Diketopiperazines from marine organisms

CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) 2809 REVIEW Diketopiperazines from Marine Organisms by Riming Huang a ) b ), Xuefeng Zhou a ), Tunhai Xu c ), Xianwen Yang a ), and Yonghong Liu* a ) a ) Key Laboratory of Marine Bio-resources Sustainable Utilization/Guangdong Key Laboratory of Marine Materia Medica/Research Center for Marine Microbes, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, P. R. China (phone: þ 86-20-89023244; fax: þ 86-20-84451672; e-mail: [email protected]) b ) Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou 510650, P. R. China c ) School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, P. R. China Diketopiperazines (DKPs), which are cyclic dipeptides, have been detected in a variety of natural resources. Recently, the interest in these compounds increased significantly because of their remarkable bioactivity. This review deals with the chemical structures, biosynthetic pathways, and biological activities of DKPs from marine microorganisms, sponges, sea stars, tunicates (ascidians), and red algae. The literature has been covered up to December 2008, and a total 124 DKPs from 104 publications have been discussed and reviewed. Some of these compounds have been found to possess various bioactivities including cytotoxicity, and antibacterial, antifungal, antifouling, plant-growth regulatory, and other activities. Contents 1. Introduction 2. Marine Organisms 2.1. Microorganisms 2.2. Sponges 2.3. Sea Stars 2.4. Tunicates 2.5. Red Algae 3. Biosynthetic Pathways 4. Biological Activities 4.1. Cytotoxicity 4.2. Antibacterial Activity 4.3. Antifungal Activity 4.4. Antifouling Activity 4.5. Plant-Growth Regulatory Activity 4.6. Other Activities 5. Conclusions 1. Introduction. – Marine organisms are an established source of structurally unique and biologically active natural products [1 – 3]. The work on marine natural products  2010 Verlag Helvetica Chimica Acta AG, Zrich 2810 CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) started 54 years ago, when Bergman and Freeney discovered the novel bioactive arabino-nucleoside from the marine sponge Cryptotethya crypta [4]. This discovery encouraged natural-product chemists to pay attention to marine natural products as important biomedical sources. These compounds are mainly isolated from marine microorganisms and phytoplankton, green algae, brown algae, red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, and true mangrove plants [5]. According to their chemical structures, the compounds isolated form marine organisms belong to various classes of compounds, including long-chain polyols and polyethers [6], alkaloids [7 – 10], monoterpenoids [11], diterpenoids [12] [13], sesterterpenoids [14 – 16], peptides [17] [18], triterpene glycosides [19], gangliosides [20] [21], conotoxins [22 – 24], and steroids [25]. Diketopiperazines (DKPs) are a relatively unexplored class of bioactive peptides that may hold great promise for the future [26]. Recently, the interest in these compounds increased because of their significant bioactivities including plant-growth promotion [27], antimicrobial activity [28], quorum-sensing signalling [29] [30], antitumor activity [31], antiviral activity [31], and inhibition against aflatoxin production [32]. So far, no review on the DKPs isolated from marine organisms has been published. Here, we try to present the DKPs isolated from marine organisms to date. 2. Marine Organisms. – Compounds 1 – 124 are the DKPs isolated from marine organisms since 1972 (Table 1). They were obtained from marine microorganisms, sponges, sea star, tunicates (ascidians), and red algae. 2.1. Microorganisms. DKPs 1 – 95 were isolated from marine microorganisms (Table 1). DKPs 1 – 3 were produced by a species of Micrococcus isolated from the marine sponge Tedania ignis [33] [34]. A culture of Pseudoalteromonas luteoviolacea isolated from the surface of the Hawaiian alga Padina australis produced the diketopiperazine cyclo(l-Phe-(4R)-hydroxy-l-Pro) (4), which stimulated antibiotic production in this strain [35]. Cyclo(l-Arg-d-Pro) (aka CI-4; 5) was identified as a chitinase inhibitor produced by a cultured Pseudomonas sp. IZ208 that was isolated form seawater (Shizuoka Prefecture, Japan) [36]. A strain of Pseudomonas aeruginosa isolated from the Antarctic sponge Isodictya setifera contained cyclo(l-Pro-l-Met) (6) [37]. Cyclo(l-(4-hydroxy)-Pro-d-Leu) (7) was isolated as plant-growth promotor from a marine bacterium A108 associated with a species of Palythoa [38]. Mactanamide (8) is a fungistatic diketopiperazine produced by an Aspergillus sp. that was obtained from a brown alga Sargassum sp. from the Philippines [39]. An enantiospecific total synthesis of tryprostatin A (9), which is a cytotoxic diketopiperazine from Aspergillus fumigatus strain BM939 [40], employed a new regiospecific bromination procedure [41] [42]. The marine sediment origin of A. fumigatus produced tryprostatin B (10) [43]. A saltwater culture of A. niger derived from the sponge Hyrtios proteus from Florida produced a cytotoxic dimeric diketopiperazine alkaloid, asperazine (11) [44]. Golmaenone (12), a diketopiperazine alkaloid, obtained from an Aspergillus species isolated from a red alga Lomentaria catenata (Ulsan City, Korea), exhibited significant radical-scavenging and UV-A protecting properties [45]. The diketopiperazine dimer 13 was obtained from a marine-derived A. niger supplied by the Australian Institute of Marine Sciences, and the absolute configuration was determined by chiral HPLC [46]. Notoamides A – D CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) 2811 2812 CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) 2813 2814 CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) 2815 2816 CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) Table 1. DKPs from Marine Organisms 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 Compound name Sources Ref. Cyclo(Pro-Leu) Cyclo(Pro-Val) Cyclo(Pro-Ala) Cyclo(l-Phe-(4R )-hydroxy-l-Pro) Cyclo(l-Arg-d-Pro) Cyclo(l-Pro-l-Met) Cyclo(l-(4-hydroxy-Pro)-d-Leu) Mactanamide Tryprostatin A Tryprostatin B Asperazine Golmaenone Diketopiperazine dimer Notoamide A Notoamide B Notoamide C Notoamide D 11,11’-Dideoxyverticillin A 11’-Deoxyverticillin A Cyclo(d-Hyp-l-Phe) Cyclo(d-Hyp-l-Leu) Cyclo(d-pipecolinyl-l-Ile) Dehydroxybis(dethio)bis(methylthio)gliotoxin Janthinolide B Cyclo(d-6-Hyp-l-Phe) Cyclo(l-6-Hyp-l-Phe) Cyclo(6,7-en-Pro-l-Phe) Leptosin A Leptosin B Leptosin C Leptosin D Leptosin E Leptosin F Leptosin G Leptosin G1 Leptosin G2 Leptosin H Leptosin K Leptosin K1 Leptosin K2 Leptosin M Leptosin M1 Leptosin N Leptosin N1 Leptosin O Leptosin P Leptosin Q Leptosin R Leptosin S Micrococcus sp. Micrococcus sp. Micrococcus sp. Pseudoalteromonas luteoviolacea Pseudomonas sp. P. aeruginosa Bacterium A108 Aspergillus sp. A. fumigatus A. fumigatus A. niger Aspergillus sp. A. niger Aspergillus sp. Aspergillus sp. Aspergillus sp. Aspergillus sp. Penicillium sp. Penicillium sp. Aureobasidium pullulans A. pullulans Pseudoalteromonas haloplanktis Pseudallescheria sp. Penicillium janthinellum Chromocleista sp. Chromocleista sp. Chromocleista sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. Leptosphaeria sp. [33] [34] [33] [34] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [40] [43] [44] [45] [46] [47] [47] [47] [47] [48] [48] [49] [49] [50] [51] [52] [53] [53] [53] [54] [55] [54] [55] [54] [55] [54] [55] [54] [55] [54] [55] [56] [56] [56] [56] [57] [57] [57] [58] [58] [58] [58] [59] [59] [59] [59] [59] CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) 2817 Table 1 (cont.) 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 Compound name Sources Ref. Fusaperazine A Fusaperazine B Sch54794 Sch54796 Cyclo(d-Pro-d-Val) Cyclo(d-Pro-d-Ile) Cyclo(d-Pro-d-Leu) Cyclo(l-Tyr-trans-4-hydroxy-l-Pro) Gliocladin A Gliocladin B Gliocladin C Glioperazine Gliocladride Gliocladride A Rostratin A Rostratin B Rostratin C Rostratin D Gliovictin Bilain A Bilain B Bilain C Maremycin A Maremycin B 6-Methoxyspirotryprostatin B 18-Oxotryprostatin A 14-Hydroxyterezine D (3R,11aR)-11,11a-Dihydro-7,9-dihydroxy-3(1H-indol-3-ylmethyl)-8-methoxy-2H-pyrazino[1,2-b]isoquinoline-1,4(3H,6H )-dione (3R,6Z )-6-Benzylidene-3-(hydroxymethyl)-1,4dimethyl-3-(methylsulfanyl)piperazine-2,5-dione Notoamide F Notoamide G Notoamide H Notoamide I Notoamide J Notoamide K Cyclomarazine A Cyclomarazine B (1S,2S,3S,5aS,10aR )-5a,6,7,8-Tetrahydro-1,10adihydroxy-6’-methoxy-3-(2-methylprop-1-en-1-yl)1H,5H-spiro[dipyrrolo[1,2-a:1’,2’-d]pyrazine-2,2’indole]-3’,5,10(1’H,10aH )-trione Spirotryprostatin C Spirotryprostatin D Spirotryprostatin E 24-Hydroxyfumitremorgin B ([a] 20 D ¼  5.7) 24-Hydroxyfumitremorgin B ([a] 20 D ¼ þ 15.0) 13-Oxoverruculogen Fusarium chlamydosporum F. chlamydosporum Tolypocladium sp. Tolypocladium sp. Pecten maximus P. maximus P. maximus Ruegeria sp. Gliocladium sp. Gliocladium sp. Gliocladium sp. Gliocladium sp. Gliocladium sp. Gliocladium sp. Exserohilum rostratum E. rostratum E. rostratum E. rostratum Asteromyces cruciatus Penicillium bilaii P. bilaii P. bilaii Streptomyces sp. Streptomyces sp. Aspergillus sydowi A. sydowi A. sydowi A. flavus [61] [60] [61] [60] [61] [60] [61] [62] [62] [62] [63] [64] [64] [64] [64] [65] [66] [65] [67] [68] [68] [68] [68] [69] [70] [70] [70] [71] [71] [72] [72] [72] [73] Pleosporales sp. [74] Aspergillus sp. Aspergillus sp. Aspergillus sp. Aspergillus sp. Aspergillus sp. Aspergillus sp. Salinispora arenicola S. arenicola Aspergillus fumigatus [75] [75] [75] [75] [75] [75] [76] [76] [77] A. fumigatus A. fumigatus A. fumigatus A. fumigatus A. fumigatus A. fumigatus [77] [77] [77] [77] [77] [77] 2818 CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) Table 1 (cont.) 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 Compound name Sources Ref. Roquefortine F Roquefortine G Cyclo(4-methyl-(R )-Pro-(S )-Nva) Didechlorodihydrodysamide C (3S,6E )-1-Methyl-3-[(2S )-3,3,3-trichloro-2-methylpropyl]-6[(2S )-3,3,3-trichloro-2-methylpropylidene]piperazine2,5-dione Dysamide D Dysamide I Dysamide J Dysamide K Dysamide L Dysamide M Dysamide N Dysamide O Dysamide P Dysamide Q Dysamide R Dysamide S Dysamide T Cyclo(l-Pro-l-thioPro) Cyclo(l-Pro-l-Tyr) Barettin Cyclo(6-bromo-8-en-(l-Pro-l-Trp)) 3-[(6-Bromo-1H-indol-3-yl)methylidene]-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione Bromobenzisoxazolone barettin (3R,3’R)-1,1’-[(1R,2R,4R,5S )-2,5-dihydroxy-cyclohexane1,4-diyl]bis(3-methylpiperazine-2,5-dione) Etzionin Penicillium sp. Penicillium sp. Calyx cf. podatypa Dysidea herbacea D. herbacea [78] [78] [79] [80] [80] D. fragilis D. chlorea D. chlorea D. chlorea D. chlorea D. chlorea D. chlorea D. chlorea D. chlorea D. chlorea D. chlorea D. chlorea D. chlorea Tedania ignis Jaspis digonoxea Geodia barretti Synthesis Synthesis [81] [82] [82] [82] [82] [82] [82] [82] [82] [82] [82] [82] [82] [83] [84] [85] [86] [87] [87] G. barretti Pentaceraster regulus [88] [89] Unidentified Red Sea tunicate Synthesis [90] [91] Axinella vaceleti A. vaceleti A. vaceleti A. vaceleti [92] [92] [92] [92] N-[3-( Acetylamino)propyl]-3-(3-benzyl-2,5dioxopiperazin-1-yl)dodecanamide Verpacamide A Verpacamide B Verpacamide C Verpacamide D (14 – 17, resp.) are doubly prenylated indole alkaloids obtained from a culture of Aspergillus sp. from mussel Mytilus edulis (Noto Peninsula, Sea of Japan), and they were moderately cytotoxic (HeLa and L1210) [47]. A Penicillium sp. (strain # CNC350) from the surface of the Caribbean green alga Avrainvillea longicaulis produced two diketopiperazine dimers, 11,11’-dideoxyverticillin A (18) and 11’-deoxyverticillin A (19), both of which exhibited potent in vitro cytotoxicity against the HCT-116 cell line [48]. The marine yeast Aureobasidium pullulans, which was cultured from an unidentified Okinawan sponge, produced two DKPs, 20 and 21 [49]. Cyclo(dpipecolinyl-l-Ile) (22) was isolated from the cell-free culture supernatant of the CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) 2819 Antarctic psychrophilic bacterium Pseudoalteromonas haloplanktis TAC125, which was isolated from Antarctic seawater in the vicinity of the Dumont dUrille Antarctic Station. The potential antioxidant activity of the isolated compound was evaluated by a DPPH free radical-scavenging assay [50]. A dioxopiperazine alkaloid, 23, was isolated from the culture broth of Pseudallescheria sp. separated from the surface of the brown alga Agarum cribosum (Uljin, Korea), which was active against MRSA and MDRSA [51]. P. janthinellum, isolated from the soft coral Dendronephthya sp. (Hainan Island, South China Sea), was the source of a piperazine-2,5-dione alkaloid, janthinolide B (24) [52]. Chromocleista sp. from sediment (Gulf of Mexico) provided DKPs 25 – 27, but 27 was identified as a decomposition product of 25 and 26 [53]. Leptosins A – F (28 – 33, resp.) are cytotoxic dimeric derivatives that were obtained from the fungus Leptosphaeria sp. found on the brown alga Sargassum tortile [54]. The structures of 28 – 33 were determined by spectroscopic analyses. A report on the chemistry of Lignincola laevis provided insufficient data to support the unusual structures proposed [55]. A strain of the fungus Leptosphaeria sp. that was isolated from the surface of the brown alga Sargassum tortile contained leptosins G, G1 , G2 , H, K, K1 , and K2 (34 – 40, resp.) [56] [57]. Four epipolysulfanyl-dioxopiperazines, leptosins M, M1 , N, and N1 (41 – 44, resp.), were isolated from a culture of the fungus Leptosphaeria sp. originating from the Japanese brown alga Sargassum tortile [58]. The absolute configurations were determined by chemical analyses and transformations. Each compound possessed significant cytotoxic activity against the P388 cell line, while leptosin M (41) also exhibited appreciable cytotoxicity against a disease-oriented panel of 39 human cancer cell lines, and specifically inhibited two protein kinases and topoisomerase II. The five leptosins O – S (45 – 49, resp.) were obtained from a Leptosphaeria species, originally separated from Sargassum tortile (Tanabe Bay, Japan) [54], but structure and absoluteconfiguration determinations were performed on the derived acetates. Leptosins O and P (45 and 46, resp.) exhibited significant cytotoxicities against P388 cells, while leptosins O and S (45 and 49, resp.) were moderately cytotoxic against 39 human tumor cell lines [59]. Cultured Fusarium chlamydosporum, isolated from the Japanese marine red alga Carpopeltis affinis, was the source of four sulfur-containing dioxopiperazine derivatives, fusaperazines A and B (50 and 51, resp.), as well as compounds 52 and 53, which had been originally isolated from a fermentation of the fungus Tolypocladium sp. [60]. The absolute configurations of 52 and 53 were determined by chemical transformations [61]. Cultures of two marine bacterial strains isolated from cultures of Pecten maximus larvae in Galicia, Spain, led to the first reported isolation, as natural products, of a series of DD-DKPs, 54 – 56, and established them as potent inhibitors of the pathogenic marine bacterium Vibrio anguillarum. The structures were confirmed by synthesis [62]. The DKP diastereoisomer 57 was obtained from a bacterial Ruegeria species associated with cell cultures of the sponge Suberites domuncula (Gulf of Naples, Italy) [63]. The moderately cytotoxic oxopiperazine metabolites gliocladins A – C (58 – 60, resp.) and glioperazine (61) were isolated from a strain of Gliocladium species separated from the sea hare Aplysia kurodai (Kata coast, Japan). The relative configurations were determined by NOESY spectroscopy [64]. Three DKPs, gliocladride and gliocladride A (62 and 63, resp.), as well as the (6E)-isomer of 63, were obtained from a culture of Gliocladium sp. that was isolated from sea mud (Rushan, China) [65 – 67]. Gliocladride (62) was cytotoxic to the human A375-S melanoma cell 2820 CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) line [66]. The modestly cytotoxic cyclic dipeptides rostratins A – D (64 – 67, resp.) were isolated from Exserohilum rostratum, a fungal strain associated with a marine cyanobacterial mat (Lanai, Hawaii). The absolute configurations of the rostratins were determined [68]. Gliovictin (68) was isolated from the marine deuteromycete Asteromyces cruciatus that was isolated from drift wood [69]. A culture of Penicillium bilaii (Huon estuary, Tasmania) produced three DKPs, bilains A – C (69 – 71, resp.) [70]. Maremycins A and B (72 and 73, resp.) are unusual DKPs from a Streptomyces sp. that were isolated from a marine sediment from Chile [71]. Three diketopiperazine alkaloids, 6-methoxyspirotryprostatin B (74), 18-oxotryprostatin A (75), and 14hydroxyterezine D (76), were isolated from the AcOEt extract of a marine-derived fungal strain, Aspergillus sydowi PFW1-13, isolated from a drift-wood sample collected from the beach of Baishamen (China). Compounds 74 – 76 exhibited weak cytotoxicities against A-549 cells, and 74 also showed slight cytotoxicity against HL-60 cells [72]. A diketopiperazine alkaloid containing the uncommon amino acid l-7,9dihydroxy-8-methoxy-Phe, 77, has been isolated from the algicolous Aspergillus flavus strain. Compound 77 showed weak cytotoxicity against HL-60 cell line [73]. (3R,6Z)-6Benzylidene-3-(hydroxymethyl)-1,4-dimethyl-3-(methylsulfanyl)piperazine-2,5-dione (78) was obtained from the culture broth of the marine-derived fungus of the order Pleosporales, strain CRIF2, that was isolated from an unidentified sponge (Surin Island, Thailand). Compound 78 exhibited only weak cytotoxic activity [74]. Six prenylated indole alkaloids, notoamides F – K (79 – 84, resp.), were obtained from a marine-derived Aspergillus sp. that was isolated from the mussel Mytilus edulis galloprovincialis (Noto Peninsula). Their structures, including absolute configurations, were elucidated by spectroscopic methods. Notoamide I (82) showed weak cytotoxicity against HeLa cells [75]. Cyclomarazines A and B (85 and 86, resp.) were isolated from the marine bacterium Salinispora arenicola CNS-205 that was obtained from a marine sediment (Palau) [76]. Seven prenylated indole diketopiperazine alkaloids, including 87, spirotryprostatins C – E (88 – 90, resp.), derivatives of fumitremorgin B, 91 and 92, and 13-oxoverruculogen (93), have been isolated from the sea cucumber-derived fungus Aspergillus fumigatus. All compounds, except 87 (tested only against HL-60 and A549), were evaluated for their cytotoxicities against MOLT-4, HL-60, A549, and BEL-7402 cell lines. They showed the selective activities against the four cancer cell lines, and further analysis of the activity data suggested that compounds 90 – 92 showed better susceptivity to MOLT-4, HL-60, and A549, than compounds 87 – 89 and 93 [77]. Two diketopiperazines, roquefortines F and G (94 and 95, resp.), were isolated from a deep-ocean sediment-derived fungus Penicillium sp. The cytotoxicities of 94 and 95 against the HL-60, A-549, BEL-7402, and MOLT-4 cell lines were evaluated [78]. 2.2. Sponges. Among marine invertebrates, the sponges represent a particularly rich source of secondary metabolites with a great diversity of structures and bioactivities. During the investigation to find potential lead compounds for the development of pharmaceutical interesting products, DKPs 96 – 117 have been isolated from marine sponges (Table 1). Although known to be ubiquitous, DKPs are still being reported as natural products rather than primary metabolites: cyclo(4-methyl-(R)-Pro-(S)-Nva) (96) was isolated from Calyx cf. podatypa from a Caribbean sponge [79]. Dysidea herbacea from the southern Great Barrier Reef has yielded the DKPs 97 and 98, the structure of 98 was determined by single-crystal X-ray-analysis [80]. The structure of an CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) 2821 additional diketopiperazine, dysamide D (99), obtained from a specimen of D. fragilis from the South China Sea, was reported without stereochemical details [81]. Twelve polychlorinated DKPs, dysamides I – T (100 – 111, resp.), were obtained from D. chlorea from Yap, Micronesia [82]. Of greater interest is the unusual S-containing diketopiperazine 112 from the marine sponge Tedania ignis [83]. South African specimen of Jaspis digonoxea contained cyclo(l-Pro-l-Tyr) (113) [84]. A diketopiperazine, 114, isolated from Geodia barretti collected at 300 m from Norwegian waters [85], was found to have spectral data identical to that of barettin, previously isolated from the same sponge and originally assigned the structure 115, which has significant activity on the isolated guinea-pig ileum [86]. A subsequent synthesis of 115 disproved this structure for barettin [87]. Both the (E)- and the (Z)-isomer of the proposed structure 116 of barettin, which is a metabolite of Geodia baretti [86], were synthesized and were shown to have completely different spectral data from barettin [87]. G. barretti contained a dibrominated cyclopeptide, bromobenzisoxazolone barettin (117), which displays settlement inhibition of barnacle larvae (Balanus improvisus) [88]. 2.3. Sea Stars. The majority of secondary metabolites reported from sea star are saponins or polyhydroxylated sterols, but there are some interesting exceptions. An unusual dimeric dipeptide, 118, was isolated from the sea star Pentaceraster regulus from India and was identified by interpretation of spectral data [89]. 2.4. Tunicates (ascidians). The absolute configuration of etzionin (119), an antifungal diketopiperazine hydroxamate originally isolated from an unidentified Red Sea tunicate [90], has been secured by synthesis of all four stereoisomers of the derivative 120, and direct comparison of optical-rotation values with those of the natural derivative [91]. 2.5. Red Algae. Verpacamides A – D (121 – 124, resp.), isolated from Axinella vaceleti (Mediterranean Sea), are considered to represent possible intermediates in an alternative biogenetic pathway to pyrrole-2-aminoimidazole alkaloids such as oroidin [92]. Verpacamide A is known as a synthetic product [92]. 3. Biosynthetic Pathways. – The 2,5-DKPs, head-to-tail dipeptide dimers, represent a common naturally occurring structural motif. They are also frequently generated as undesired by-products or degradation products in the syntheses of oligopeptides [93]. Although the number of newly isolated naturally occurring DKPs has increased during the last few years, the biosynthetic pathways of these molecules remain largely unexplored. Generally, DKP derivatives seem to be produced by three different ways [94]. The first one is nonribosomal pathway, and product formation takes place under the catalytic control of a large multimodular enzyme complex, termed NRP synthetase (NRPS). The second biosynthetic way is that DKP derivatives can be also obtained as a side-product in the course of nonribosomal synthesis. The third biosynthetic way has been described from Streptomyces noursei. For cyclomarzaine A (85) from the marine bacterium Salinispora arenicola CNS-205, the biosynthesis was based on the biosynthetic gene cluster organization of cym [76] (Table 2). Albonoursin (125), an antibacterial peptide isolated from Streptomyces noursei, is one of the simplest representatives of the large diketopiperazine family. Formation of a,b-unsaturations was previously shown to occur on cyclo(l-Phe-l-Leu), catalyzed by the cyclic dipeptide 2822 CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) oxidase [95]. A plausible biosynthetic pathway for vertihemiptellide A (126) from the insect pathogenic fungus Verticillium hemipterigenum BCC 1449 was proposed. The presence of the diketopiperazine 127 as a co-metabolite in BCC 1449 indicated that replacement of the a-H-atoms with S-atoms (i.e., 127 to 128) should take place with retention of configuration. Also other possible mechanisms for the formation of 126 have been considered, for example, a) a radical pathway, instead of the ionic dimerization shown, and b) dimerization of bis-thioradical intermediates, generated by the cleavage of SS bond in 128 or directly from 127 [96]. Notoamide E (129) was a key precursor in the biosynthesis of prenylated indole alkaloids in a marine-derived fungus Aspergillus sp., which was produced by the fungus in the early phase of growth and was presumably rapidly converted to notoamide E4 (130) [97]. 1-N-Methylalbonoursin (131) was produced by Streptomyces sp. isolated from perennial ryegrass seedling tissues, from which it emerged in liquid culture after surface sterilization of seed. The biosynthesis of the diketopiperazine skeleton of 131 from Leu and Phe was demonstrated [98]. Epipolythiodioxopiperazines (ETPs) are toxic secondary metabolites produced only by fungi. The availability of complete genome sequences for many fungi has facilitated the identification of putative ETP biosynthetic gene clusters. Expression and mutational analyses have confirmed the role of such gene clusters in the biosynthesis of two ETPs, sirodesmin PL (132) and gliotoxin (133) [99 – 101]. Rhodotorulic acid (134) was structurally the simplest siderophore-forming dipeptide consisting of two N5-acetyl-N5-hydroxyornithine units linked head-to-head to form a diketopiperazine ring. These siderophores are produced by basidomycetous yeasts such as Rhodotorula spp. and form a moiety in coprogen (135) [102]. Molecular genetic studies of Streptomyces acidiscabies (using a gene disruption approach) have demonstrated a good agreement with the proposed production sequence in S. scabies [103]. They indicate that the biosynthesis of the thaxtomin A (136) involves conserved nonribosomal peptide synthetases encoded by genes named TxtA and TxtB [104]. 4. Biological Activities. – 4.1. Cytotoxicity. Compound 11 from a marine-derived Aspergillus niger displayed an unusual profile of cytotoxicity. It showed significant leukemia-selective cytotoxicity in the Corbett – Valeriote soft agar disk diffusion assay. CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) 2823 Table 2. DKPs with Characterized Biosynthetic Clusters Compound Source organism used to Known medicinal isolate biosynthetic genes properties Biosynthetic enzymes Cyclomarzaine A Salinispora arenicola Albonoursin Streptomyces noursei Vertihemiptellide A Unknown Notoamide E4 Unknown 1-N-MethylUnknown albonoursin 132 Sirodesmin PL Leptosphaeria maculans Antibacterial Antibacterial Antimycobacterial Unknown Weakly antibiotic NRPS, CymQ NRPS, albC, albD Unknown Unknown Unknown Cytotoxicity 133 Gliotoxin 134 Rhodotorulic acid Aspergillus fumigatus Rhodotorula spp. Cytotoxicity Unknown 135 Coprogen Rhodotorula spp. Unknown 136 Thaxtomin A Streptomyces scabies Phytotoxicity SirD, SirP, SirT, SirM, SirN, SirH Gilp, GliT, GliM, GliN l-Ornithine N5-oxygenase, N5-transacylases, NRPSs l-Ornithine N5-oxygenase, N5-transacylases TxtA, TxtB 85 125 126 130 131 Interesting selective activity was observed for 11 at 50 mg/disk in the primary in vitro assay employing human leukemia murine colon 38 and human colon H116 or CX1 cell lines [44]. Notoamides A – D (14 – 17, resp.) were isolated from a marine-derived Aspergillus sp. Compounds 14 – 16 showed moderate cytotoxicities against HeLa and L1210 cells with IC50 values in the range of 22 – 52 mg/ml, but the IC50 value of 17 is greater than 100 mg/ml [47]. Compounds 25 – 27 from Chromocleista sp. showed no activity at concentrations up to 50 mg/ml. The cytoxicities of these compounds were evaluated against a panel of cancer cell lines: P388 murine leukemia, A549 human lung adenocarcinoma, PANC-1 human pancreatic cancer, and NCIADR-RES tumor cells. All the compounds failed to exhibit any cytotoxicity at a concentration of 5 mg/ml [53]. The cytotoxic activities of 34 – 37 from the fungus Leptosphaeria sp. were examined in the P388 lymphocytic leukemia test system. All the compounds exhibited potent cytotoxic activities [57]. Leptosins 41 – 44 from the fungus Leptosphaeria sp. were used against the murine P388 lymphocytic leukemia cell line and a disease-oriented panel of 39 human cancer lines (HCC panel) in the Japanese Foundation for Cancer Research. All of these metabolites exhibited significant cytotoxic activities against the murine P388 cell line, and the activities of 43 and 44 were almost tenfold more potent than those of 41 and 42. In addition, 41 showed appreciable cytotoxic activities against the 39 human cancer cell lines [58]. Compound 52 from the fungus Tolypocladium sp. exhibited weak cytotoxic activity (7.7 mg/ml) against P388 lymphocytic leukemia cells [61]. Gliocladride (62) from a marine-derived Gliocladium sp. showed a cytotoxic effect with an IC50 value of 3.86 mg/ml against human A375-S2 melanoma cell line [66]. Rostratins A – D (64 – 67, resp.) from the fungus Exserohilum rostratum showed in vitro cytotoxicities against human colon carcinoma (HCT-116) with IC50 values of 8.5, 1.9, 0.76, and 16.5 mg/ml, respectively [68]. Compounds 74 – 76 from a marine-derived fungus Aspergillus sydowi PFW1-13 exhibited weak cytotoxicities against A-549 cells with IC50 values of 8.29, 1.28, and 7.31 mm, respectively. Compound 74 also showed a slight cytotoxicity against HL-60 cells with an IC50 value of 9.71 mm [72]. Compound 77 2824 CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) showed a weak cytotoxicity against HL-60 cell lines with an IC50 value of 36.5 mg/ml [73]. Four prenylated indole alkaloids, 79, 82, 83, and 84, were isolated form a marinederived Aspergillus sp. Notoamide I (82) showed weak cytotoxicity against HeLa cells with an IC50 value of 21 mg/ml, whereas, for notoamides F, J, and K (79, 83, and 84, resp.), the IC50 values were more than 50 mg/ml [75]. Seven prenylated indole diketopiperazine alkaloids, 87 – 93, from the holothurian-derived fungus A. fumigatus, except 87 (treated only against HL-60 and A549), were evaluated for their cytotoxicities against MOLT-4, HL-60, A549, and BEL-7402 cell lines. They showed selected activities against the four cancer cell lines, and compounds 90 – 92 showed better susceptivities to MOLT-4, HL-60, and A549 than compounds 87 – 89 and 93 [77]. The compounds 94 and 95 from a marine-derived fungus Penicillium sp. were evaluated for their cytotoxicities against the HL-60 and MOLT-4 cell lines by the MTT method, and against the A-549 and BEL-7402 cell lines by the SRB method. The compounds showed no cytotoxicity against all the four cell lines [78]. 4.2. Antibacterial Activity. Asperazine 11 did not exhibit antibacterial activity (Bacillus subtilis) [44]. Compound 23 from the culture broth of Pseudallescheria sp. exhibited potent antibacterial activity against the methicillin-resistant and multidrugresistant Staphylococcus aureus with a MIC value of 31.2 mg/ml [51]. Compounds 25 – 27 from Chromocleista sp. showed activities against S. aureus when tested at 50 mg/ml [53]. Cyclomarazines A (85) and B (86) from the marine bacterium Salinispora arenicola CNS-205 were identified as moderate antimicrobial agents with MIC values of 18 and 13 mg/ml against methicillin-resistant Staphylococcus aureus and vancomycinresistant Entrococcus faecium, respectively [76]. Compound 112 from marine sponge Tedania ignis was inactive in antimicrobial tests [83]. 4.3. Antifungal Activity. Etzionin (119) from an unidentified Red Sea tunicate was considered to be responsible for the antifungal activity [91]. Asperazine (11) did not exhibit any activity in antifungal assays (Candida albicans) [44]. 4.4. Antifouling Activity. Compound 114 from the marine sponge Geodia barretti has successfully been incorporated in antifouling paints and has been shown to be active in field tests. Bromobenzisoxazolone barettin (117), also from G. barretti, displayed settlement inhibition of barnacle larvae (Balanus improvisus) with an EC50 value of 15 nm [88]. 4.5. Plant-Growth Regulatory Activity. The compounds 4 from Pseudoalteromonas luteoviolacea and 7 from a marine bacterium A108 were found to stimulate plantgrowth activity [38], while 112 was inactive [83]. 4.6. Other Activities. Compound 5 produced by a cultured Pseudomonas sp. IZ208 showed inhibitory activity against chitinase [36]. Compound 12 from an Aspergillus species exhibited a significant radical-scavenging activity against 1,1-diphenyl-2picrylhydrazyl (DPPH) with an IC50 value of 20 mm, similar to that of the positive control, ascorbic acid (IC50 , 20 mm). Compound 12 also showed an ultraviolet-A (UVA; 320 – 390 nm) protecting activity with an ED50 value of 90 mm, i.e., it is more active than oxybenzone (ED50 350 mm) currently being used as sunscreen [45]. The potential antioxidant activity of 22 from the Pseudoalteromonas haloplanktis was evaluated by a DPPH free radical-scavenging assay [55]. CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) 2825 5. Conclusions. – Up to December 2008, studies on DKPs have concerned bacteria, fungi, and actinomycetes, isolated from seawater, sediments, algae, and marine invertebrates such as sponges, corals, sea anemones, sea hares, and sea cucumber (Tables 1 and 3). It appears, from Table 3, that 32% of studied microorganisms have been isolated from algae. Interestingly, algae-derived microorganisms account for the largest number (40%) of total DKPs isolated from marine microorganisms (Fig. 1). 124 DKPs have been isolated from marine organisms, among them, 95 DKPs (i.e., 1 – 95) Table 3. Origin of the Microorganisms Origin % Seawater Sediment Algae Mussel Invertebrate Sponge Sea anemone Coral Sea hare Sea cucumber Other: wood, boat ... Total 5 16 32 8 28 16 3 3 3 3 11 100 Fig. 1. The distribution of DKPs reported from marine-derived microorganisms 2826 CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) were from microorganisms, including 10 DKPs (i.e., 1 – 7, and 54 – 56) from marine bacteria, 4 DKPs (i.e., 72, 73, 85, and 86) from marine actinomycetes, the other 81 DKPs from marine fungi. Only 23 DKPs were reported from marine sponges, one DKP from sea star, one DKP from sea tunicate, and four DKPs from red algae (Table 1). So, the natural sources of DKPs isolated from marine organisms are microorganisms and sponges, accounting for 76 and 19%, respectively (Fig. 2). These compounds have attracted increasing interest because of their potent biological activities [26]; consequently, marine microorganisms can be a promising source for this class of bioactive compounds. Although the number of DKPs isolated from marine resources has increased during the last few years, the biosynthetic pathways of these molecules remained largely unexplored. Also little is known of the mechanism of action of these compounds from marine organisms. In this regard, the biosynthesis of these molecules through bacterial fermentation combined with genetic engineering is a key issue to increase the chance for their full biological evaluation and their possible pharmacological investigation. Data reported above clearly demonstrate that the marine resources contain a number of DKPs that could act as lead structures for further researches on other biological tests. Of course, the structure – activity relationships of biologically active naturally occurring marine DKPs reported in this review also can be investigated. Thus, much more chemical, biosynthetic, synthetic, and biological studies should be carried out on DKPs in order to disclose their potency, selectivity, toxicity, and availability. Fig. 2. The distribution of DKPs reported from marine organisms This study was supported by grants from the National Natural Science Foundation of China (No. 40706046, 30973679, and 20902094), Knowledge Innovation Program of Chinese Academy of Sciences (LYQY200703, SQ200904, KSCX2-EW-G-12B, and KSCX2-YW-G-073), the National Key Basic CHEMISTRY & BIODIVERSITY – Vol. 7 (2010) 2827 Research Program of China (973)s Project (2010CB833800 and 2011CB915503), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, and the LMB (091002) Foundation. REFERENCES [1] J. J. Bowling, A. J. Kochanowska, N. Kasanah, M. T. Hamann, Expert Opin. Drug Discovery 2007, 2, 1505. [2] M. D. Lebar, J. L. Heimbegner, B. J. Baker, Nat. Prod. Rep. 2007, 24, 774. [3] F. Folmer, W. E. 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