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 anti-proliferative activity was evaluated by Sulforhodamine B (SRB) assay. Some of the target compounds exhibited significant antitumor activity, including compounds 6h and 6k (against K562?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?μM) 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-3β (Ser9), β-catenin and c-myc proteins, up-regulated the expression of GSK-3β, consequently, suppressed Wnt/β-catenin signaling pathway and induced the apoptosis of K562?cells. The binding mode of compound 6k with GSK-3β 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-3β (Ser9) phosphorylation inhibitors applied in cancer chemotherapy.

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