Garg Gaurav, Zhao Huiping, Blagg Brian S J
Department of Medicinal Chemistry, The University of Kansas , 1251 Wescoe Hall Drive, Malott 4070, Lawrence, Kansas 66045-7563, United States.
ACS Med Chem Lett. 2014 Dec 12;6(2):204-9. doi: 10.1021/ml5004475. eCollection 2015 Feb 12.
Hsp90 C-terminal inhibitors represent a novel and alternative chemotherapeutic approach for the treatment of cancer. Novobiocin was the first natural product identified as an Hsp90 C-terminal inhibitor; however, it manifests poor antiproliferative activity. In contrast to N-terminal inhibitors, novobiocin does not induce the pro-survival heat shock response. Structural investigations on novobiocin have elucidated some structure-activity relationships and several promising compounds. On the basis of structure-activity relationships and computational studies, a library of ring-constrained novobiocin analogues was designed, synthesized, and evaluated in antiproliferative assays. Results obtained from these studies provide insights into the Hsp90 C-terminal binding site, and new analogues that were developed manifest low micromolar to mid-nanomolar antiproliferative activity resulting from Hsp90 inhibition.
热休克蛋白90（Hsp90）C端抑制剂代表了一种用于治疗癌症的新型替代化疗方法。新生霉素是首个被鉴定为Hsp90 C端抑制剂的天然产物；然而，它表现出较差的抗增殖活性。与N端抑制剂不同，新生霉素不会诱导促生存热休克反应。对新生霉素的结构研究阐明了一些构效关系以及几种有前景的化合物。基于构效关系和计算研究，设计、合成了一系列环约束新生霉素类似物，并在抗增殖试验中进行了评估。这些研究获得的结果为深入了解Hsp90 C端结合位点提供了线索，所开发的新类似物因抑制Hsp90而表现出低微摩尔至中纳摩尔的抗增殖活性。
