Plasticity in gilvocarcin-type C-glycoside pathways: discovery and antitumoral evaluation of polycarcin V from Streptomyces polyformus

Gilvocarcin-type polyketide glycosides represent some of the most powerful antitumor therapeutics. Bioactivity-guided fractionation of a culture extract of Streptomyces polyformus sp. nov. (YIM 33176) yielded the known gilvocarcin V (2) and a novel related compound, polycarcin V (1). Structure eluci...

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Published in:Organic & biomolecular chemistry 2008-10, Vol.6 (19), p.3601-3605
Main Authors: Li, Yi-qing, Huang, Xue-shi, Ishida, Keishi, Maier, Armin, Kelter, Gerhard, Jiang, Yi, Peschel, Gundela, Menzel, Klaus-Dieter, Li, Ming-gang, Wen, Meng-liang, Xu, Li-hua, Grabley, Susanne, Fiebig, Heinz-Herbert, Jiang, Cheng-lin, Hertweck, Christian, Sattler, Isabel
Format: Article
Language:English
Subjects:
Antineoplastic Agents - analysis
Antineoplastic Agents - chemistry
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cell Proliferation - drug effects
Coumarins - analysis
Coumarins - chemistry
Coumarins - pharmacology
Drug Discovery
Glycosides - analysis
Glycosides - biosynthesis
Glycosides - chemistry
Glycosides - pharmacology
Humans
Streptomyces - metabolism
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Summary:Gilvocarcin-type polyketide glycosides represent some of the most powerful antitumor therapeutics. Bioactivity-guided fractionation of a culture extract of Streptomyces polyformus sp. nov. (YIM 33176) yielded the known gilvocarcin V (2) and a novel related compound, polycarcin V (1). Structure elucidation by NMR and chemical derivatization revealed that the congener (1) features a C-glycosidically linked alpha-L-rhamnopyranosyl moiety in lieu of the D-fucofuranose. The concomitant production of two distinct furanosyl and pyranosyl C-glycosides that share the same aglycone is unprecedented in bacteria. A conversion of both isoforms via a quinone methide intermediate can be ruled out, thus pointing to two individual C-glycosylation pathways. Cytotoxicity profiling of polycarcin V in a panel of 37 tumor cell lines indicated significant antitumoral activity with a pronounced selectivity for non-small-cell lung cancer, breast cancer and melanoma cells. As the antiproliferative fingerprint is identical to that of actinomycin D, the known DNA interaction of gilvocarcins was established as a general principle of antitumorigenic activity.
ISSN:1477-0520
1477-0539
DOI:10.1039/b808633h