Yin Yong, Wu Xun, Han Hong-Wei, Sha Shao, Wang She-Feng, Qiao Fang, Lu Ai-Min, Lv Peng-Cheng, Zhu Hai-Liang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Org Biomol Chem. 2014 Dec 7;12(45):9157-65. doi: 10.1039/c4ob01589d.
A series of novel 2-alkyl-chromeno[4,3-c]pyrazol-4(2H)-one derivatives were synthesized and evaluated for their biological activities as PI3K inhibitors. In vitro biological evaluation against four human tumor cell lines revealed that most target compounds showed impressively better antiproliferative activities than that of LY294002. Among these compounds, compound 4l exhibited the most potent and selective activity for PI3Kα, with the value of 0.014 μM, an approximately 30-fold increase in comparison with LY294002. Docking simulation was performed to position compound 4l into the PI3Kα active site and the result showed that compound 4l could bind well at the PI3Kα active site and it indicated that compound 4l could be a potential inhibitor of PI3Kα.
合成了一系列新型的2-烷基-色烯并[4,3-c]吡唑-4(2H)-酮衍生物，并对其作为PI3K抑制剂的生物活性进行了评估。针对四种人类肿瘤细胞系的体外生物学评估表明，大多数目标化合物显示出比LY294002明显更好的抗增殖活性。在这些化合物中，化合物4l对PI3Kα表现出最有效和选择性的活性，其值为0.014 μM，与LY294002相比增加了约30倍。进行对接模拟将化合物4l定位到PI3Kα活性位点，结果表明化合物4l可以在PI3Kα活性位点良好结合，这表明化合物4l可能是PI3Kα的潜在抑制剂。
