通过修饰酰胺尾部实现新生霉素抗癌活性与神经保护活性的分化
Diverging Novobiocin Anti-Cancer Activity from Neuroprotective Activity through Modification of the Amide Tail.
作者信息
Ghosh Suman, Liu Yang, Garg Gaurav, Anyika Mercy, McPherson Nolan T, Ma Jiacheng, Dobrowsky Rick T, Blagg Brian S J
机构信息
Department of Medicinal Chemistry and Department of Pharmacology and Toxicology, The University of Kansas , Lawrence, Kansas 66045, United States.
Department of Medicinal Chemistry, Fujian Medical University , Fuzhou, China 350004.
出版信息
ACS Med Chem Lett. 2016 Jul 5;7(8):813-8. doi: 10.1021/acsmedchemlett.6b00224. eCollection 2016 Aug 11.
Abstract
Novobiocin is a natural product that binds the Hsp90 C-terminus and manifests Hsp90 inhibitory activity. Structural investigations on novobiocin led to the development of both anti-cancer and neuroprotective agents. The varied pharmacological activity manifested by these novobiocin analogs prompted the investigation of structure-function studies to identify these contradictory effects, which revealed that modifications to the amide side chain produce either anti-cancer or neuroprotective activity. Compounds that exhibit neuroprotective activity contain a short alkyl or cycloalkyl amide side chain. In contrast, anti-cancer agents contain five or more carbons, disrupt interactions between Hsp90α and Aha1, and induce the degradation of Hsp90-dependent client proteins.
摘要
新生霉素是一种天然产物，它与热休克蛋白90（Hsp90）的C端结合并表现出Hsp90抑制活性。对新生霉素的结构研究促成了抗癌和神经保护剂的开发。这些新生霉素类似物表现出的多种药理活性促使人们开展结构-功能研究以确定这些相互矛盾的作用，研究表明对酰胺侧链的修饰可产生抗癌或神经保护活性。具有神经保护活性的化合物含有短链烷基或环烷基酰胺侧链。相比之下，抗癌剂含有五个或更多碳原子，破坏Hsp90α与Aha1之间的相互作用，并诱导Hsp90依赖性客户蛋白的降解。
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