title: 5,5'-substituted indirubin-3'-oxime derivatives as potent cyclin-dependent kinase inhibitors with anticancer activity.
abstract: To enhance the ability of indirubin derivatives to inhibit CDK2/cyclin E, a target of anticancer agents, we designed and synthesized a new series of indirubin-3'-oxime derivatives with combined substitutions at the 5 and 5' positions. A molecular docking study predicted the binding of derivatives with OH or halogen substitutions at the 5' position to the ATP binding site of CDK2, revealing the critical interactions that may explain the improved CDK2 inhibitory activity of these derivatives. Among the synthesized derivatives, the 5-nitro-5'-hydroxy analogue 3a and the 5-nitro-5'-fluoro analogue 5a displayed potent inhibitory activity against CDK2, with IC(50) values of 1.9 and 1.7 nM, respectively. These derivatives also showed antiproliferative activity against several human cancer cell lines, with IC(50) values of 0.2-3.3 microM. A representative analogue, 3a, showed greater than 500-fold selectivity for CDK relative to selected kinase panel and potent in vivo anticancer activity.
authors.affiliation: Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
authors.forename: Soo-Jeong
authors.initials: SJ
authors.lastname: Choi
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Soon-Young
authors.initials: SY
authors.lastname: Jeong
authors.forename: Isak
authors.initials: I
authors.lastname: Im
authors.forename: So-Deok
authors.initials: SD
authors.lastname: Lee
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Lee
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
authors.forename: Seong-Min
authors.initials: SM
authors.lastname: Kwon
authors.forename: Sang-Gun
authors.initials: SG
authors.lastname: Ahn
authors.forename: Jung-Hoon
authors.initials: JH
authors.lastname: Yoon
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Han
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Kim
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
mesh_terms: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D006801:Humans; D007211:Indoles; D010091:Oximes / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D007211:Indoles; D010091:Oximes; D000255:Adenosine Triphosphate; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C027185:indirubin