As shown in Scheme 7, the key intermediate 465 possessing a bicyclo[3.3.1]nonane core with C-7 and C-8 quaternary stereocenters was accessed from cyclohexadiene 463 via a groupselective, Lewis acid-mediated epoxide-opening cyclization. Cyclohexadiene 463 would be synthesized in two steps through the regioselective coupling of 1,5-dimethoxy-1,4-cyclohexadiene 461 with prenyl chloride and epoxygeranyl bromide 460. Exposure of 463 to TMSOTf and 2,6-lutidine via a favored chair transition state 464 gave the ketal 465 in 79% yield as the 3535


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Table 9. Cytotoxicity of Selected PPAPs compounds

cell lines

garcinialiptone D (1)49

attenuatumione H (10)58 garcinialiptone C (17)49

63

hyperforatin I (48) dihroxuralodin (52)74 hyperforatin F (69)63 hyphenrone X (80)81 hypercohin B (84)67 hypercohin C (85)67 hypercohin D (86)67

hyperattenin A (87)71 attenuatumione C (89)60 hyperisampsin J (93)84

hyperisampsin K (94)

a

84

hyperisampsin L (95) hyperisampsin M (96)

hyphenrone U (104)81 hyphenrone E (105)85 13-deoxy-guttiferone J (136)105 guttiferone J (137)105 guttiferone K (138)101,107,321

oblongifolin C (141)101,321

Table 9. continued IC50 values

A549 human lung carcinoma DU145 prostate cancer KB nasopharyngeal carcinoma KBvin (vincristine-resistant KB subline) HepG2 human hepatocellular carcinoma A549 human lung carcinoma DU145 prostate cancer KB nasopharyngeal carcinoma KBvin (vincristine-resistant KB subline) SMMC7721 human hepatocarcinoma MCF-7 human breast adenocarcinoma SMMC7721 human hepatocarcinoma HL-60 acute myeloid leukemia MCF-7 human breast adenocarcinoma HL-60 acute myeloid leukemia SMMC-7721 human hepatocarcinoma SW480 human colon cancer HL-60 acute myeloid leukemia SMMC-7721 human hepatocarcinoma A-549 human lung carcinoma MCF-7 breast adenocarcinoma SW480 human colon cancer HL-60 acute myeloid leukemia SMMC-7721 human hepatocarcinoma MCF-7 human breast adenocarcinoma HL-60 acute myeloid leukemia SMMC-7721 human hepatocarcinoma A-549 human lung carcinoma MCF-7 human breast adenocarcinoma SW480 human colon cancer BEAS-2B human bronchial epithelial cells NB4 acute myeloid leukemia HL-60 acute myeloid leukemia SMMC-7721 human hepatocarcinoma A-549 human lung carcinoma MCF-7 human breast adenocarcinoma SW480 human colon cancer BEAS-2B human bronchial epithelial cells HL-60 acute myeloid leukemia HL-60 acute myeloid leukemia SMMC-7721 human hepatocarcinoma A-549 human lung carcinoma MCF-7 human breast adenocarcinoma SW480 human colon cancer BEAS-2B human bronchial epithelial cells HL-60 acute myeloid leukemia MCF-7 human breast adenocarcinoma HL-60 acute myeloid leukemia KB nasopharyngeal carcinoma

4.4 μM 3.3 μM 3.9 μM 4.6 μM 9.1 μM 4.3 μM 4.3 μM 3.4 μM 4.9 μM 9.1 μM 8.9 μM 10.0 μM 4.3 μM 2.1 μM 5.8 μM 8.2 μM 9.2 μM 8.8 μM 9.5 μM 5.6 μM 9.3 μM 7.4 μM 9.6 μM 9.9 μM 5.7 μM 0.56 μM 0.58 μM 0.53 μM 0.88 μM 2.5 μM 1.5 μM

KB nasopharyngeal carcinoma SW620 human colon cancer

8.5 μM 0.0017 μM

BT474 human breast cancer HepG2 human hepatocellular carcinoma KATO-III human gastric cancer CHaGo human lung cancer HeLa human cervical carcinoma A2780 human ovarian carcinoma HT-29 human colon adenocarcinoma SW620 human colon cancer

9.9 μM 0.13 μM 0.13 μM 0.10 μM 9.7 μM 6.0 μM 5.4 μM 20:1). Successful completion of the total synthesis also served to confirm the absolute configuration of the naturally occurring substance.374 7.9.2. Plukenetione A and 7-epi-Nemorosone. As an extension of their synthetic studies toward the PPAPs through an alkylative dearomatization−annulation strategy, they later demonstrated an acid-mediated site-selective alkylation that allows facile access to the type A adamantane PPAP plukenetione A (583), a regioisomer of hyperibone K (575) (Scheme 19).376 Scheme 19. Porco’s Total Syntheses of Plukenetione A and 7-epi-Nemorosone

In this context, protected acylphloroglucinol methyl ether 576 was employed with the intention that the alkylative dearomatization would take place at the C-1 and C-5 positions 3544


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Scheme 20. Porco’s Asymmetric Syntheses of (−)-Clusianone and Non-natural PPAPs

Scheme 22. George’s Biomimetic Syntheses of Ialibinones A and B

in 58% yield (1:1) via a selective radical cascade reaction to install the bicyclo[3.2.1]octane ring system.381 Using a similar strategy, George et al. also provided four-step syntheses of the highly complex PPAPs (+)-garcibracteatone (392) and (±)-doitunggarcinone A (393) (Scheme 23). The key Scheme 23. George’s Biomimetic Syntheses of Garcibracteatone and Doitunggarcinone A

and a dearomative conjunctive allylic alkylation (DCAA) (Scheme 21).380 Scheme 21. Porco’s Synthesis Approach to PPAPs Using Double-DcA/Claisen Rearrangement and DCAA biomimetic transformation is a cascade of 7-endo-trig and 5-exo-trig radical cyclizations followed by a terminating aromatic substitution reaction.166,169 The synthesis of doitunggarcinone A (393) confirmed its C-5 relative configuration and also led to a structural revision for doitunggarcinone A (393) and its biosynthetic precursor doitunggarcinone B (402).166,169 The success of the strategy highlights the power of biomimetic synthesis as applied to the rapid generation of molecular complexity. Furthermore, the efficiency and inherent selectivity of the radical cascade reactions strongly suggest that a similar process is involved in the biosynthesis of the natural products.166,169 In addition to total synthesis studies of PPAPs, other teams such as Couladouros,383,384 Marazano,385−387 Mehta,388−394 Takagi,395,396 and Chen,397 et al., have also made efforts to develop synthetic methodologies and strategies toward construction of the bicyclo[3.3.1]nonane core of these complicated natural products.398−402 This work has been summarized in other reviews and hence is not elaborated in detail here.23−25

7.10. Biomimetic Syntheses of PPAPs Using Radical Cyclization

George’s research group accomplished the biomimetic syntheses of four PPAPs, ialibinones A and B,381 garcibracteatone (392), and doitunggarcinone A (393) in 4 steps,166,169 using a key radical cyclization reaction of MPAPs (Schemes 22 and 23). Independently, Simpkins and co-workers also reported similar biomimetic syntheses of ialibinones A and B in 2010 through a Mn(OAc)3-mediated domino radical cyclization.382 As shown in Scheme 22, the proposed biosynthetic precursor 600 was synthesized from phloroglucinol (598) via acylphloroglucinol 599 in three steps. Oxidative radical cyclization of 600 with PhI(OAc)2 gave (±)-ialibinones A (601) and B (602)

8. SUMMARY AND FUTURE DIRECTIONS In summary, this review presents general insight into the chemistry and biological activities of PPAPs in the past 11 years. As chemists discover and report new PPAPs and as they correct errors in the literature, we will update the online database in real time. Our hope is that the tables will serve as a continuing resource both for natural products chemists and for 3545


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synthetic chemists looking both to clarify structural assignments and to prepare new compounds. The presence of multiple prenyl groups and the derived complex ring systems in the diverse structures of PPAPs are distinctive among plant secondary metabolites. Generally, polyketide and prenylation synthases are widespread in plants and often coexist in certain species, as evidenced by the presence of natural prenylated flavones and xanthones. Notably, complex PPAPs are hitherto restricted to plants in the family Guttiferae, which indicated the prenyltransferase in these plants should possess high activity and selectivity. Furthermore, the intriguing structures of PPAPs and their biogenetic relationship also suggest there are complex postmodification processes including oxidation, rearrangement, and cyclization in plants. Only a few studies on the biosynthesis of PPAPs were reported before 2007; more in-depth research is still needed to elucidate the interesting biosynthetic pathway of this special group of metabolites. Systematic SAR evaluation of pharmacological parameters, especially in vivo studies using suitable higher animal species, are urgently demanded so that the limitations of the clinical application of some promising molecules, such as garcinol, oblongifolin C, and hyperforin’s synthetic derivatives, can be overcome. Moreover, more investigations into the bioactivities and corresponding molecular mechanisms of other types of PPAPs (besides BPAPs) are also needed. In the aspect of organic synthesis, these complex and fascinating chemical structures of PPAPs continue to be a challenging task for chemists, although much progress has been made in recent years. The currently accomplished molecules are mainly type A and B BPAPs with a bicyclo[3.3.1]nonane core, and only total syntheses of two adamantane-type PPAPs, plukenetione A and hyperibone K, and the biomimetic syntheses of four PPAPs using radical cyclization strategy have been achieved. The total syntheses of other PPAPs including adamantane/homoadamantane and spirocyclic types, as well as some structurally complex PPAPs with unprecedented carbon skeletons reported in recent years remain to be achieved.

Plant Resources in West China, Kunming Institute of Botany, CAS. His research interests include the structures and bioactivities of natural PPAPs and other secondary metabolites in traditional Chinese medicines. Robert B. Grossman, a native of Long Island, NY, earned his A.B. degree at Princeton University, where he carried out research under the direction of Robert A. Pascal. After graduating in 1987, he moved to MIT and worked under the direction of Stephen L. Buchwald to develop zirconium- and titanium-mediated and -catalyzed organic synthetic methodology. He earned his Ph.D. degree in 1992 and moved from Steve’s lab in Cambridge, MA, to Steve’s lab in Cambridge, England, where he worked in the Ley group on various aspects of the chemistry of azadirachtin. In 1994 he left the United Kingdom to join the faculty at the University of Kentucky in Lexington, KY. His research interests are currently focused on synthetic methodology, total synthesis, and biosynthetic pathways. He is the author of The Art of Writing Reasonable Organic Reaction Mechanisms, 2nd ed. (Springer, 2002), and one of the cocreators of ACE Organic, a Web-based organic chemistry homework program that provides response-specific feedback to structures drawn by students. Gang Xu is a professor of natural products chemistry at the State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, CAS. He received his Ph.D. degree in Phytochemistry from the Kunming Institute of Botany, CAS (2005). He worked at the Chinese Medicine Laboratory, Hong Kong Jockey Club Institute of Chinese Medicine (2007). His interests focus on the systematic chemical studies of natural PPAPs as well as research of the exploration and utilization of traditional medicinal herbs in the west of China.

ACKNOWLEDGMENTS The work was financially supported by the Natural Sciences Foundation of Yunnan Province (No. 2015FA032, 2016FB017), foundation from the Youth Innovation Promotion Association CAS to X.W.Y. (No. 2016350), and foundation from Kunming Institute of Botany (KIB2017001). The authors thank Prof. Hong-Xi Xu, Drs. Juan Huang and Liang-Qun Li, and Mr. YaoTao Duan for their valuable suggestions during the preparation of this review. Thanks also to Dr. Helen Jacobs for her contributions to this project.

ASSOCIATED CONTENT S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemrev.7b00551. Complete author list of references with more than 10 authors (PDF)

REFERENCES (1) Yang, X.-W.; Li, M.-M.; Liu, X.; Ferreira, D.; Ding, Y.; Zhang, J.J.; Liao, Y.; Qin, H.-B.; Xu, G. Polycyclic Polyprenylated Acylphloroglucinol Congeners Possessing Diverse Structures from. J. Nat. Prod. 2015, 78, 885−895. (2) Adam, P.; Arigoni, D.; Bacher, A.; Eisenreich, W. Biosynthesis of Hyperforin in. J. Med. Chem. 2002, 45, 4786−4793. (3) Boubakir, Z.; Beuerle, T.; Liu, B.; Beerhues, L. The First Prenylation Step in Hyperforin Biosynthesis. Phytochemistry 2005, 66, 51−57. (4) Klingauf, P.; Beuerle, T.; Mellenthin, A.; El-Moghazy, S. A. M.; Boubakir, Z.; Beerhues, L. Biosynthesis of the Hyperforin Skeleton in Hypericum calycinum Cell Cultures. Phytochemistry 2005, 66, 139−145. (5) Karppinen, K.; Hokkanen, J.; Tolonen, A.; Mattila, S.; Hohtola, A. Biosynthesis of Hyperforin and Adhyperforin from Amino Acid Precursors in Shoot Cultures of. Phytochemistry 2007, 68, 1038−1045. (6) Gurevich, A. I.; Dobrynin, V. N.; Kolosov, M. N.; Popravko, S. A.; Ryabova, I. D.; Chernov, B. K.; Derbentseva, N. A.; Aizenman, B. E.; Garagulya, A. D. Hyperforin, an Antibiotic from Hypericum perforatum. Antibiotiki 1971, 16, 510−513. (7) Bystrov, N. S.; Chernov, B. K.; Dobrynin, V. N.; Kolosov, M. N. The Structure of Hyperforin. Tetrahedron Lett. 1975, 16, 2791−2794.

AUTHOR INFORMATION Corresponding Author

*Phone/Fax: (86) 871-65217971. E-mail: xugang008@mail. kib.ac.cn. ORCID

Xing-Wei Yang: 0000-0002-9578-2986 Gang Xu: 0000-0001-7561-104X Notes

The authors declare no competing financial interest. Biographies Xing-Wei Yang was born in Sichuan province, China, in 1985. He received his Ph.D. degree in Pharmaceutical Chemistry from the University of Chinese Academy of Sciences in 2015. Now he is an associate professor in the State Key Laboratory of Phytochemistry and 3546


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NOTE ADDED AFTER ASAP PUBLICATION This paper was published ASAP on February 20, 2018 with an error in the first bullet in section 3.2 and Table 1. The corrected version reposted to the Web on March 12, 2018.

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