Bacterial Production of the Tunicate-Derived Antitumor Cyclic Depsipeptide Didemnin B

Tsukimoto, Moriya; Nagaoka, Masato; Shishido, Yoshihiro; Fujimoto, Junji; Nishisaka, Fukiko; Matsumoto, Sachiko; Harunari, Enjuro; Imada, Chiaki; Matsuzaki, Takeshi

doi:10.1021/np200543z

Cited by 98 publications

(105 citation statements)

References 15 publications

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“…Recently, a new approach for the production of such compounds is the use of culturable microorganisms. Tsukimoto and coworkers 110 have reported the isolation of didemnin B and nordidemnin B from the extract of a culture broth of a marine bacterium. Optimization of the fermentation conditions might produce a new, economically viable production of didemnin B, leading to larger scale production, testing, and distribution of this interesting and novel class of drug.…”

Section: Discussionmentioning

confidence: 99%

Didemnins, tamandarins and related natural products

et al. 2012

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Since the discovery and isolation of the didemnin family of marine depsipeptides in 1981, the synthesis and biological activity of its congeners have been of great interest to the scientific community. The didemnins have demonstrated antitumor, antiviral, and immunosuppressive activity at low nano- and femtomolar levels. Of the congeners, didemnin B was the first marine natural product to reach phase II clinical trials in the United States, stimulating many analogue syntheses to date. About two decades later, tamandarins A and B were isolated, and were found to possess very similar structure and biological activity to that of the didemnin B. These compounds have shown impressive biological activity and some progress has been made in establishing structure-activity relationships. However, their molecular mechanism of action still remains unclear. This review highlights the long-standing study of didemnins and its critical application towards the understanding of the molecular mechanism of action of tamandarins and their potential use as therapeutic agents.

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Section: Discussionmentioning

confidence: 99%

Didemnins, tamandarins and related natural products

et al. 2012

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“…The didemnins are a family of cyclic depsipeptide compounds originally isolated from the Trididemnum genus of Caribbean tunicates, with preliminary assays showing potent antitumor activity [99]. The most potent was didemnin B, which represents the first natural product isolated from a marine source to enter anticancer clinical trials [100]. However, during Phase II clinical trials cardiac and pulmonary toxicities precluded it from further evaluations [101].…”

Section: Utility In Natural Products De-replication and Drug Discomentioning

confidence: 99%

“…Using the marine bacteria Tistrella mobilis, discovered to biosynthesize didemnin B, Xu et al [98] utilized 454 pyrosequencing to sequence the complete genome [100]. They developed a biosynthesis model for didemnins based on a non-ribosomal peptide synthetase-polyketide synthase (NRPS-PKS) modular pathway, which they then used to query the genome for the corollary gene cluster [98].…”

Section: Utility In Natural Products De-replication and Drug Discomentioning

confidence: 99%

The utility of metabolomics in natural product and biomarker characterization

Cox

Keasling

et al. 2014

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Metabolomics is a well-established rapidly developing research field involving quantitative and qualitative metabolite assessment within biological systems. Recent improvements in metabolomics technologies reveal the unequivocal value of metabolomics tools in natural products discovery, gene-function analysis, systems biology and diagnostic platforms. Scope of review We review of some of the prominent metabolomics methodologies employed in data acquisition and analysis of natural products and disease-related biomarkers. Major conclusions This review demonstrates that metabolomics represents a highly adaptable technology with diverse applications ranging from environmental toxicology to disease diagnosis. Metabolomic analysis is shown to provide a unique snapshot of the functional genetic status of an organism by examining its biochemical profile, with relevance toward resolving phylogenetic associations involving horizontal gene transfer and distinguishing subgroups of genera possessing high genetic homology, as well as an increasing role in both elucidating biosynthetic transformations of natural products and detecting preclinical biomarkers of numerous disease states. General significance This review expands the interest in multiplatform combinatorial metabolomic analysis. The applications reviewed range from phylogenetic assignment, biosynthetic transformations of natural products, and the detection of preclinical biomarkers.

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“…Instead of trying to completely rebuild the complex cyclic depsipeptide structure through chemical synthesis or attempting to inefficiently farm tunicates through aquaculture, a better solution appears to be a focus on synthetically producing these same compounds in associated microorganisms [46]. In fact, aplidine has been produced by the marine α-proteobacteria Tistrella mobilis and Tistrella bauzanensis via a unique post-assembly line maturation process [44].…”

Section: Biosynthesis: a Possible Solution?mentioning

confidence: 99%

Tunicates: A Vertebrate Ancestral Source of Antitumor Compounds

Cooper

Albert

2014

Handbook of Anticancer Drugs From Marine Origin

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An alarming increase in cancer deaths around the globe has sparked a quest for new effective antitumor drugs developed through biological screening of both terrestrial and marine organisms. Recently, analyses of marine-derived alkaloids isolated from tunicates, a close relative to vertebrates, reveal various anti-cancer activities including anti-angiogenic action, anti-proliferative activity, inhibition of key cellular events like topoisomerase function and tubulin polymerization with respect to cytotoxicity and apoptosis. Vast numbers of potential anticancer molecules in the marine biosphere cannot be underestimated. Tunicate compounds have already entered the market and shown significant success. Moreover, improved technology has enabled synthesis of these molecules by a diverse cadre of professionals including career biologists, immunobiologists, invertebrate immunologists, and marine biologists who use an amazing array of procedures. Although there are no guarantees of consistently reliable success, identifying and comprehending the basic nature of these compounds is a promising first step towards unique pharmaceutical designs that promise to provide a therapeutic solution.

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Bacterial Production of the Tunicate-Derived Antitumor Cyclic Depsipeptide Didemnin B

Cited by 98 publications

References 15 publications

Didemnins, tamandarins and related natural products

Didemnins, tamandarins and related natural products

The utility of metabolomics in natural product and biomarker characterization

Tunicates: A Vertebrate Ancestral Source of Antitumor Compounds

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