Plasticity in gilvocarcin-type C-glycoside pathways:: discovery and antitumoral evaluation of polycarcin V from Streptomyces polyformus
Plasticity in gilvocarcin-type C-glycoside pathways:: discovery and antitumoral evaluation of polycarcin V from Streptomyces polyformus
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DOI：
10.1039/b808633h
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发表时间：
2008-10-07
影响因子：
3.2
通讯作者：
Sattler, Isabel
中科院分区：
文献类型：
--
作者：
Li, Yi-qing;Huang, Xue-shi;Sattler, Isabel
Gilvocacin 型聚酮苷代表了一些最有效的抗肿瘤疗法。多形链霉菌培养物提取物的生物活性引导分级分离。十一月(YIM 33176) 产生了已知的 gilvocacin V (2) 和一种新型相关化合物，polycarcin V (1)。通过 NMR 和化学衍生化的结构解析表明，同源物 (1) 具有 C-糖苷连接的 α-L-吡喃鼠李糖基部分，而不是 D-呋喃岩藻糖。共享相同苷元的两种不同的呋喃糖基和吡喃糖基C-糖苷的同时产生在细菌中是前所未有的。排除了两种亚型通过醌甲基化物中间体调用的转换，从而指出了两个单独的 C-糖基化途径。 Polycarcin V 在 37 个肿瘤细胞系中的细胞毒性分析表明其具有显着的抗肿瘤活性，对非小细胞肺癌、乳腺癌和黑色素瘤细胞具有明显的选择性。由于抗增殖指纹与放线菌素 D 相同，因此已知的 gilvocarcins 的 DNA 相互作用被确立为抗肿瘤活性的一般原理。
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 call 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.