Antineoplastic Agents. 520. Isolation and Structure of Irciniastatins A and B from the Indo-Pacific Marine Sponge Ircinia ramosa

Pettit, George R.; Xu, Jun‐Ping; Chapuis, Jean‐Charles; Pettit, Robin K.; Tackett, Larry P.; Doubek, Dennis L.; Hooper, John N. A.; Schmidt, Jean M.

doi:10.1021/jm030207d

Cited by 135 publications

(139 citation statements)

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“…Intriguingly, metabolites with high structural similarity to pederin are also known from several different marine sponges (14). Many of these compounds exhibit extremely potent antitumor activity, and psymberin (15) [also known as irciniastatin A (16)] has recently been demonstrated to exhibit remarkably selective activity against solid tumor cell lines, which makes it a promising drug lead. The biological complexity of sponges can be enormous, because many species contain hundreds of distinct bacteria that can occupy up to 40% of their biomass (17).…”

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confidence: 99%

Antitumor polyketide biosynthesis by an uncultivated bacterial symbiont of the marine sponge Theonella swinhoei

Piel

Hui

Wen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

503

405

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Bacterial symbionts have long been suspected to be the true producers of many drug candidates isolated from marine invertebrates. Sponges, the most important marine source of biologically active natural products, have been frequently hypothesized to contain compounds of bacterial origin. This symbiont hypothesis, however, remained unproven because of a general inability to cultivate the suspected producers. However, we have recently identified an uncultured Pseudomonas sp. symbiont as the most likely producer of the defensive antitumor polyketide pederin in Paederus fuscipes beetles by cloning the putative biosynthesis genes. Here we report closely related genes isolated from the highly complex metagenome of the marine sponge Theonella swinhoei, which is the source of the onnamides and theopederins, a group of polyketides that structurally resemble pederin. Sequence features of the isolated genes clearly indicate that it belongs to a prokaryotic genome and should be responsible for the biosynthesis of almost the entire portion of the polyketide structure that is correlated with antitumor activity. Besides providing further proof for the role of the related beetle symbiont-derived genes, these findings raise intriguing ecological and evolutionary questions and have important general implications for the sustainable production of otherwise inaccessible marine drugs by using biotechnological strategies. F or almost 30 years, symbiotic bacteria have been discussed as the likely true producers of numerous natural products isolated from marine invertebrates (1). Particularly suggestive of a bacterial origin is the similarity of many compounds from sponges, tunicates, or bryozoans to complex polyketides and nonribosomal peptides, two groups of metabolites that are otherwise known exclusively from microorganisms (2, 3). Into these structural families fall some of today's most promising drug candidates, such as discodermolide, bryostatin 1, aplidine, and ET-743 (4). The existence of producing symbionts could have far reaching consequences for the development of sustainable, fermentation-based sources of invertebrate-derived drug candidates, almost all of which are currently inaccessible in large amounts. Several studies have tried to pinpoint the producers by using cultivation (5), cell separation (6), immunolocalization (7), or in situ hybridization (8) approaches. However, as none of these methods have so far provided unambiguous results, the true origin of the compounds still remains an enigma. We have recently used a genetic strategy to provide insights into natural product symbiosis in terrestrial insects (9). Rove beetles of the genera Paederus and Paederidus are the source of the highly active antitumor polyketide pederin (Fig. 1), which they use as chemical defense (10). We isolated a set of putative pederin biosynthesis genes (9, 11) from the metagenome of Paederus fuscipes beetles and traced them to a bacterial symbiont with the closest relationship to Pseudomonas aeruginosa (12). The genes encode a mixed modul...

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confidence: 99%

Antitumor polyketide biosynthesis by an uncultivated bacterial symbiont of the marine sponge Theonella swinhoei

Piel

Hui

Wen

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

503

405

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“…On the other hand they can be activated with suitable Lewis or Brønsted acids to generate reactive N-acylimines. In addition the N-acyl-N,O-acetal and the analogous N-acylhemiaminal motifs are found in a number of natural products with interesting biological activities, such as zampanolide (1), [2] psymberin (2), [3] or pederin (3) [4] ( Figure 1). Due to their importance several synthetic routes to Nacyl-N,O-acetals have been developed.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of N‐Acyl‐N,O‐acetals from Aldehydes, Amides and Alcohols

et al. 2015

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“…and Ircinia ramose off the coast of Papua New Guinea by two independent research groups. [1,2] Its structural resemblance to other cytotoxins of the pederin family [e.g. pederin (2), mycalamide A (3) and the non-natural psympederin (4)], which are known to have strong antitumour properties, also suggested cytotoxic activity.…”

Section: Introductionmentioning

confidence: 99%

“…[1,2] Its structural resemblance to other cytotoxins of the pederin family [e.g. pederin (2), mycalamide A (3) and the non-natural psympederin (4)], which are known to have strong antitumour properties, also suggested cytotoxic activity. Screening showed that psymberin (1) shows remarkable cytostatic activity against multiple human cancer cell lines with an LC 50 in nanomolar concentrations.…”

Section: Introductionmentioning

confidence: 99%