title: 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.
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.
authors.affiliation: School of Pharmacy, Shanghai Jiaotong University, No. 800, Dongchuan Road, Shanghai 200240, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, Shanghai Jiaotong University, No. 800, Dongchuan Road, Shanghai 200240, China.
authors.forename: Yanzhong
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shanghai Jiaotong University, No. 800, Dongchuan Road, Shanghai 200240, China.
authors.forename: Guangwei
authors.initials: G
authors.lastname: Gao
authors.affiliation: School of Pharmacy, Shanghai Jiaotong University, No. 800, Dongchuan Road, Shanghai 200240, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shanghai Jiaotong University, No. 800, Dongchuan Road, Shanghai 200240, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yan
authors.affiliation: School of Pharmacy, Shanghai Jiaotong University, No. 800, Dongchuan Road, Shanghai 200240, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhan
authors.affiliation: School of Pharmacy, Shanghai Jiaotong University, No. 800, Dongchuan Road, Shanghai 200240, China.
authors.forename: Zenglu
authors.initials: Z
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Shanghai Jiaotong University, No. 800, Dongchuan Road, Shanghai 200240, China. Electronic address: zmmao@sjtu.edu.cn.
authors.forename: Zhenmin
authors.initials: Z
authors.lastname: Mao
authors.affiliation: Strategic Alliance of Biomedical Technology, No. 333, Cailun Road, Shanghai 201210, China.
authors.forename: Shaoxiong
authors.initials: S
authors.lastname: Chen
authors.affiliation: Strategic Alliance of Biomedical Technology, No. 333, Cailun Road, Shanghai 201210, China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020014:K562 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C049010:isoindigotin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D038362:Glycogen Synthase Kinase 3
keywords: Antitumor; Apoptosis; CDKs; GSK-3β; Isoindigo derivative; Mechanism