Structural Diversity and Biological Activities of Indole Diketopiperazine

Review pubs.acs.org/JAFC

Structural Diversity and Biological Activities of Indole Diketopiperazine Alkaloids from Fungi Yang-Min Ma,* Xi-Ai Liang, Yang Kong, and Bin Jia Key Laboratory of Auxiliary Chemistry & Technology for Chemical Industry, Ministry of Education, Shaanxi University of Science & Technology, Xi’an 710021, Shaanxi, China ABSTRACT: Indole diketopiperazine alkaloids are secondary metabolites of microorganisms that are widely distributed in filamentous fungi, especially in the genera Aspergillus and Penicillium of the phylum Ascomycota or sac fungi. These alkaloids represent a group of natural products characterized by diversity in both chemical structures and biological activities. This review aims to summarize 166 indole diketopiperazine alkaloids from fungi published from 1944 to mid-2015. The emphasis is on diverse chemical structures within these alkaloids and their relevant biological activities. The aim is to assess which of these compounds merit further study for purposes of drug development. KEYWORDS: indole diketopiperazine alkaloids, structural diversity, biological activity, natural product, fungi

1. INTRODUCTION Indole diketopiperazine alkaloids are metabolic products of microbes. They are commonly isolated from fungi, such as Aspergillus, Penicillium, Pestalotiopsis, and Chromocleista, especially from the genera Aspergillus and Penicillium.1 Interest in indole diketopiperazines is due to their significant biological activities such as antimicrobial, antiviral,2−6 anticancer,7−15 immunomodulatory,16,17 antioxidant,18 and insecticidal activities.19 Therefore, they may have the potential to be used in drugs and/or serve as lead structures for drug development. Indole diketopiperazine alkaloids are characterized by certain products of condensation, including a complete tryptophan and a second amino acid such as L-tryptophan, L-proline, Lphenylalanine, L-histidine, or L-leucine, forming an indole diketopiperazine unit. Reported in the early 1940s, the indole diketopiperazine chaetomin was the first of these alkaloids explored in research; in that work it was isolated from the fungus Chaetomium cochliodes.20 Since then, other indole diketopiperazine alkaloids have been successfully isolated and characterized. Through the end of the 20th century, the study of activities in the biological metabolic process attracted increasing interest in the scientific community as researchers worked to study and develop compounds of interest in the pharmaceutical industry. For this reason, many synthetic and isolated strategies have been developed for working with indole diketopiperazines. Therefore, the emphasis of this review is on the structural characteristics and biological activities of indole diketopiperazine alkaloids isolated from various fungal strains.

dipeptide brevianamide F 1 is the common precursor of these compounds. It was first isolated from P. piscarium (near Moscow, Russia) by Vinokurova’s research team in 2000.15 On the basis of this research it was reported that brevianamide F 1 was a new type of natural potential plant growth inhibitor. Three years later it was identified in A. clavatus and A. ochraceus (soils, Russia).21 P. piscarium yielded dehydropropyltryptophanyldiketopiperazine 2.15 Notoamides 3−11 were isolated from a marine-derived Aspergillus sp. (Mytilus edulis, Noto peninsula, Ishikawa, Japan). Compounds 4−11 are diprenylated compounds derived from cyclo-L-tryptophan-L-proline. One of the prenyl residues was found at position C2 or C3. The second prenyl moiety is the dimethyldihydropyran ring.22−25 Notoamide K 10 showed weak activity against HeLa cells (human cervical cancer cell) with an IC50 value of >50 μg mL−1.8 It should be mentioned that notoamide P 11 is the first brominated compound in the prenylated indole diketopiperazine alkaloids.25 Tryprostatins A 12 and B 13 were inhibitors of microtubule assembly and obtained from A. fumigatus (sea sediment, Sizuoka, Japan; Lingshan Island, Shandong, China) and A. tamarii (Ficus carica, Shaanxi, China).9,26−31 They had antiphytopathogenic activity30 and could inhibit tumor cell cycle at the G2/M phase with IC50 values of 16.4 and 4.4 μmol L−1, respectively.29 Tryprostatin B 13 with a regular prenyl moiety at position C2 is a key biosynthetic intermediate of tryprostatin A 12. 18-Oxotryprostatin A 14 from the fungus A. sydowi (Baishamen shore, Hainan, China) showed cytotoxic activity against A-549 cells (lung cancer cells) with an IC50 value of 1.28 μmol L−1.26 Cyclo-(N-benzyl-Trp-Pro) 15 is a benzene ring connected to the diketopiperazine ring consisting of Ltryptophan and L-proline. It was first chemically synthesized in 200032 and was subsequently isolated from the endophytic

2. MONOINDOLE DIKETOPIPERAZINE Indole diketopiperazine alkaloids of this category are commonly derived from L-tryptophan and L-proline or from L-tryptophan and L-alanine. They were isolated from various fungal strains. 2.1. Derivatives of Indole Diketopiperazine Containing L-Proline and L-Tryptophan. There is a large group of indole diketopiperazine alkaloids derived from L-tryptophan and L-proline in fungal natural products (Chart 1). The cyclic © 2016 American Chemical Society

Received: Revised: Accepted: Published: 6659

May 19, 2016 August 16, 2016 August 19, 2016 August 19, 2016 DOI: 10.1021/acs.jafc.6b01772 J. Agric. Food Chem. 2016, 64, 6659−6671

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Journal of Agricultural and Food Chemistry Chart 1. Derivatives of Indole Diketopiperazine Containing L-Tryptophan and L-Proline (1−54)

fungus A. tamarii (F. carica, Shaanxi, China) by Ma’s group. It was reported to exhibit antibacterial activity and was isolated from a natural source for the first time in 2012.30,33 Cui et al. isolated cyclotryprostatins A−D 16−19 from A. fumigatus (sea mud, Japan) in 1997.34 This was the first time

cyclotryprostatins A−D 16−19 were isolated from a natural source. In 2012, Ma’s group obtained cyclotryprostatin B 17 from an endophytic fungus A. tamarii (F. carica, Shaanxi, China).30 It was reported that four compounds could inhibit the cell cycle progression of tsFT210 cells at the G2/M phase 6660

DOI: 10.1021/acs.jafc.6b01772 J. Agric. Food Chem. 2016, 64, 6659−6671

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Journal of Agricultural and Food Chemistry Chart 2. Derivatives of Indole Diketopiperazine Containing L-Tryptophan and L-Alanine (55−92)

with IC50 values of 5.6, 19.5, 23.4, and 25.3 μmol L−1, respectively.34 Compounds 20−22 were isolated from A. fumigatus from holothurian Stichopus japonicus (Lingshan Island, Shandong, China). They displayed significantly cytotoxic activity against MOLT-4, A-549, and HL-60 cells. It is speculated that this cytotoxic activity may be linked to hydroxyl groups in the side chains.9 Fumitremorgin B 23 was first isolated from A. fumigatus by Yamazaki et al. in 197135 and was later isolated from different Penicillium, Aspergillus, and Neosartoria strains;27,30,36−42 it was

shown that these alkaloids could cause DNA damage in Salmonella spp. and in human lymphocytes.43 In 1986, 13-oxofumitremorgin B 24 was reported to be an intermediate in the synthesis of fumitremorgin B 24.44 This compound was isolated for the first time from the ascomycete Sordaria gondaensis in 200045 and then from the holothurianderived A. fumigatus in 2008.10 Verruculogen 25, containing a peroxide bridge, was obtained from P. paraherquei, P. verruculosum, P. piscarium, P. janthinellum, and P. estinogenum as well as A. fumigatus and A. caespitosus.27,39,40,46−52 It was found that this compound can 6661


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Journal of Agricultural and Food Chemistry

ation inhibitor neoechinulin A 56 was isolated from P. griseofulvum and Aspergillus sp. (the marine red alga Lomentaria catenata, Ulsan City, Korea)4,76 and showed significant cytotoxic activity against P388 cells.4,18 Echinulin 57 was first obtained from A. amstelodami and was subsequently isolated from different Aspergillus sp. and P. griseofulvum.3,4,77−81 It was also found in different members of the Orchidaceae, Cucurbitaceae, and Anacardiaceae plant families.82 Compounds 55−57 showed radical-scavenging activity against DPPH.3,4 Variecolorin L 58 contains prenyl moieties at positions C2, C4, and C5 and was isolated from A. variecolor.4 Tardioxopiperazines A 59 and B 60 from A. variecolor and Microascus tardifaciens4,83 showed moderate immunosuppressive activity.83 Itabashi et al. found arestrictin B 61 from A. penicilloides in 2007.84 Variecolorins M 62 and N 63 were isolated from P. griseofulvum (sediment, deep-ocean, depth 2481m) by Zhou et al. in 2010.3 Terezine D 64 was first isolated from Sporormiella teretispora in 1995.85 It was later identified in A. sydowi (Baishamen shore, Hainan, China) and A. fumigatus (stem bark of Melia azedarach, Yang ling, China), respectively.86 14-Hydroxyterezine D 65 was taken from the fungus A. sydowi (Baishamen shore, Hainan, China); it had a cytotoxic effect against A-549 cells with an IC50 value of 7.31 μmol L−1.26 Neoechinulin B 66 was obtained from P. griseofulvum, A. variecolor, A. amstelodami, and A. effuses.3,4,87,89 Isoechinulin B 67, didehydroechinulin 68, and dihydroneochinulin B 69 came from Penicillium sp. and Aspergillus sp.3,88,89 Didehydroechinulin 68 significantly inhibited BEL-7402 and A-549 cells with IC50 values of 4.20 and 1.43 μmol L−1, respectively.88 Dihydroneochinulin B 69 showed weak inhibitory activity against BEL-7402 and A-549 cells.88 Variecolorin O 70 and H 71 from P. griseofulvum3 (sediment, deep-ocean, depth 2481m) and a halotolerant fungus A. variecolor exhibited significant cytotoxic activity in P388 cells and exhibited inhibitory activity toward cell proliferation.3,4 Compounds 66, 70, and 71 also showed radical-scavenging activity against DPPH.3,4 Compounds 72−92 contain a bridged polysulfide piperazine ring. Most of them were biologically active against P388 cells such as gliocladins A 72 and B 73, leptosins D−F 84−86, and T988s A−C 87−89, with cytotoxicity being the most commonly observed biological activity. Investigation of the structure−activity relationship showed that the sulfide linkage is important to these effects. Gliocladins A−E 72−76 were obtained from Gliocladium roseum.90,91 Compounds 72 and 73 showed nematicidal activity.91 Sporidesmin A 77 isolated from Pithomyces chartarum (New Zealand)92−94 exhibited immunoregulatory activity16 and could selectively inactivate glutaredoxin.95 Sporidesmins G, H, and J 78−80 displayed antiproliferative, cytotoxic, immunomodulatory, antiviral, antibacterial, and antifungal activities.11,12 Three plectosphaeroic acids A−C 81−83 were obtained from Plectosphaerella cucumerina (ocean sediment, depth 100 m) by Carr et al. These compounds were inhibitors of indoleamine 2,3-dioxygenase (IDO), which existed in primary tumor cells and therefore became an important molecular target for cancer therapy.96 Leptosins D−F 84−86 were isolated from brown alga fungus Leptosphaeria sp. (Sargassum tortile, Japan); these leptosins exhibited anticancer activity against P388 cells with ED50 values of 0.086, 0.046, and 0.056 μg mL−1, respectively.5

inhibit the cell cycle progression of mouse tsFT210 cells in the M phase with a MIC value of 12.2 μmol L−1.29 It was also shown to change the electrophysiological character of human nasal epithelial cells.53−55 Fumitremorgin A 26 came from A. fumigatus and A. caespitosus as well as from P. piscarium and P. janthinellum and finally from Neosartoria fischeri.35,37−42 In comparison to the structure of verruculogen 25 it contains one additional prenyl moiety. It was reported that verruculogen 25 and fumitremorgin A 26 can lead to sudden death, convulsions, and sustained tremors in animals.35,56−59 Fumitremorgin C 27 was obtained from A. fumigatus and A. tamarii.27,30,60 It was a specific reversal agent for the breast cancer resistance protein (BCRP) transporter,61−63 showed tremor-inducing activity,64 and exhibited anti-phytopathogenic activity against Pyricularia oryzae, Fusarium graminearum, Botrytiscinerea, and Phytophthora capsici.30 12,13-Dihydroxyfumitremorgin C 28 was shown to be a cell cycle inhibitor and was isolated from the fungi A. sydowi and A. fumigates, respectively.3,4,27,29,65 Demethoxyfumitremorgin C 29 came from A. fumigatus (sea mud, Japan),27,29 showed inhibitory activity in the mouse cell cycle against tsFT210, and also inhibited tumor cell cycle arrest at G2/M with a MIC value of 0.45 μmol L−1.29 Spirotryprostatins A 30 and B 31 were obtained from A. fumigatus (Lingshan Island, Shandong, China) and A. sydowi (Baishamen shore, Hainan, China), respectively.9,10,66 Both compounds inhibit the tumor cell cycle at G2/M with IC50 values of 197.5 and 14.0 μmol L−1, respectively.10 The marinederived fungus A. sydowi (Baishamen shore, Hainan, China) was the source of isolated samples of 6-methoxyspirotryprostatin B 32, which exhibited cytotoxicity against tumor cells HL60 and A-549 with IC50 values of 9.71 and 8.29 μmol L−1, respectively.3 The fungus A. fumigatus (holothurian Stichopus japonicus, Lingshan Island, China) yielded spirotryprostatins C−E 33−35, which exhibited cytotoxicity against four cancer cell strains: BEL-7402, A-549, HL-60, and MOLT-4, respectively.9 Spirotryprostatins C 33 and D 34 exhibited modest cytotoxicity toward MOLT-4, A-549, HL-60, and BEL7420 cells.9 Compound 35 was more cytotoxic to A549, HL-60, and MOLT-4 than were compounds 33 and 34. Sclerotiamide 36 isolated from the sclerotia of A. sclerotiorum could enhance the death rate of the corn earworm Helicoverpa zea.67 Notoamides A 37, B 38, F−I 39−42, N 43, and O 44 and stephacidin A 45 were obtained from the fungus Aspergillus sp. (Noto peninsula, Ishikawa, Japan).8,25,68−70 Both compounds 39 and 40 were initially isolated from Aspergillus sp.22 and displayed moderate cytotoxicity. Notoamide F 39 showed weak cytotoxicity against HeLa cells with an IC50 value of >50 μg mL−1.9 A. ostianus was the source of the analogue 21hydroxystephacidin 46.71 Avrainvillamide 47 was first obtained from a marine-derived Aspergillus sp. by Fenical et al. in 200072 and was subsequently isolated from Aspergillus ochraceus by Sugie et al. in 2001.73 It could inhibit the growth of multidrug-resistant Enterococcus faecalis, Staphylococcus aureus, and Streptococcus pyogenes, with MICs of 25, 12.5, and 12.5 μg mL−1, respectively.73 Peng et al. obtained versicamides A−F and (−)-enamide 48−54 from the marine-derived fungus A. versicolor in 2014.74 2.2. Derivatives of Indole Diketopiperazine Containing L-Tryptophan and L-Alanine. Both preechinulin 55 and neoechinulin A 56 contain a C2-prenyl moiety attached to the diketopiperazine ring (Chart 2). Preechinulin 55 came from P. griseofulvum, A. variecolor, and A. chevalieri.3,4,75 Cell-prolifer6662


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Journal of Agricultural and Food Chemistry T988s A−C 87−89 were obtained from Tilachlidium sp. and showed strong cytotoxic activity against P388 cells with ID50 values of 0.25, 2.18, and 0.56 μmol L−1, respectively.97,98 Bionectins A−C 90−92 from Bionectra byssicola displayed activity against methicillin-resistant S. aureus and quinoloneresistant S. aureus, each with MIC values of 10−30 μg mL−1.99 2.3. Derivatives of Indole Diketopiperazine Consisting of Two L-Tryptophan Molecules. Fellutanine A 93 was isolated from P. piscarium19 and P. fellutanu;100 it is a precursor of both compounds fellutanines B 94 and C 95 from P. fellutanum(Chart 3).100,101 Fellutanine D 96 taken from P.

Chart 4. Derivatives of Indole Diketopiperazine Consisting of L-Tryptophan and Other Amino Acids (106−119)

Chart 3. Derivatives of Indole Diketopiperazine Consisting of Two L-Tryptophan Molecules (93−105)

and L-phenylalanine. It was also named rugulosuvine B in P. rugulosum and P. piscarium.111 and showed both potent antiinflammatory and antitumor activities in vitro.13 Cryptoechinuline D 112 was first obtained from A. amstelodami in 1976.112 It was later identified in Eurotium rubrum and A. effuses, respectively.88,113 (+)-Cryptoechinuline D 112a and (−)-cryptoechinuline D 112b are enantiomers of cryptoechinuline D 112. Compounds 112 and 112a exhibited potent cytotoxicity against P388 cells with IC50 values of 3.43 and 2.50 μmol L−1, respectively, whereas compound 112b exhibited moderate activity against P388 cells with an IC50 value of 11.3 μmol L−1.88 The fungus P. piscarium yielded verrucofortine 113.15 Brevicompanine G 114 was isolated from Penicillium sp. and can be formed by the combination of valine and tryptophan.114 Glioperazine 115 from Gliocladium sp. (sea hare, Aplysia kurodai, Kata beach, Japan) is a rare sulfur-containing prenylated cyclo-Trp-Thr compound. It exhibited potent inhibitory activity against P388 cells.90 In 2015, Lhamo et al. isolated aspertryptanthrins A−C 116− 118 from a terrestrial-derived fungus Aspergillus sp. These compounds all contain an anthranilate unit and a tryptophan residue. The most interesting thing is aspertryptanthrin C 118 contains a rare 16-membered ring.115 Lumpidin 119 is a condensate of L-tryptophan and Lphenylalanine and was isolated from P. nordicum in 2001.116

fellutanum showed cytotoxicity against K-562, L-929, and HeLa cells with IC50 values of 9.5, 11.6, and 19.7 μg mL−1, respectively.100 Cai et al. found okaramines U 97, S 98, and T 99 from A. taichungensis in 2014. Okaramine S 98 exhibited cytotoxic activity against K-562 and HL-60 cells.6 Okaramines 100−103 came from P. simplicissimum and A. aculeatus.102−106 In the most okaramines, such as okaramines A 100, C 101, and L 102, one reverse prenyl moiety is found at position N1 of the tryptophan unit and another is found at position C2. Amauromine 104 was first isolated from Amauroascus sp. in 1985107 and identified as a hypotensive vasodilator. Elsebai et al. later isolated amauromine 104 from the fungus Auxarthron reticulatum in 2011 and identified it as a selective cannabinoid CB1 receptor antagonist.108 On the other hand, its stereoisomer epiamauromine 105 showed insecticidal activity.16,109 2.4. Derivatives of Indole Diketopiperazine Consisting of L-Tryptophan and Other Amino Acids. Many members of this group contain 1,1-dimethyl-allylmoieties at position C3 of the indole ring (Chart 4). Roquefortine C 106, roquefortine E 107, and 3,12-dihydroroquefortine 10815 as well as roquefortines F 109 and G 110110 were isolated from the fungus Penicillium sp. and are a combination of L-histidine and L-tryptophan. A plant growth inhibitor fructigenine A 111 was isolated from P. auratiogriseum and derived from L-tryptophan 6663


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Journal of Agricultural and Food Chemistry Chart 5. Bisindole Diketopiperazine Derivatives (120−166)

ascites.6 Compound 129 was a selective inhibitor of Topo II with an IC50 value of 59.1 μmol L−1.120 Compound 132 was a potent inhibitor of Topo II, protein kinase PTK, and CaMKIII.5,120 Chaetocin 140 from C. minzltum122 can be used to selectively kill human myeloma cells as it showed weak cytotoxicity to normal immune cells.15 It also inhibited thioredoxin reductase123 and selectively inhibited lysine-specific histone methyltransferase,124 suggesting that it can clear latent HIV-1 in vivo by connecting with certain chromosomal rearrangement therapy drugs.125 Chetocins B 141 and C 142 from a Chaetomium sp. fermentation broth were potent inhibitors of S. aureus and exhibited potent cytotoxicity against Hela cells with IC50 values of 0.03 and 0.02 μg mL−1, respectively.126 Verticillin A 143 was obtained from Gliocladium roseum91 and Verticillium sp.127,128 It showed weak nematicidal activity

3. BISINDOLE DIKETOPIPERAZINE DERIVATIVES Bisindole diketopiperazine alkaloids are characterized by the presence of two indole diketopiperazines in the molecule (Chart 5); these compounds are a family of very important natural products that are mainly isolated from marine organisms in recent years. Comparison of the activities of different compounds indicated an important factor in their cytotoxic action may be linked to the sulfide bridge in the molecule. 3.1. Sulfur-Substituted Derivatives. Brown alga fungus Leptosphaeria sp. produced leptosins A−C 120−122, G 123, G1 124, G2 125, H−K 126−129, K1 130, K2 131, M 132, M1 133, N 134, N1 135, and O−R 136−139; all isolated compounds displayed cytotoxicity against P388 cells.5,117−121 Compounds 120 and 122 inhibited the growth of Sarcoma-180 6664


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Journal of Agricultural and Food Chemistry Scheme 1. Biosynthetic Pathway for Verruculogen or Fumitremorgin A in Aspergillus fumigates

against Panagrellus redivivus and Caenorhabditis elegans and cytotoxic activity against Hela cells with an ED50 value of 0.2 μg mL−1.91 It was also an inhibitor of c-fos protooncogene induction from a Gliocladium species.129 Verticillins B 144 and C 145 were obtained from Verticillium sp.128,129 The fungus V. tenerum yielded 11,11′-dihydroxychaetocin 146, which exhibited antibacterial and antimitotic activity.130 In 1977, Argoudelis and Mizsak isolated melinacidins II 147 and III 148 from Acrostalagmus cinnabarinus var. melinacidinus.131 Melinacidin was highly active against Gram-positive but not Gram-negative bacteria (with the exception of Proteus vulgaris).132 Chetracin A 149 was obtained from V. tenerum in 1972,130 from Acrostalagmus cinnabarinus in 1977,131 and from C. retardatum and C. abuense (Tokyo, Japan) in 1985.133 Gliocladium catenulatum and Bionectria byssicola produced verticillin D 150, which exhibited antibacterial activity against S. aureus.91,134 Verticillins E 151 and F 152 from G. catenulatum showed antimicrobial activity.134 Kim’s group first isolated verticillin G 153 from Bionectria byssicola in 2007.2 It inhibited the growth of S. aureus including methicillin-resistant and quinoloneresistant varieties with MICs of 3−10 μg mL−1.2 G. roseum was the source of gliocladines A 154, B 155, sch52900 156, and sch52901 157.91 All isolated compounds displayed weak nematicidal activity against Panagrellus redivivus and Caenorhabditis elegans.91 Sch52900 156 and sch52901 157

were inhibitors of c-fos protooncogene induction from a Gliocladium sp. with IC50 values of 1.5 and 18 μmol L−1, respectively.129 11′-Deoxyverticillin A 158 was isolated from Penicillium sp. (green alga, Caribbean) and G. roseum.91 Chaetomin 159 from C. cochliodes displayed antibacterial and immunosuppressive activities.20 It was an inhibitor of the combination of HIF-1 and coactivator p300, which suggests that it might be used to suppress the expression of downstream genes.135 C. eminudum produced chetoseminudin A 160, which displayed immunosuppressive activity and had a strong inhibitory effect on the proliferation of mouse splenic lymphocytes induced by ConA and LPS, with IC50 values of 0.18 and 0.13 μg mL−1, respectively.136 The fungus C. cochliodes yielded chaetocochins B 161 and C 162, which were cytotoxic to Bre-04 (breast cancer cells), Lu04 (big cell lung cancer cells), and N-04 cells (glioma cells).136 3.2. Compounds Not Containing a Sulfur Substituent Group. Compounds in this category constitute a small group of derivatives. Asperazine 163 was isolated in 1997 from A. niger (Hyrtios proteus, sponge, Florida). It exhibited significant leukemia-selective cytotoxicity.137 WIN 64821 164 and WIN 64754 165 were isolated from an Aspergillus sp. (soil, Taiwan, China).138 Stephacidin B 166 was isolated from A. ochraceus in 2001 and exhibited potent cytotoxicity against LNCaP (a testosterone6665


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Journal of Agricultural and Food Chemistry Scheme 2. Biosynthetic Pathway for Notoamide in Aspergillus sp.

hydroxylation steps, respectively (Scheme 1). In the end, fumitremorgin C (27) was formed. Kato et al. proved the capability of FtmP450-1/FtmC, FtmP450-2/FtmE, and FtmP450-3/FtmG in the biosynthesis of tryprostatin A (12) in 2009.144 Steffan et al. have demonstrated that FtmPT2/ FtmH was the catalyst in the conversion of 12,13-dihydroxyfumitremorgin C (28) to fumitremorgin B (23) in the cluster.145 It was reported that the conversion of fumitremorgin B (23) to verruculogen (25) required an α-ketoglutaratedependent dioxygenase FtmOx1/FtmF and the nonheme Fe(II).146 Kato et al. reported that the biosynthesis of fumitremorgin B (23) or verruculogen (25) may not need the f tmO (AFUA_8G00260).144 4.2. Biosynthesis of Notoamide. Notoamide biosynthesis can undergo intramolecular cyclization (Scheme 2).146 Brevianamide F (1) is a key biosynthetic intermediate of indole diketopiperazine and the combination of L-proline and Ltryptophan. It can be applied to synthesize a series of compounds, such as notoamides, fumitremorgins, spirotryprostatins, and tryprostatins. In the fumitremorgin pathway, a PTase such as FtmB catalyzes C2 prenylation in brevianamide F (1), which can be transformed into tryprostatin B (13). On the other hand, in the notoamide pathway, NotF catalyzes a reverse prenylation in brevianamide F (1), which can be converted to deoxybrevianamide E. Deoxybrevianamide E then transformes into brevianamides, such as stephacidins, versicolamide, and notoamide.147,148 Oxidative coupling between the diketopiperazine ring and the prenyl group can form tryprostatin A (12) and tryprostatin B (13). In the fumitremorgin pathway, this reaction can be caused by a cytochrome P450 monooxygenase (CYP) such as FtmE.149 Through further oxidative modifications, spirotryprostatins can be synthesized by two different routes.150 One

dependent prostate cancer cell line), with GI50 values from 91 to 621 nM.139−141

4. BIOSYNTHESIS OF INDOLE DIKETOPIPERAZINE ALKALOIDS The biosynthesis of indole diketopiperazine alkaloids has made preliminary progress in biochemical and molecular biological investigations in recent years. Tryptophan is a biosynthetic precursor for indole diketopiperazine alkaloids. In the genome sequences, by bioinformatic approaches, the biosynthetic genes were often identified as a cluster. In different strains they can be identified as candidate genes for an enzymatic reaction by comparison of the orthologous gene clusters, which can then be confirmed by biochemical and molecular biological characterization. The biosynthetic pathways for fumitremorgin/verruculogen and notoamide have been intensively studied in this way. 4.1. Biosynthesis of Fumitremorgin/Verruculogen. The biosynthesis of fumitremorgin/verruculogen started with the combination of L-proline and L-tryptophan. This reaction was catalyzed by FtmPS (a nonribosomal peptide synthetase) (Scheme 1). The accumulation of brevianamide F (1) was the expression of FtmPS in A. fumigates.142 Tryprostatin B (13) was converted from compound 1 by FtmPT1/FtmB (prenyltransferase) under the condition of the existence of dimethylallyl diphosphate.143 Then, tryprostatin B (13) was transformed into tryprostatin A (12), and this reaction was done in two steps. The first step was that FtmP450-1/FtmC catalyzed the conversion of tryprostatin B (13) to 6-hydroxytryprostatin B, and the second step was that FtmMT/FtmD (methyltransferase) catalyzed the conversion of 6-hydroxytryprostatin B to tryprostatin A (12). Then, FtmP450-3/FtmG and FtmP450-2/ FtmE catalyzed the connection between the prenyl moiety of tryprostatin A (12) and the diketopiperazine ring via two 6666


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from halotolerant Aspergillus variecolor. J. Nat. Prod. 2007, 70, 1558− 1564. (5) Takahashi, C.; Numata, A.; Ito, Y.; Matsumura, E.; Araki, H.; Iwaki, H.; Kushida, K. Leptosins, antitumour metabolites of a fungus isolated from a marine alga. J. Chem. Soc., Perkin Trans. 1 1994, 1859− 1864. (6) Cai, S. X.; Sun, S. W.; Peng, J. X.; Kong, X. L.; Zhou, H. N.; Zhu, T. J.; Gu, Q. Q.; Li, D. H. Okaramines S−U, three new indole diketopiperazine alkaloids from Aspergillus taichungensis ZHN-7−07. Tetrahedron 2014, 71, 3715−3719. (7) Zhao, W. Y.; Zhang, Y. P.; Zhu, T. J.; Fang, Y. C.; Liu, H. B.; Gu, Q. Q.; Zhu, W. M. Studies on the indolyl diketopiperazine analogs produced by marine-derived fungus A-f-11. J. Chin. Antibiot. 2006, 31, 749−752. (8) Tsukamoto, S.; Kato, H.; Samizo, M.; Nojiri, Y.; Onuki, H.; Hirota, H.; Ohta, T. Notoamides F−K, prenylated indole alkaloids isolated from a marine-derived Aspergillus sp. J. Nat. Prod. 2008, 71, 2064−2067. (9) Wang, F. Z.; Fang, Y.; Zhu, T.; Zhang, M.; Lin, A.; Gu, Q.; Zhu, W. M. Seven new prenylated indole diketopiperazine alkaloids from holothurian-derived fungus Aspergillus f umigatus. Tetrahedron 2008, 64, 7986−7991. (10) Cui, C. B.; Kakeya, H.; Osada, H. Novel mammalian cell cycle inhibitors, spirotryprostatins A and B, produced by Aspergillus f umigatus, which inhibit mammalian cell cycle at G2/M phase. Tetrahedron 1996, 52, 12651−12666. (11) Francis, E.; Rahman, R.; Safe, S.; Taylor, A. Sporidesmins. XII. Isolation and structure of sporidesmin G, a naturally-occuring 3,6epitetrahiopiperazine-2,5-dione. J. Chem. Soc., Perkin Trans. 1 1972, 470−472. (12) Rahman, R.; Safe, S.; Taylor, A. Sporidesmins. Part 17. Isolation of sporidesmin H and sporidesmin J. J. Chem. Soc., Perkin Trans. 1 1978, 12, 1476−1479. (13) Arai, K.; Kimura, K.; Mushiroda, T.; Yamamoto, Y. Structures of fructigenines A and B, new alkaloids isolated from Penicillium f ructigenum Takeuchi. Chem. Pharm. Bull. 1989, 37, 2937−2939. (14) Isham, C. R.; Tibodeau, J. D.; Jin, W.; Xu, R. F.; Timm, M. M.; Bible, K. C. Chaetocin: a promising new antimyeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress. Blood 2007, 109, 2579−2588. (15) Kozlovskii, A. G.; Vinokurova, N. G.; Adanin, V. M. Diketopiperazine alkaloids from the fungus Penicillium piscarium Westling. Appl. Biochem. Microbiol. 2000, 36, 317−321. (16) Mullbacher, A.; Waring, P.; Tiwari-Palni, U.; Eichner, R. D. Structural relationship of epipolythiodioxopiperazines and their immunomodulating activity. Mol. Immunol. 1986, 23, 231−235. (17) Fujimoto, H.; Sumino, M.; Okuyama, E.; Ishibashi, M. Immunomodulatory constituents from an Ascomycete. J. Nat. Prod. 2004, 67, 98−102. (18) Kuramochi, K.; Ohnishi, K.; Fujieda, S.; Nakajima, M.; Saitoh, Y.; Watanabe, N.; Takeuchi, T.; Nakazaki, A.; Sugawara, F.; Arai, T.; Kobayashi, S. Synthesis and biological activities of neoechinulin A derivatives: new aspects of structure-activity relationships for neoechinulin A. Chem. Pharm. Bull. 2008, 56, 1738−1743. (19) De Guzman, F. S.; Glober, J. B. New diketopiperazine metabolites from the sclerotia of Aspergillus ochraceus. J. Nat. Prod. 1992, 55, 931−939. (20) Waksman, S. A.; Bugie, E. Chaetomin, a new antibiotic substance produced by Chaetomium cochliodes. I. Formation and properties. J. Bacteriol. 1944, 48, 527−530. (21) Vinokurova, N. G.; Khmel’nitskaya, I. I.; Baskunov, B. P.; Arinbasarov, M. U. Occurrence of indole alkaloids among secondary metabolites of soil Aspergillus spp. Appl. Biochem. Microbiol. 2003, 39, 192−196. (22) Kato, H.; Yoshida, T.; Tokue, T.; Nojiri, Y.; Hirota, H.; Ohta, T.; Williams, R. M.; Tsukamoto, S. Notoamides A−D: prenylated indole alkaloids isolated from a marine-derived fungus, Aspergillus sp. Angew. Chem. 2007, 119, 2304−2306.

route is a radical-mediated, two-step hydroxylation on fumitremorgin C (27) or demethoxyfumitremorgin C followed by dehydration and rearrangement to form spirotryprostin B (31), which is catalyzed by the CYP FtmG (Scheme 2).150 Another route is through epoxidation, rearrangement, and hydroxylation two times; fumitremorgin C (27) can be transformed into fumitremorgin B by FtmH.149,151 In the presence of an Fe(II)-dependent α-ketoglutarate dioxygenase, through further oxidation verruculogen (25) can be formed146 The first step of notoamide biosynthesis is the forming of the common intermediate notoamide S, which is formed by C7 prenylation and C6 hydroxylation of deoxybrevianamide E. The formation of notoamide C (4) is as follows. The C6 hydroxyl and C7 prenyl groups are oxidatively coupled in the beginning and in the reaction notoamide E (6) is generated. Then epoxidation of notoamide E (6) can be caused by NotB,147 whereas a semipinacol rearrangement on the hydroxyiminium intermediate produces notoamide C (4). Notoamide D is formed by a nucleophilic attack from the α-amide of Trp.147,148 The formation of (+)- or (−)-notoamide B (38) needs additional oxidative steps for notoamide C (4).

5. PERSPECTIVES Indole diketopiperazine alkaloids with diverse chemical structures and biological activities are widely distributed in nature. As a result, effective research and development methods for these alkaloids should be explored to maximize their usefulness in the drug discovery and development processes. First, indole diketopiperazine alkaloids must be available in sufficient quantities for further biological analysis by both chemical and biological synthesis methods. The understanding of biosynthetic mechanism of these alkaloids needs the combination of both biochemical and genetic approaches; more and more designed biologically active substances will be expected to be produced by genetic manipulation. Second, efforts should be made to determine the nature of the structural and functional relationship for the indole diketopiperazines on a large scale.

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AUTHOR INFORMATION

Corresponding Author

*(Y.-M.M.) E-mail: [email protected]. Phone/fax: +86-2986168312. Funding

This work was cofinanced by the Natural Science Basic Research Plan in Shaanxi Province of China (2014JZ003). Notes

The authors declare no competing financial interest.

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REFERENCES

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