Malayeri Sina Omid, Abnous Khalil, Arab Atefeh, Akaberi Maryam, Mehri Soghra, Zarghi Afshin, Ghodsi Razieh
Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Pharmaceutical Research Center, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Bioorg Med Chem. 2017 Feb 1;25(3):1294-1302. doi: 10.1016/j.bmc.2016.12.050. Epub 2017 Jan 2.
A new series of quinoline analogues was designed and synthesized as Hsp90 inhibitors. The cytotoxic activity of the synthesized compounds was evaluated against three human cancer cell lines including MCF-7 (human breast cancer cells), DU145 (human prostate cancer cell lines), and A549 (adenocarcinomic human alveolar basal epithelial cells). Some of our compounds (13a-13f) showed significant cytotoxic activity on MCF-7 cells. The most potent anti-proliferative compounds were also tested against Her2, a client protein of Hsp90. Compound 13d that demonstrated the highest antiproliferative activity in the series, was found the most potent one for both Her2 protein degradation and Hsp70 protein induction as well. Molecular modeling studies displayed possible mode of interaction between this compound and N-terminal ATP-binding site of Hsp90.
设计并合成了一系列新型喹啉类似物作为热休克蛋白90（Hsp90）抑制剂。评估了合成化合物对三种人类癌细胞系的细胞毒性活性，包括MCF-7（人乳腺癌细胞）、DU145（人前列腺癌细胞系）和A549（人肺泡基底上皮腺癌细胞）。我们的一些化合物（13a - 13f）对MCF-7细胞显示出显著的细胞毒性活性。还针对Hsp90的客户蛋白Her2测试了最有效的抗增殖化合物。在该系列中表现出最高抗增殖活性的化合物13d，被发现对Her2蛋白降解和Hsp70蛋白诱导也是最有效的。分子模拟研究展示了该化合物与Hsp90的N端ATP结合位点之间可能的相互作用模式。
