Park Sun Jun, Kim Eunjin, Yoo Miyoun, Lee Joo-Youn, Park Chi Hoon, Hwang Jong Yeon, Ha Jae Du
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
Korea Chemical Bank, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea.
Bioorg Med Chem Lett. 2017 Sep 15;27(18):4399-4404. doi: 10.1016/j.bmcl.2017.08.018. Epub 2017 Aug 12.
A novel 6-aminopurine scaffold bearing an N9-cis-cyclobutyl moiety was designed using structure-based molecular design based on two known CDK inhibitors, dinaciclib and Cmpd-27. A series of novel 6-aminopurine compounds was prepared for structure-activity relationship (SAR) studies of CDK2 and CDK5 inhibitors. Among the compounds synthesized, compound 8l displayed potent CDK2 and CDK5 inhibitory activities with low nanomolar ranges (IC=2.1 and 4.8nM, respectively) and showed moderate cytotoxicity in HCT116 colon cancer and MCF7 breast cancer cell lines. Here, we report the synthesis and evaluation of novel 6-aminopurine derivatives and present molecular docking models of compound 81 with CDK2 and CDK5.
基于两种已知的细胞周期蛋白依赖性激酶（CDK）抑制剂地西他滨和化合物27，利用基于结构的分子设计，设计了一种带有N9-顺式环丁基部分的新型6-氨基嘌呤支架。制备了一系列新型6-氨基嘌呤化合物，用于CDK2和CDK5抑制剂的构效关系（SAR）研究。在合成的化合物中，化合物8l表现出强效的CDK2和CDK5抑制活性，其抑制浓度在低纳摩尔范围内（IC分别为2.1和4.8 nM），并且在HCT116结肠癌细胞系和MCF7乳腺癌细胞系中显示出中度细胞毒性。在此，我们报告新型6-氨基嘌呤衍生物的合成与评价，并展示化合物81与CDK2和CDK5的分子对接模型。
