Accepted Manuscript Title: Marine actinobacteria: An important source of bioactive natural products Author: Panchanathan Manivasagan Kannan Sivakumar Eunice C.Y. Li-Chan Hyun-Myung Oh Se-Kwon Kim PII: DOI: Reference:

S1382-6689(14)00138-0 http://dx.doi.org/doi:10.1016/j.etap.2014.05.014 ENVTOX 2021

To appear in:

Environmental Toxicology and Pharmacology

Received date: Revised date: Accepted date:

27-3-2014 21-5-2014 26-5-2014

Please cite this article as: Manivasagan, P., Sivakumar, K., Li-Chan, E.C.Y., Oh, H.-M., Kim, S.-K.,Marine actinobacteria: An important source of bioactive natural products, Environmental Toxicology and Pharmacology (2014), http://dx.doi.org/10.1016/j.etap.2014.05.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Marine actinobacteria: An important source of bioactive natural products

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Panchanathan Manivasagan 1, Kannan Sivakumar 2, Eunice C.Y. Li-Chan 3, Hyun-Myung

Specialized Graduate School Science & Technology Convergence, Department of Marine-Bio.

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Oh 1, Se-Kwon Kim 1*

Convergence Science and Marine Bioprocess Research Center, Pukyong National University,

Centre of Advanced Study in Marine Biology, Faculty of Marine Sciences,

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Busan 608-739, Republic of Korea.

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Annamalai University, Parangipettai – 608 502, Tamil Nadu, India

The University of British Columbia, Faculty of Land and Food Systems, Food Nutrition and

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Health Program, 2205 East Mall, Vancouver, British Columbia, Canada V6T 1Z4.

*Corresponding author: Email: [email protected], [email protected], Tel: +82-51-629-6870, Fax: +82-51-629-6865

Contents 1. Introduction................................................................................................................................. 3 1

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2. Polyketides.................................................................................................................................. 4 3. Peptides ....................................................................................................................................... 7 4. Quinones ..................................................................................................................................... 9 5. Macrolides................................................................................................................................. 10

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6. Terpenes.................................................................................................................................... 10 7. Alkaloids ................................................................................................................................... 11

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8. Indole compounds..................................................................................................................... 12 9. Pyrroloiminoquinone ................................................................................................................ 13

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10. Butenolides ............................................................................................................................. 13 11. Benzoxazole............................................................................................................................ 13 12. Piericidins ............................................................................................................................... 14

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13. Methylpyridine........................................................................................................................ 14 14. Trioxacarcins........................................................................................................................... 14

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15. Marinopyrroles........................................................................................................................ 15 16. Manumycin derivatives........................................................................................................... 15

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17. Triazolopyrimidine ................................................................................................................. 15 18. Macrocyclic lactam................................................................................................................. 16

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19. Sisomicin................................................................................................................................. 16 20. Esters....................................................................................................................................... 16

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21. Conclusion .............................................................................................................................. 16 Conflict of interest statement ........................................................................................................ 17 Acknowledgments......................................................................................................................... 17 References..................................................................................................................................... 18

Abstract

Marine environment is largely an untapped source for deriving actinobacteria, having potential to produce novel, bioactive natural products. Actinobacteria are the prolific producers of pharmaceutically active secondary metabolites, accounting for about 70% of the naturally derived compounds that are currently in clinical use. Among the various actinobacterial genera,

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Actinomadura, Actinoplanes, Amycolatopsis, Marinispora, Micromonospora, Nocardiopsis, Saccharopolyspora, Salinispora, Streptomyces and Verrucosispora are the major potential producers of commercially important bioactive natural products. In this respect, Streptomyces

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ranks first with a large number of bioactive natural products. Marine actinobacteria are unique enhancing quite different biological properties including antimicrobial, anticancer, antiviral,

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insecticidal and enzyme inhibitory activities. They have attracted global in the last ten years for

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their ability to produce pharmaceutically active compounds. In this review, we have focused attention on the bioactive natural products isolated from marine actinobacteria, possessing

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unique chemical structures that may form the basis for synthesis of novel drugs that could be

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used to combat resistant pathogenic microorganisms.

1. Introduction

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Natural products.

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Keywords: Marine actinobacteria, Bioactive compounds, Chemical structures, Antibiotics,

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Marine actinobacteria are emerging as important sources for bioactive natural products, encompassing a variety of distinct structural classes (Fenical and Jensen, 2006). There is a tremendous potential and novelty among the marine actinobacteria present in marine environments (Lam, 2006). Actinobacteria are widely distributed in the oceans and, moreover, indigenous marine actinobacteria have now been described (Bull et al., 2005). Although several questions remain to be answered regarding the ecological role of actinobacteria in the marine environment as well as their biogeographic distribution and evolutionary history, it is becoming increasingly clear that marine actinobacteria, in particular, present a major resource for biotechnological search and discovery (Bull, 2004; Fiedler et al., 2005; Jensen et al., 2005;

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Manivasagan et al., 2013; Manivasagan et al., 2014). Most of the antibiotics in use today are derivatives of novel natural products of actinobacteria and fungi (Butler and Buss, 2006; Newman and Cragg, 2007; Baltz, 2008).

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Recent years have witnessed a significant progress in the investigation of marine microorganisms including actinobacteria. Preparation of new structural types of bioactive

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substances and the detection of highly efficient producers of such compounds are the main

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factors that have attracted the scientists’ attention to marine microbial metabolites. In this context, marine actinobacteria are a potential source of bioactive substances (Blunt et al., 2007;

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Blunt et al., 2006; Fiedler et al., 2005; Imada, 2005; Jensen et al., 2005; Palaniappan et al., 2013; Sobolevskaya and Kuznetsova, 2010; Wagner-Döbler et al., 2002). These live in sea water in the

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form of a very few colonies, most of which cannot grow under laboratory conditions. They are

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frequently present in bottom sediments, but they rarely constitute more than 10% of the living

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microflora. Most of the actinobacterial representatives can be isolated from seashores, coastal waters, bottom sediments, fishes, molluscs, sponges, seaweeds and mangroves (Elyakov et al.,

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1996; Maldonado et al., 2005; Stach and Bull, 2005). In recent years, newly discovered bioactive metabolites have encouraged growing interest in marine actinobacteria in parallel with the need for new antibiotics (Hameş-Kocabaş and Uzel, 2012; Hughes et al., 2009; Jensen et al., 2007; Mincer et al., 2005; Mincer et al., 2002). In this review, we focus on new bioactive natural products identified from marine actinobacteria and classified them in terms of their unique chemical structures (Table 1), covering the literature to date. 2. Polyketides Polyketides constitute a large and structurally diverse family of natural products synthesised by multifunctional or mono- or bi-functional enzymes called polyketide synthases

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(PKSs), by the repetitive decarboxylative condensation of acyl-CoA derived extender units in a similar process to fatty acid synthesis (Staunton and Weissman, 2001). They are divided into three types: Types I, II and III. Many of them are of biological activities and pharmacological

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properties. Some of the polyketides of medical importance like epirubicin, doramectin and compounds like chartreusin, aurantimycin, kirromycin, concanamycin, polyketomycin and

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lysolipin have been used for therapeutic treatments (Weber et al., 2003).

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Li and Piel (2002) isolated Streptomyces sp. JP95, associated with the marine ascidian Aplidium lenticulum from the Heron Island, Australia and it was found to biosynthesize the

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polyketide, griseorhodin A (1) (Fig 1) and the biological activity of the compound has not yet been determined (Li and Piel, 2002). Daryamides are cytotoxic polyketides isolated from the

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marine-derived Streptomyces strain, CNQ-085. Daryamides A (2), B (3) and C (4) (Fig 1)

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showed weak to moderate cytotoxicity against the human colon carcinoma cell line HCT-116.

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Daryamide A exhibited significantly more potent cancer cell cytotoxicity, with an IC50 of 3.15 μg/ml, than daryamides B and C and very weak antifungal activity against Candida albicans

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(Asolkar et al., 2006). Actinofuranones A (5) and B (6) (Fig 1) are new polyketides isolated from the culture extract of a marine-derived Streptomyces strain CNQ766, which showed weak in vitro cytotoxicity against mouse splenocyte T-cells and macrophages (Cho et al., 2006b). Phaeochromycins F (7), G (8) and H (9) (Fig 2) are new polyketides isolated from the culture broth of the marine actinomycete strain Streptomyces sp. DSS-18 and the biological activity of the compound has not yet been determined (Li et al., 2008). Saliniketals A (10) and B (11) (Fig 2) are the unusual bicyclic polyketides isolated from the marine actinomycetes, Salinispora arenicola and they are the inhibitors of ornithine decarboxylase biosynthesis.

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Inhibition of ornithine decarboxylase production is a potential target for the chemoprevention of cancer, with IC50 values of 1.95±0.37 and 7.83±1.2 µg/ml, respectively (Williams et al., 2007a). Abyssomicin C (12) (Fig 2) is a novel polycyclic polyketide isolated from

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Verrucosispora sp. (Riedlinger et al., 2004) and is a potential target for para-aminobenzoic acid biosynthesis and, therefore, inhibits the folic acid biosynthesis at an earlier stage as compared to

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the well-known synthetic sulfa drugs (Bister et al., 2004). Abyssomicin C possesses antibacterial

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activity against gram-positive bacteria, including clinical isolates of multiple resistant and vancomycin-resistant Staphylococcus aureus. Abyssomicin C and its analogues thus have the

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potential to be developed as antibacterial agents against drug-resistant pathogens (Rath et al., 2005). Arenicolides (13) (Fig 2) are a higher number of type I polyketide derived compounds

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with antitumor activity isolated from Salinispora arenicola strain CNR-005. Once such

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compound is arenicolides, 26-membered polysaturated macrolactones, produced by an obligate

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marine actinobacterium, isolated from the marine sediments, at a depth of 20 m from the island of Guam. Arenicolide A has been found to moderate cytotoxicity against the human colon

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adenocarcinoma cell line HCT-116 with an IC50 value of 30 μg/ml (Williams et al., 2007b). Chartreusin (14) (Fig 3) is an aromatic polyketide glycoside isolated from Streptomyces chartreusis and is a potent antitumor agent. Type II polyketide synthase gene clusters were identified from S. chartreusis HKI-249 (Xu et al., 2005). Salinipyrones (A (15) and B (16)) (Fig 3) and pacificanones (A (17) and B (18)) (Fig 3) are four new polyketides isolated from the marine actinobacterium, Salinispora pacifica CNS-237. Biologically active salinipyrones and pacificanones are currently being examined in diverse bioassays. In the preliminary screening, these compounds showed no significant activity in a cancer cytotoxicity bioassay using HCT-

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116 human colon cancer cells. Salinipyrone A exhibited moderate human cell cytotoxicity (Oh et al., 2008). 3. Peptides

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Peptides are short chains of amino acids. Most of the actinobacterial peptides are cyclic and contain further rare structural elements such as chromophores or uncommon amino acids.

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Peptides include mechercharmycins which are the new cytotoxic substance obtained from

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marine-derived Thermoactinomyces sp. YM3-251. Cyclic nature of mechercharmycin A (19) (Fig 4) exhibited relatively strong antitumor activity and the related compound,

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mechercharmycin B (20) (Fig 4) exhibited no such activity (Kanoh et al., 2005). Thiocoraline (21) (Fig 4) is a novel cyclic thiodepsipeptide isolated from Micromonospora sp. L-13-ACM2-

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092 and it showed a potent antitumor activity against P388, A549, and MEL288. There was also

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Romero et al., 1997).

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a strong antimicrobial activity against Gram-positive microorganisms (Perez et al., 1997;

Cyclomarin A (22) (Fig 5) is a new cyclic heptapeptide produced by a Streptomyces sp. It

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showed significant anti-inflammatory activity in both in vivo and in vitro assays (Renner et al., 1999). Piperazimycins (23) (Fig 5) are cytotoxic hexadepsipeptides obtained from the fermentation broth of a Streptomyces sp. strain CNQ- 593, isolated from the marine sediments at a depth of approximately 20 m near the island of Guam. Piperazimycin A exhibited potent in vitro cytotoxic activity against the human colon carcinoma HCT-116 cell line (Miller et al., 2007). Two new dipeptide derivatives, 8-amino-[1,4]diazonane-2,5-dione (24) (Fig 5) and leucyl-4-hydroxyproline (25) (Fig 5) were isolated from Streptomyces acrimycini and their biological roles are not yet to be determined (Hernández et al., 2004).

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Salinamides A and B (26) (Fig 6) are bicyclic depsipeptides, produced by Streptomyces sp. CNB-091, isolated from the jelly fish Cassiopeia xamachana. These metabolites are valuable as antibiotic and anti-inflammatory agents (Moore et al., 1999). Arenamides A-C (27-29) (Fig 6)

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are three new cyclohexadepsipeptides isolated from the fermentation broth of a marine actinobacterial strain identified as Salinipora arenicola CNT-088 which was obtained from the

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marine sediment sample collected at a depth of 20 m off the Great Astrolab Reef, in the Kandavu

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Island chain, Fiji, in 2006. Arenamides A (27) and B (28) showed weak in vitro cytotoxicity against human colon carcinoma HCT-116 with IC50 values of 13.2 and 19.2 μg/ml, respectively.

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The effect of arenamides A and B on NFκB activity was studied with stably transfected 293/NFκB-Luc human embryonic kidney cells induced by treatment with tumor necrosis factor

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(TNF). Arenamides A and B blocked TNF-induced activation in a dose- and time-dependent

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manner with IC50 values of 3.7 and 1.7 µM, respectively (Asolkar et al., 2008).

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Lucentamycins A-D (30) (Fig 7) are four new 3-methyl-4-ethylideneproline-containing peptides isolated from Nocardiopsis lucentensis strain CNR-712, obtained from the sediments of

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a shallow saline pond from the island of Little San Salvador, the Bahamas. Lucentamycins A and B exhibited significant in vitro cytotoxicity against human colon carcinoma cell line HCT116 with IC50 values of 0.20 and 11 μM, respectively. However, lucentamycins C and D were not cytotoxic in the same assay suggesting that the presence of an aromatic ring is essential for the biological activity of this class of compounds (Cho et al., 2007). Proximicins are novel aminofuran antibiotics produced by Verrucosispora strain MG-37 isolated from the sediments collected in the Raune Fjord, Norway at a depth of 250 m and the Sea of Japan at a depth of 289 m, respectively (Fiedler et al., 2008; Riedlinger et al., 2004). Proximicin A was discovered in parallel in the marine abyssomicin produced by Verrucosispora

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maris AB-18-032. The characteristic structural element of proximicins is 4-amino-furan-2carboxylic acid, a hitherto unknown γ-amino acid. Proximicins A (31), B (32) and C (33) (Fig 7) showed a strong cytostatic effect to various human tumor cell lines and a weak antibacterial

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activity. Proximicins A, B and C showed significant growth inhibitory activity against human gastric adenocarcinoma AGS (GI50 of 0.6, 1.5 and 0.25 µM, respectively) and hepatocellular

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carcinoma Hep G2 (GI50 of 0.82, 9.5 and 0.78 µM, respectively), and were found to induce the

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arrest of AGS cells in G0/G1 and to increase the levels of p53 and p21 (Schneider et al., 2008). 4. Quinones

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Quinones are compounds having a fully conjugated cyclic dione structure. They are common constituents of biologically relevant molecules. Marine actinobacteria are especially

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rich in highly biologically active quinones. The complex C-glycosides himalomycins A (34) and

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B (35) (Fig 8) are two new anthraquinones antibiotics with the rare fridamycin E chromophore, a

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precursor of the anthracycline antibiotics. They were obtained from Streptomyces sp. B6921 isolated from the marine sediments of Mauritius. Himalomycins exhibited strong antibacterial

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activity against Bacillus subtilis, Streptomyces viridochromogenes, Staphylococcus aureus and Escherichia coli (Maskey et al., 2003). Tetracenomycin D (36) (Fig 8) is an anthraquinone antibiotic obtained from Streptomyces corchorusii AUBN1/7, isolated from a sediment sample collected from the Bay of Bengal. It showed in vitro potent cytotoxic activity against cell line HMO2 (gastric adenocarcinoma) and HepG2 (hepatic carcinoma) and also exhibited weak antibacterial activity against Gram-positive and Gram-negative bacteria (Adinarayana et al., 2006). Komodoquinone A (37) (Fig 8) is a novel anthracycline antibiotics and its aglycone, komodoquinone B (38) (Fig 8) belong to the anthrocycline antibiotics produced by Streptomyces sp. KS3 isolated from

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marine sediments. Komodoquinone A showed neuritogenic activity. It induced neuronal cell differentiation in the neuroblastoma cell line Neuro 2A at a concentration of 1 µg/ml and arrested the cell cycle at the G1 phase (Itoh et al., 2003a; Itoh et al., 2003b).

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5. Macrolides

Macrolides are a cluster of drugs whose activity stems from the presence of a macrolide

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ring, a large macrocyclic lactone ring to which one or more deoxy sugars may be attached.

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Generally, macrolides are protein synthesis inhibitors. Chalcomycin A (39) (Fig 9) is a macrolide antibiotic obtained from the crude extract of the marine Streptomyces sp. M491 from

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the Qingdao coast (China). It exhibited activity against Escherichia coli, Bacillus subtilis, and Staphylococcus aureus and a weak inhibition of Streptomyces viridochromogenes in biological

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screening (Wu et al., 2007). Chalcomycin B (40) (Fig 9) is a new macrolide antibiotic obtained

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from the culture broth of a marine Streptomyces sp. B7064, isolated from the mangrove

6. Terpenes

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sediments near Pohoiki, Hawaii (Pacific Ocean) (Asolkar et al., 2002).

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Terpenes are a large and various class of hydrocarbons. They are the major biosynthetic building blocks within nearly every living creature. Terpenes are derived biosynthetically from units of isoprene, which has the molecular formula of C5H8. As the chains of isoprene units are built, resulting terpenes are classified sequentially by size as hemiterpenes, monoterpenes, sesquiterpenes, diterpenes, sesterterpenes, triterpenes, and tetraterpenes. Glyciapyrroles A (41), B (42) and C (43) (Fig 9) are a new pyrrolosesquiterpenes produced by Streptomyces sp. NPS008187 isolated from the marine sediments collected in Alaska.

They exhibited

antibacterial activity (Macherla et al., 2005).

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Azamerone (44) (Fig 10) is a novel meroterpenoid produced by a new marine-derived bacterium related to the genus Streptomyces. Azamerone is composed of an unprecedented chloropyranophthalazinone core with a 3-chloro-6-hydroxy-2,2,6-trimethylcyclohexylmethyl

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side chain (Cho et al., 2006a). Selina-4(14),7(11)-diene-8,9-dio (45) (Fig 10) is a new sesquiterpene isolated from Streptomyces sp. QD518. This compound exhibited anticancer

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activity (Wu et al., 2006). 10α,11-dihydroxyamorph-4-ene (46), 10α,15-dihydroxyamorph-4-en-

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3-one (47) and 5α,10α,11-trihydroxyamorphan-3-one (48) (Fig 10) are the new amorphane sesquiterpenes isolated from Streptomyces sp. M491. Biological activity of amorphane is

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unknown (Wu et al., 2007). 15-hydroxy-T-muurolol (49) (Fig 10) is a new sesquiterpenes obtained from the marine-derived Streptomyces sp. M491 isolated from the marine sediments of

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the Qingdao coast, China. This compound was tested for its cytotoxicity against a range of

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human tumor cells with a mean IC50 of 6.7 µg/ml (Ding et al., 2008).

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Neomarinone (50) (Fig 10) is a novel metabolite possessing a new sesquiterpene and polyketide-derived carbon skeleton and several derivatives of the marinone class of

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naphthoquinone antibiotics produced by novel marine actimomycete CNH-099 isolated from a sediment sample at 1 m depth in Batiquitos Lagoon, North of San Diego, California. These bioactive molecules showed moderate in vitro cytotoxicity (IC50 of 8 µg/ml) against human colon carcinoma HCT-116 cells (Hardt et al., 2000). 7. Alkaloids

Alkaloids are a class of naturally occurring organic nitrogen-containing bases. Alkaloids have various and important physiological effects on humans and other animals. They are produced by a large variety of organisms and are part of the group of natural products. Bohemamines (51) (Fig 11) are a new pyrrolizidine alkaloids obtained from Streptomyces sp.

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CNQ-583 isolated from a marine sediment sample collected at a depth of 82 m off the island of Guam. Bohemamine, bohemamine B, bohemamine C and 5-chlorobohemamine C were tested for inhibition of the HCT-116 colon carcinoma cell line and antimicrobial activity, but were

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found to be essentially inactive (Bugni et al., 2006). Aburatubolactams A (52), B (53) and C (54) (Fig 11) were obtained from the cultured broth of a Streptomyces sp. SCRC-A20 (Bae et al.,

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1996; Yamada et al., 1999). Two indolocarbazole alkaloids, K252c (55) and Arcyriaflavin A

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(56) (Fig 11) were isolated from the fermentation broth of a marine-derived actinomycete Z20392. These compounds exhibited moderate cytotoxicity against the K562 cell line and induced

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apoptotic activities at 10 and 100 µM, respectively (Liu et al., 2007).

Altemicidin (57) (Fig 11) is a monoterpene alkaloid obtained from Streptomyces

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sioyaensis SA-1758 isolated from Gamo, Miyagi Prefecture, Japan (Takahashi et al., 1989a).

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This compound inhibited the growth of carcinoma IMC and murine lymphoid leukemia L1210

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cell lines with IC50 values of 0.82 and 0.84 μg/ml, respectively, although it showed high acute toxicity in mice. Altemicidin showed not only acaricidal activity but also antitumor activity. The showed

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antimicrobial

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compound

activity

except

the

inhibitory

activity

to

Xanthomonas strains (Takahashi et al., 1989b). 8. Indole compounds

Three new cytotoxic 3,6-disubstituted indoles A, B and C (58) (Fig 12) were obtained from Streptomyces sp. BL-49-58-005,

isolated from an unidentified marine invertebrate

collected in Mexico. These compounds were tested against a panel of 14 different tumor cell lines. Indole A (6-prenyltryptophol) exhibited cytotoxicity against human leukemia K-562 cell line with a GI50 value of 8.46 μM. Aldoxime indole B exhibited activity with GI50 values within μM range against different cancer cell lines. Nitrile indole C showed no activity (Sánchez López

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et al., 2003). Streptochlorin (59) (Figure 12) is a 3-substituted indole compound produced by Streptomyces sp. 04DH110 isolated from the shallow water sediments at 1 m depth of Ayajin Bay, on the East Sea of Korea. Streptochlorin showed significant antiproliferative activity

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against human cultured cell lines with an IC50 of 1.05 µg/ml (Jae et al., 2007). 9. Pyrroloiminoquinone

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Ammosamides (60) (Fig 12) are pyrroloiminoquinone compounds obtained from

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Streptomyces sp. CNR-698 isolated from the bottom sediments collected at a depth of 1618 meters in the Bahamas Islands. Ammosamide A and B showed cell growth inhibitors while

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using in vitro cytotoxicity assays against the colon carcinoma cancer cell line HCT-116, with an IC50 of 320 nM. These compounds also demonstrated pronounced activity in a diversity of

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cancer cell lines with values ranging from 20 nM to 1 µM, indicating a specific target

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mechanism of action. Using the cell and molecular biology approach, target of the ammosamides

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was identified as a member of the myosin family, important cellular proteins that are involved in numerous cell processes, including cell cycle regulation, cytokinesis, and cell migration (Hughes

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et al., 2009) .

10. Butenolides

Four known butenolides were obtained from Streptoverticillium luteoverticillatum 11014 isolated from the Taipingjiao, Qingdao, China. The butenolides include (4S)-4,10-dihydroxy-10methyl-undec-2-en-1,4-olide (61), (4S)-4,10-dihydroxy-10-methyl-dodec-2-en-1,4-olide (62) and the mixture of 3 and 4, (4S)-4,11-dihydroxy-10-methyl-dodec-2-en-1,4-olides (63) (Figure 12). These compounds exhibited in vitro cytotoxicity against the murine lymphoma P388 and human leukemia K562 cell lines (Li et al., 2006). 11. Benzoxazole

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Caboxamycin (64) (Fig 12) is a new benzoxazole antibiotic produced by Streptomyces sp. NTK 937 isolated from the deep-sea sediments collected from the Canary Basin.

cell lines and the enzyme phosphodiesterase (Hohmann et al., 2009). 12. Piericidins

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Caboxamycin exhibited inhibitory activity against Gram-positive bacteria, selected human tumor

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Piericidins C7 and C8 (65) (Fig 12) are the two new members of the piericidin family,

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obtained from Streptomyces sp. Piericidins C7 and C8 exhibited cytotoxic activity against rat glia cells transformed with the adenovirus E1A gene with IC50 value of 1.5 nM and 0.45 nM and

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Neuro-2a mouse neuroblastoma cells with IC50 0.83 nM and 0.21 nM (Hayakawa et al., 2007). 13. Methylpyridine

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Streptokordin (66) (Fig 12) is a new methylpyridine obtained from Streptomyces sp.

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KORDI-3238 isolated from a deep-sea sediment at Ayu Trough. Streptokordin exhibited

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significant in vitro cytotoxicity against several human cancer cell lines, MDA-MB-231, HCT 15, PC-3, NCl-H23, ACHN, LOX-IMVI and K-562 with IC50 values ranging from 3.2 to 8.6 µg/ml.

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This compound did not show any obvious inhibitory effect at the concentration of 1.0 mg/ml on the growth of bacteria and fungi (Jeong et al., 2006). 14. Trioxacarcins

Trioxacarcins (67) (Fig 13) are complex antibiotics produced by Streptomyces sp. isolate B8652 derived from the Gulf of Mexico. All trioxacarcins exhibited high antibacterial and some of them showed higher anti-tumor and anti-malaria activities. Trioxacarcin A exhibited antifungal activity. Trioxacarcins A, B and C were isolated from Streptomyces ochraceus and Streptomyces bottropensis. Some of these compounds possessed extremely high antiplasmodial activity, which is comparable to that shown by artemisinin, the most active compound against

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the pathogen of malaria. Producers of trioxacarcins also biosynthesized the related metabolite, gutingimycin (Maskey et al., 2004). 15. Marinopyrroles

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Marinopyrroles A (68) and B (69) (Fig 13) are densely halogenated and axially chiral metabolites that contain an uncommon bispyrrole structure obtained from Streptomyces sp.

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CNQ-418 isolated from a marine sediment collected near La Jolla, California. The

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marinopyrroles possess potent antibiotic activities against methicillin-resistant Staphylococcus aureus (MRSA) (Hughes et al., 2008).

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16. Manumycin derivatives

Chinikomycins A (70) (Fig 14) and B are chlorine-containing aromatized manumycin

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derivatives of the type 64-pABA-2 with an unusual para orientation of the side chains. These

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compounds are produced by Streptomyces sp. isolate M045 derived from the sediments of

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Jiaozhau Bayin, China. These compounds exhibited moderate antitumor activity, but were inactive in antiviral, antimicrobial and phytotoxicity tests. Chinikomycins A selectively inhibited

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proliferation in cell lines of mammary cancer (MAXF 401NL, IC50 value of 2.41 µg/ml), melanoma (MEXF 462NL, IC50 value of 4.15 µg/ml), and renal cancer (RXF 944L, IC50 value of 4.02 µg/ml). Chinikomycins B exhibited selective antitumor activity against the mammary cancer cell line MAXF 401NL with the IC50 value of 3.04 µg/ml (Li et al., 2005). 17. Triazolopyrimidine

Essramycin (71) (Fig 14) is a novel triazolopyrimidine antibiotic obtained from the culture broth of the marine Streptomyces sp. Merv8102 isolated from the sediments of the Mediterranean Sea at the Egyptian Coast. The compound showed potent antibacterial activities with MIC ranging between 1.0-8.0 µg/ml against Gram-positive and Gram-negative bacteria

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(Escherichia coli (ATCC 10536), Pseudomonas aeruginosa (ATCC 10145), Bacillus subtilis (ATCC 6051), Staphylococcus aureus (ATCC 6538) and Micrococcus luteus (ATCC 9341)) which were used as test organisms and the compared displayed no antifungal activity against

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Aspergillus flavus, Trichoderma ressei and Alternaria alternate (El-Gendy et al., 2008). 18. Macrocyclic lactam

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Aureoverticillactam (72) (Fig 14) is a novel 22-membered macrocyclic lactam obtained

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from Streptomyces aureoverticillatus NPS001583 isolated from the marine sediments. Aureoverticillactam showed moderate activity against human colorectal adenocarcnioma HT-29

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(EC50 value of 3.6±2.6 µM), Jurkat leukemia (EC50 value of 2.3±1.1 µM) and mouse melanoma B16F10 cell lines (EC50 value of 2.2±0.9 µM) (Mitchell et al., 2004).

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19. Sisomicin

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Sisomicin (73) (Fig 14) is an antibacterial substance produced by Streptomyces sp. GB-2,

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isolated from the Lianyungang coastal soil, China. The compound possessed antibacterial activity against Bacillus cereus and Escherichia coli (Lu et al., 2009).

Ac ce p

20. Esters

Esters are chemical compounds. Bonactin (74) (Fig 14) is a new antimicrobial ester obtained from the liquid culture of a Streptomyces sp. BD21-2, isolated from a shallow-water sediment sample collected at Kailua Beach, Oahu, Hawaii. Bonactin exhibited antimicrobial activity against Gram-positive and Gram-negative bacteria as well as antifungal activity (Schumacher et al., 2003). 21. Conclusion Marine actinobacteria have a tremendous potential to provide therapeutic leads with distinct chemical structures and biological activities. Actinobacteria and in particular the genus

16

Page 16 of 46

Streptomyces, have the ability to produce a wide variety of secondary metabolites as bioactive compounds, including antimicrobial, anticancer, antitumor, anti-inflammatory, anti-malarial, antiviral, anti-angiogenesis drugs, etc.

With the increasing development in science and

ip t

technology of oceanographic studies leading to the isolation of novel actinobacteria from marine sources, new prolific genera in the production of potential bioactive compounds have been

cr

found, such as Salinispora. As marine microorganisms, particularly actinobacteria, have

us

developed the greatest genomic and metabolic diversity and efforts should be directed towards exploring them as an important source for the discovery of novel bioactive natural products, for

an

the development of new drugs.

There is no conflict of interest.

d

Acknowledgments

M

Conflict of interest statement

te

This research was supported by a grant from Marine Bioprocess Research Center of the Marine Biotechnology Program funded by the Ministry of Oceans and Fisheries, Republic of

Ac ce p

Korea. One of the authors, E.C.Y. Li-Chan expresses his thanks to the Natural Sciences and Engineering Council of Canada (NSERC). Kannan Sivakumar expresses his thanks to the Dean, Centre of Advanced Study in Marine Biology, Faculty of Marine Sciences and Annamalai University authorities for facilities and encouragement. Authors also thank Prof. L. Kannan, Former Vice-chancellor of Thiruvalluvar University, for critically going through the manuscript and offering comments.

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Page 17 of 46

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Table 1. Bioactive compounds produced by marine actinobacteria.

Daryamides

Polyketide

Actinofuranones

Polyketide

Phaeochromycins

Polyketide

Saliniketals

Polyketide

Abyssomicin C

Polyketide

Arenicolides

Polyketide

Chartreusin

Polyketide

Salinipyrones

Polyketide

Pacificanones

Polyketide

Mechercharmycins

Peptides

Thiocoraline

Peptides

Cyclomarin A

Peptides

Piperazimycins

Peptides

Salinamides

Peptides

8-amino[1,4]diazonane-2,5dione Leucyl-4hydroxyproline Arenamides

Peptides

Streptomyces acrimycini

Peptides

Streptomyces acrimycini Salinipora arenicola

Antitumor, Antifungal Cytotoxic -

Anticancer

M

Streptomyces sp. Streptomyces sp.

References Li and Piel (2002) Asolkar et al. (2006) Cho et al., (2006b) Li et al. (2008)

Antitumor

Williams et al. (2007b) Riedlinger et al. (2004) Williams et al. (2007a) Xu et al. (2005)

Cytotoxic

Oh et al. (2008)

Cytotoxic

Oh et al. (2008)

Antitumor

Kanoh et al. (2005) Romero et al. (1997) Renner et al. (1999)

Antibacterial Antitumor

an

Salinispora arenicola Streptomyces chartreusis Salinispora pacifica CNS237 Salinispora pacifica CNS237 Thermoactinom yces sp. Micromonospor a sp. Streptomyces sp.

d

te

Ac ce p Peptides

Activity -

ip t

Source Streptomyces sp. JP95 Streptomyces sp. CNQ-085 Streptomyces CNQ766 Streptomyces sp. DSS-18 Salinispora arenicola Verrucosispora

cr

Structural type Polyketide

us

Compound Griseorhodin A

Antitumor; antimicrobial Antiinflammator y Cytotoxic Antibacterial ; antiinflammator y Cytotoxic

Miller (2007) Moore (1999)

et

al.

et

al.

Hernández et al. (2004) Hernández et al. (2004) Asolkar et al. (2008) 29

Page 29 of 46

Proximicins

Peptides

Himalomycins

Quinones

Tetracenomycin D

Quinones

Komodoquinone A

Quinones

Chalcomycin A

Macrolides

Azamerone

Terpenes

Glyciapyrroles

Terpenes

Selina-4(14),7(11)diene-8,9-dio 10α,11dihydroxyamorph-4ene, 10α,15dihydroxyamorph-4en-3-one and 5α,10α,11trihydroxyamorphan -3-one 15-hydroxy-Tmuurolol Neomarinone

Terpenes

3,6-disubstituted indoles

Indole

Streptochlorin

Indole

Bohemamines

Alkaloids

Aburatubolactams

Alkaloids

Ammosamides

Pyrroloiminoquino ne Butenolide

Cytostatic

Schneider et al. (2008) Maskey et al. (2003) Adinarayana et al. (2006)

Antibacterial Cytotoxic

Neuritogenic

M

Itoh et al. (2003b) and Itoh et al. (2003a) Wu et al. (2007)

Antibacterial -

Antibacterial Anticancer -

Cho et al. (2006a) Macherla et al. (2005) Wu et al. (2006) Macherla et al. (2005)

te

d

Terpenes

Ac ce p

Butenolides

Cho et al. (2007)

an

Streptomyces sp. M491 Streptomyces sp. Streptomyces sp. Streptomyces sp. QD518 Streptomyces sp.

Cytotoxic

ip t

Nocardiopsis lucentensis Verrucosispora sp. Streptomyces sp. Streptomyces corchorusii AUBN1/7 Streptomyces sp. KS3

cr

Peptides

us

Lucentamycins

Terpenes Terpenes

Streptomyces sp. M491 Strain CNH099 Streptomyces sp. BL-49-58005 Streptomyces sp. 04DH110 Streptomyces sp. CNQ-583 Streptomyces sp. SCRC-A20 Streptomyces sp. CNR-698 Streptoverticilli um

Cytotoxic Cytotoxic Cytotoxic Anticancer Cytotoxic Cytotoxic

Ding et al. (2008) Hardt et al. (2000) Sánchez López et al. (2003) Jae et al. (2007) Bugni et al. (2006) Yamada et al. (1999) Hughes et al. (2009) Li et al. (2006)

30

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Complex compounds

Trioxacarcins

Marinopyrroles

Marinopyrrole

Chinikomycins

Manumycin derivatives

Essramycin

Triazolopyrimidine

Aureoverticillactam

Macrocyclic lactam

Sisomicin

Sisomicin

Bonactin

Esters

Streptomyces sp. CNQ-418 Streptomyces sp. M045

Anticancer

ip t

Methylpyridine

Streptomyces sp. Merv8102 Streptomyces aureoverticillat us NPS001583 Streptomyces sp. GB-2 Streptomyces sp. BD21-2

Anticancer; Antimalarial Antibacterial

Maskey et (2004)

al.

Antitumor

Antibacterial Antitumor

Hughes et al. (2008) Li et al. (2005)

El-Gendy et al. (2008) Mitchell et al. (2004)

Antibacterial

Lu et al. (2009)

Antimicrobia l

Schumacher al. (2003)

et

Ac ce p

te

Hohmann et al. (2009) Hayakawa et al. (2007) Jeong et al. (2006)

cr

Streptokordin

Anticancer

us

Piericidin

Anticancer

an

Piericidins

M

Benzoxazole

d

Caboxamycin

luteoverticillatu m Streptomyces sp. NTK 937 Streptomyces sp. Streptomyces sp. KORDI3238 Streptomyces sp. B8652

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Figure legends Fig 1. Chemical structures of griseorhodin A, daryamides A, daryamides B, daryamides C, actinofuranones A and actinofuranones B.

ip t

Fig 2. Chemical structures of phaeochromycins F, phaeochromycins G, phaeochromycins H, saliniketals A, saliniketals B, abyssomicin C and arenicolides.

cr

Fig 3. Chemical structures of chartreusin, salinipyrones and pacificanones

us

Fig 4. Chemical structures of mechercharmycin A, mechercharmycin B and thiocoraline.

dione and leucyl-4-hydroxyproline.

an

Fig 5. Chemical structures of cyclomarin A, piperazimycins, 8-amino-[1,4]diazonane-2,5-

Fig 6. Chemical structures of salinamides and arenamides.

M

Fig 7. Chemical structures of lucentamycins and proximicins.

d

Fig 8. Chemical structure of himalomycins A, himalomycins B, tetracenomycin D,

te

komodoquinone A and komodoquinone B. Fig 9. Chemical structures of chalcomycin A, chalcomycin B, glyciapyrroles A,

Ac ce p

glyciapyrroles B and glyciapyrroles C. Fig 10. Chemical structures of azamerone, selina-4(14),7(11)-diene-8,9-dio, 10α,11dihydroxyamorph-4-ene,

10α,15-dihydroxyamorph-4-en-3-one,

5α,10α,11-

trihydroxyamorphan-3-one, 15-hydroxy-T-muurolol and neomarinone. Fig 11. Chemical structure of bohemamines, aburatubolactams, K252c, arcyriaflavin A and altemicidin. Fig 12. Chemical structures of 3,6-disubstituted indoles, streptochlorin, ammosamides, butenolides, caboxamycin, piericidins and streptokordin. Fig 13. Chemical structures of trioxacarcins and marinopyrroles.

32

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Fig 14. Chemical structures of chinikomycins A, essramycin, aureoverticillactam, sisomicin

Fig 1

Ac ce p

te

d

M

an

us

cr

ip t

and bonactin.

33

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ip t cr us an M Ac ce p

te

d

Fig 2

34

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ip t cr us an M Ac ce p

te

d

Fig 3

35

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ip t cr us an M Ac ce p

te

d

Fig 4

36

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ip t cr us an M Ac ce p

te

d

Fig 5

37

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ip t cr us an M Ac ce p

te

d

Fig 6

38

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ip t cr us an M Ac ce p

te

d

Fig 7

39

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ip t cr us an M Ac ce p

te

d

Fig 8

40

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ip t cr us an M Ac ce p

te

d

Fig 9

41

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ip t cr us an M Ac ce p

te

d

Fig 10

42

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ip t cr us an M Ac ce p

te

d

Fig 11

43

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ip t cr us an M Ac ce p

te

d

Fig 12

44

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ip t cr us an M d Ac ce p

te

Fig 13

45

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ip t cr us an M Ac ce p

te

d

Fig 14

46

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