Ziedan Noha I, Hamdy Rania, Cavaliere Alessandra, Kourti Malamati, Prencipe Filippo, Brancale Andrea, Jones Arwyn T, Westwell Andrew D
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.
Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
Chem Biol Drug Des. 2017 Jul;90(1):147-155. doi: 10.1111/cbdd.12936. Epub 2017 Feb 24.
A new series of oxadiazoles were designed to act as inhibitors of the anti-apoptotic Bcl-2 protein. Virtual screening led to the discovery of new hits that interact with Bcl-2 at the BH3 binding pocket. Further study of the structure-activity relationship of the most active compound of the first series, compound 1, led to the discovery of a novel oxadiazole analogue, compound 16j, that was a more potent small-molecule inhibitor of Bcl-2. 16j had good in vitro inhibitory activity with submicromolar IC values in a metastatic human breast cancer cell line (MDA-MB-231) and a human cervical cancer cell line (HeLa). The antitumour effect of 16j is concomitant with its ability to bind to Bcl-2 protein as shown by an enzyme-linked immunosorbent assay (IC = 4.27 μm). Compound 16j has a great potential to develop into highly active anticancer agent.
设计了一系列新型恶二唑作为抗凋亡Bcl-2蛋白的抑制剂。虚拟筛选发现了与Bcl-2在BH3结合口袋相互作用的新活性化合物。对第一系列中活性最高的化合物即化合物1的构效关系进行进一步研究，发现了一种新型恶二唑类似物化合物16j，它是一种更有效的Bcl-2小分子抑制剂。16j在转移性人乳腺癌细胞系（MDA-MB-231）和人宫颈癌细胞系（HeLa）中具有良好的体外抑制活性，其IC值为亚微摩尔级。如酶联免疫吸附测定所示（IC = 4.27μm），16j的抗肿瘤作用与其结合Bcl-2蛋白的能力相关。化合物16j具有很大的潜力发展成为高活性抗癌药物。
