Design, synthesis and biological evaluation of N-alkyl or aryl substituted isoindigo derivatives as potential dual cyclin-dependent kinase 2 (CDK2)/glycogen synthase kinase 3β (GSK-3β) phosphorylation inhibitors

A series of N-alkyl or aryl substituted isoindigo derivatives have been synthesized and their antiproliferative activity was evaluated by Sulforhodamine B (SRB) assay. Some of the target compounds exhibited significant antitumor activity, including compounds 6h and 6k (against 1(562 cells), 6i (against HeLa cells) and 6j (against A549 cells). N-(p-methoxy-phenyl)-isoindigo (6k) exhibited a high and selective anti-proliferative activity against K562 cells (IC50 7.8 mu M) and induced the apoptosis of K562 cells in a dose-dependent manner. Compound 6k arrested the cell cycle at S phase in K562 cells by decreasing the expression of cyclin A and CDK2, which played critical roles in DNA replication and passage through G2 phase. Moreover, compound 6k down-regulated the expression of p-GSK-3 beta (Ser9), beta-catenin and c-myc proteins, up-regulated the expression of GSK-3 beta, consequently, suppressed Wnt/beta-catenin signaling pathway and induced the apoptosis of K562 cells. The binding mode of compound 6k with GSK-3 beta was simulated using molecular docking tools. All of these studies gave a better understanding to the molecular mechanisms of this class of agents and clues to develop dual CDK2/GSK-3 beta (Ser9) phosphorylation inhibitors applied in cancer chemotherapy. (c) 2014 Elsevier Masson SAS. All rights reserved.