Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern , Erwin-Schrödinger-Strasse 52, D-67663 Kaiserslautern, Germany.
Department of Pharmacy and Molecular Biotechnology, Division of Pharmaceutical Biology, University of Heidelberg , Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
J Med Chem. 2017 Jun 22;60(12):4949-4962. doi: 10.1021/acs.jmedchem.7b00324. Epub 2017 Jun 6.
Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3'-position have been extensively investigated, but the impact of substituents in 5'-position is not equally well-studied. Here, we report the synthesis of new indirubin 3'- and 5'-derivatives in the search of water-soluble indirubins by introducing basic centers. Antiproliferative activity of all compounds in tumor cells was evaluated along with kinase inhibition of selected compounds. The results show the 3'-position to tolerate large substituents without compromising activity, whereas bulk and rigid substituents in 5'-position appear unfavorable. Screening molecular targets of water-soluble 3'-oxime ethers revealed 6ha as preferential inhibitor of insulin-like growth factor 1 receptor (IGF-1R) in a panel of 22 protein kinases and in cells. Consistently, 6ha inhibited tumor cell growth in the NCI 60 cell line panel and induced apoptosis. The results indicate that the 5'-position provides limited space for chemical modifications and identify 6ha as a potent water-soluble indirubin-based IGF-1R inhibitor.
靛玉红已被确定为有效的 ATP 竞争性蛋白激酶抑制剂。5-位和 3'-位的结构修饰已得到广泛研究，但 5'-位取代基的影响尚未得到同等深入的研究。在这里，我们通过引入碱性中心，报告了新的吲哚 3'-和 5'-衍生物的合成，以寻找水溶性靛玉红。评估了所有化合物在肿瘤细胞中的抗增殖活性以及选定化合物的激酶抑制活性。结果表明，3'-位可以容忍大的取代基而不影响活性，而 5'-位的大体积和刚性取代基则不利。对水溶性 3'-肟醚的分子靶标进行筛选，发现 6ha 在 22 种蛋白激酶和细胞中优先作为胰岛素样生长因子 1 受体 (IGF-1R) 的抑制剂。一致地，6ha 抑制了 NCI 60 细胞系panel 中的肿瘤细胞生长并诱导凋亡。结果表明，5'-位为化学修饰提供的空间有限，并确定 6ha 为一种有效的基于水溶性靛玉红的 IGF-1R 抑制剂。
