5,5'-substituted indirubin-3'-oxime derivatives as potent cyclin-dependent kinase inhibitors with anticancer activity.
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.
Choi
Soo-Jeong
SJ
Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
Lee
Jung-Eun
JE
Jeong
Soon-Young
SY
Im
Isak
I
Lee
So-Deok
SD
Lee
Eun-Jin
EJ
Lee
Sang Kook
SK
Kwon
Seong-Min
SM
Ahn
Sang-Gun
SG
Yoon
Jung-Hoon
JH
Han
Sun-Young
SY
Kim
Jae-Il
JI
Kim
Yong-Chul
YC
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
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