靶向热休克蛋白 90 二聚体的二聚抑制剂。
Targeting the heat shock protein 90 dimer with dimeric inhibitors.
机构信息
Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045-7563, USA.
出版信息
J Med Chem. 2011 Sep 22;54(18):6234-53. doi: 10.1021/jm200553w. Epub 2011 Aug 23.
Abstract
The design, synthesis, and biological evaluation of conformationally constrained coumermycin A1 analogues are reported. Compounds were evaluated against both breast cancer (SKBr3 and MCF7) and prostate cancer (PC3 mm2, A549, and HT29) cell lines. Non-noviosylated coumermycin A1 analogues that manifest potent antiproliferative activity resulting from Hsp90 inhibition are provided, wherein replacement of the stereochemically complex noviose sugar with readily available piperidine rings resulted in ∼100 fold increase in antiproliferative activities as compared to coumermycin A1, producing small molecule Hsp90 inhibitors that exhibit nanomolar activities.
摘要
报道了构象受限的黏菌素 A1 类似物的设计、合成和生物评价。对化合物进行了针对乳腺癌（SKBr3 和 MCF7）和前列腺癌（PC3mm2、A549 和 HT29）细胞系的评估。提供了非诺伏酰化的黏菌素 A1 类似物，它们通过抑制热休克蛋白 90 表现出有效的抗增殖活性，其中用易得的哌啶环替代立体化学复杂的诺伏糖导致与黏菌素 A1 相比抗增殖活性增加约 100 倍，产生了具有纳摩尔活性的小分子热休克蛋白 90 抑制剂。
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