Novologues containing a benzamide side chain manifest anti-proliferative activity against two breast cancer cell lines.
Novologues containing a benzamide side chain manifest anti-proliferative activity against two breast cancer cell lines.
复制标题
含有苯甲酰胺侧链的新型同源物对两种乳腺癌细胞系表现出抗增殖活性。
DOI：
10.1016/j.bmcl.2014.05.020
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发表时间：
2014
影响因子：
2.7
通讯作者：
Blagg,BrianSJ
中科院分区：
文献类型：
--
作者：
Zhao,Huiping;Anyika,Mercy;Girgis,Antwan;Blagg,BrianSJ
Hsp90是开发抗癌和神经保护剂的一个有希望的靶点。对新生物素和新生物素类似物的构效关系研究导致KU-32和最近的KU-596被开发为神经退行性疾病的潜在治疗先导化合物。与KU-32类似，我们已经证明，在用苯酰胺取代KU-32中存在的乙酰胺侧链后，这种神经保护剂转化为具有抗增殖活性的支架。为了评估这种新支架的结构-活性关系，制备了一个含苯酰胺的新支架文库，并对两种乳腺癌细胞系进行了评估。在这些研究中，化合物14表现出最有效的抗增殖活性，并以浓度依赖的方式诱导hsp90依赖的客户蛋白降解。
Hsp90 represents a promising target for the development of both anti-cancer and neuroprotective agents. Structure–activity relationship studies on novobiocin and novobiocin analogues, led to the development of KU-32 and recently, KU-596, as lead compounds for the potential treatment of neurodegenerative diseases. Similar to KU-32, we have demonstrated that upon replacement of the acetamide side chain present in KU-32 with a benzamide, this neuroprotective agent was transformed into a scaffold that manifests anti-proliferative activity. To assess structure–activity relationships for this new scaffold, a library of benzamide-containing novologues was prepared and evaluated against two breast cancer cell lines. Compound14amanifested the most potent anti-proliferative activity from these studies and induced Hsp90-dependent client protein degradation in a concentration-dependent manner.