Yang Ying-Rui, Wei Jin-Lian, Mo Xiao-Fei, Yuan Zhen-Wei, Wang Jia-Lin, Zhang Chao, Xie Yi-Yue, You Qi-Dong, Sun Hao-Peng
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Bioorg Med Chem Lett. 2016 Jun 1;26(11):2713-8. doi: 10.1016/j.bmcl.2016.03.112. Epub 2016 Apr 1.
p53-independent malignant cancer is still severe health problem of human beings. HIF-1 pathway is believed to play an important role in the survival and developing progress of such cancers. In the present study, with the aim to inhibit the proliferation of p53-independent malignant cells, we disclose the optimization of 6a, the starting compound which is discovered in the screening of in-house compound collection. The structure-activity relationship (SAR) is summarized. The most potent derivative 8d, inhibits the proliferation of both p53-null and p53-mutated cells through inhibition of HIF-1 pathway. Our findings here provide a new chemotype in designing potent anticancer agent especially against those p53-independent malignant tumors.
不依赖p53的恶性肿瘤仍是人类面临的严重健康问题。缺氧诱导因子-1（HIF-1）信号通路被认为在此类癌症的存活和发展进程中发挥重要作用。在本研究中，为了抑制不依赖p53的恶性细胞增殖，我们公开了对6a（从内部化合物库筛选中发现的起始化合物）的优化。总结了构效关系（SAR）。最有效的衍生物8d通过抑制HIF-1信号通路抑制p53缺失和p53突变细胞的增殖。我们的研究结果为设计强效抗癌药物，尤其是针对那些不依赖p53的恶性肿瘤提供了一种新的化学类型。
