2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2014 Oct 30:86:165-74. doi: 10.1016/j.ejmech.2014.08.049.
Ping Zhao 1,  Yanzhong Li 1,  Guangwei Gao 1,  Shuai Wang 1,  Yun Yan 1,  Xiaoping Zhan 1,  Zenglu Liu 1,  Zhenmin Mao 2,  Shaoxiong Chen 3,  Liqun Wang 3
Affiliations

Affiliations

  • 1 School of Pharmacy, Shanghai Jiaotong University, No. 800, Dongchuan Road, Shanghai 200240, China.
  • 2 School of Pharmacy, Shanghai Jiaotong University, No. 800, Dongchuan Road, Shanghai 200240, China. Electronic address: zmmao@sjtu.edu.cn.
  • 3 Strategic Alliance of Biomedical Technology, No. 333, Cailun Road, Shanghai 201210, China.
PMID: 25151579 DOI: 10.1016/j.ejmech.2014.08.049
Abstract

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.

Keywords

Antitumor; Apoptosis; CDKs; GSK-3β; Isoindigo derivative; Mechanism.

Figures