在一系列设计的具有辅助碳酸酐酶抑制活性的3-烯基-氧化吲哚作为抗增殖剂中发现一种新型强效氧化吲哚多激酶抑制剂。
Discovery of a new potent oxindole multi-kinase inhibitor among a series of designed 3-alkenyl-oxindoles with ancillary carbonic anhydrase inhibitory activity as antiproliferative agents.
作者信息
Ismail Rania S M, El Kerdawy Ahmed M, Soliman Dalia H, Georgey Hanan H, Abdel Gawad Nagwa M, Angeli Andrea, Supuran Claudiu T
机构信息
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, P.O. Box 11829, Badr City, Cairo, Egypt.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt.
出版信息
BMC Chem. 2023 Jul 18;17(1):81. doi: 10.1186/s13065-023-00994-3.
An optimization strategy was adopted for designing and synthesizing new series of 2-oxindole conjugates. Selected compounds were evaluated for their antiproliferative effect in vitro against NCI-60 cell lines panel, inhibitory effect on carbonic anhydrase (CA) isoforms (hCAI, II, IX and XII), and protein kinases. Compounds 5 and 7 showed promising inhibitory effects on hCA XII, whereas compound 4d was the most potent inhibitor with low nanomolar CA inhibition against all tested isoforms. These results were rationalized by using molecular docking. Despite its lack of CA inhibitory activity, compound 15c was the most active antiproliferative candidate against most of the 60 cell lines with mean growth inhibition 61.83% and with IC values of 4.39, 1.06, and 0.34 nM against MCT-7, DU 145, and HCT-116 cell lines, respectively. To uncover the mechanism of action behind its antiproliferative activity, compound 15c was assessed against a panel of protein kinases (RET, KIT, cMet, VEGFR1,2, FGFR1, PDFGR and BRAF) showing % inhibition of 74%, 31%, 62%, 40%, 73%, 74%, 59%, and 69%, respectively, and IC of 1.287, 0.117 and 1.185 μM against FGFR1, VEGFR, and RET kinases, respectively. These results were also explained through molecular docking.
采用了一种优化策略来设计和合成新系列的2-氧代吲哚共轭物。对所选化合物进行了体外抗增殖活性评估，以检测其对NCI-60细胞系的抑制作用、对碳酸酐酶（CA）同工型（hCAI、II、IX和XII）的抑制作用以及对蛋白激酶的抑制作用。化合物5和7对hCA XII显示出有前景的抑制作用，而化合物4d是对所有测试同工型具有低纳摩尔CA抑制活性的最有效抑制剂。通过分子对接对这些结果进行了合理化分析。尽管化合物15c缺乏CA抑制活性，但它是对60种细胞系中的大多数最具活性的抗增殖候选物，平均生长抑制率为61.83%，对MCT-7、DU 145和HCT-116细胞系的IC值分别为4.39、1.06和0.34 nM。为了揭示其抗增殖活性背后的作用机制，对化合物15c针对一组蛋白激酶（RET、KIT、cMet、VEGFR1、2、FGFR1、PDFGR和BRAF）进行了评估，其抑制率分别为74%、31%、62%、40%、73%、74%、59%和69%，对FGFR1、VEGFR和RET激酶的IC值分别为1.287、0.117和1.185 μM。这些结果也通过分子对接进行了解释。
Zotero 插件