Safracins,new antitumor antibiotics III. biological activity.

Ikeda, Yoshifumi; Shimada, Yoshiko; Honjo, Katsuhiko; Okumoto, Takeki; Munakata, Tomohiko

doi:10.7164/antibiotics.36.1290

Cited by 20 publications

(10 citation statements)

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“…In addition, the ecteinascidins and their biosynthetic precursors are present in trace amounts in the tunicate extract. Despite these intrinsic challenges, information about the biosynthesis of these alkaloids has been partially obtained, owing largely to the structural similarity between the ecteinascidins, specifically Et-743, and other THIQ family members, including saframycin B ( 2 ), 44 saframycin Mx1 ( 3 ), 45 safracin A ( 4 ), 46 naphthyridinomycin ( 5 ), 47 and quinocarcin ( 6 ) (Figure 6). 48, 49 …”

Section: Biosynthesis Of the Ecteinascidinsmentioning

confidence: 99%

Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics

et al. 2015

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The Ecteinascidin family comprises a number of biologically active compounds, containing two to three tetrahydroisoquinoline subunits. Although isolated from marine tunicates, these compounds share a common pentacyclic core with several antimicrobial compounds found in terrestrial bacteria. Among the tetrahydroisoquinoline natural products, Ecteinascidin 743 (Et-743) stands out as the most potent antitumor antibiotics that it is recently approved for treatment of a number of soft tissue sarcomas. In this article, we will review the backgrounds, the mechanism of action, the biosynthesis, and the synthetic studies of Et-743. Also, the development of Et-743 as an antitumor drug is discussed.

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Section: Biosynthesis Of the Ecteinascidinsmentioning

confidence: 99%

Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics

et al. 2015

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“…These three variants account for > 97% of the 16S rRNA gene sequencing reads (Figure 3). None of these three strains form a close phylogenetic relationship with S. lavendulae , M. xanthus , or P. fluorescens, pure culture producers of the three tetrahydroisoquinoline antibiotics whose pathways have been previously characterized (11, 12, 13). …”

Section: Resultsmentioning

confidence: 99%

Meta-omic Characterization of the Marine Invertebrate Microbial Consortium That Produces the Chemotherapeutic Natural Product ET-743

Rath¹,

et al. 2011

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In many macroorganisms, the ultimate source of potent biologically active natural products has remained elusive due to an inability to identify and culture the producing symbiotic microorganisms. As a model system for developing a meta-omic approach to identify and characterize natural product pathways from invertebrate-derived microbial consortia we chose to investigate the ET-743 (Yondelis®) biosynthetic pathway. This molecule is an approved anti-cancer agent obtained in low abundance (10−4–10−5% w/w) from the tunicate Ecteinascidia turbinata, and is generated in suitable quantities for clinical use by a lengthy semi-synthetic process. Based on structural similarities to three bacterial secondary metabolites, we hypothesized that ET-743 is the product of a marine bacterial symbiont. Using metagenomic sequencing of total DNA from the tunicate/microbial consortium we targeted and assembled a 35 kb contig containing 25 genes that comprise the core of the NRPS biosynthetic pathway for this valuable anti-cancer agent. Rigorous sequence analysis based on codon usage of two large unlinked contigs suggests that Candidatus Endoecteinascidia frumentensis produces the ET-743 metabolite. Subsequent metaproteomic analysis confirmed expression of three key biosynthetic proteins. Moreover, the predicted activity of an enzyme for assembly of the tetrahydroisoquinoline core of ET-743 was verified in vitro. This work provides a foundation for direct production of the drug and new analogs through metabolic engineering. We expect that the interdisciplinary approach described is applicable to diverse host-symbiont systems that generate valuable natural products for drug discovery and development.

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“…46 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 50 51 52 53 54 55 56 57 58 59 60 Safracin B was first known to possess antibiotic properties, and shortly thereafter, its antiproliferative activity was reported. 51 The synthetic transformation of safracin B to ecteinascidin 743, initially pursued to address a clinical supply challenge, serves as an example in which the chemical transformation of a natural product starting material with known antibiotic and antiproliferative activity yields a derivative with clinically useful anticancer activity.…”

Section: Safracin B and Ecteinascidin 743mentioning

confidence: 99%

Underexplored Opportunities for Natural Products in Drug Discovery

DeCorte

2016

J. Med. Chem.

103

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The importance of natural products in the treatment of human disease is well documented. While natural products continue to have a profound impact on human health, chemists have succeeded in generating semisynthetic analogues that sometimes overshadow the original natural product in terms of clinical significance. Synthetic efforts based on natural products have primarily focused on improving their drug-like features while targeting utility in the same biological space. A less documented phenomenon is that natural products can serve as powerful starting materials to generate drug substances with novel therapeutic utility that is unrelated to the biological space of the natural product starting material. In this Perspective, examples of natural product derived marketed drugs with therapeutic utility in clinical space that is different from the biological profile of the starting material are presented, demonstrating that this is not merely a theoretical concept but both a clinical reality and an underexplored opportunity.

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Safracins,new antitumor antibiotics III. biological activity.

Cited by 20 publications

References 0 publications

Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics

Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics

Meta-omic Characterization of the Marine Invertebrate Microbial Consortium That Produces the Chemotherapeutic Natural Product ET-743

Underexplored Opportunities for Natural Products in Drug Discovery

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