设计并合成 (+)-discodermolide-紫杉醇杂合体，提高生物活性。
Design and synthesis of (+)-discodermolide-paclitaxel hybrids leading to enhanced biological activity.
机构信息
Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
出版信息
J Med Chem. 2011 Sep 22;54(18):6319-27. doi: 10.1021/jm200692n. Epub 2011 Aug 26.
Abstract
Potential binding modes of (+)-discodermolide at the paclitaxel binding site of tubulin have been identified by computational studies based on earlier structural and SAR data. Examination of the prospective binding modes reveal that the aromatic pocket occupied by the paclitaxel side chain is unoccupied by (+)-discodermolide. Based on these findings, a small library of (+)-discodermolide-paclitaxel hybrids have been designed and synthesized. Biological evaluation reveals a two- to eight-fold increase in antiproliferative activity compared to the parent molecule using the A549 and MCF-7 cancer cell lines.
摘要
基于早期的结构和 SAR 数据的计算研究已经确定了 (+)-discodermolide 在微管蛋白紫杉醇结合位点的潜在结合模式。对预期结合模式的研究表明，紫杉醇侧链占据的芳构口袋未被 (+)-discodermolide 占据。基于这些发现，设计并合成了一小部分 (+)-discodermolide-紫杉醇杂合体。在 A549 和 MCF-7 癌细胞系中，与母体分子相比，生物评估显示出 2 至 8 倍的增殖抑制活性增加。
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