title: Synthesis and structure-activity relationships of novel indirubin derivatives as potent anti-proliferative agents with CDK2 inhibitory activities.
abstract: Indirubin, an active ingredient of a traditional Chinese recipe Danggui Longhui Wan, has been known as a CDK inhibitor competing with ATP for binding to the catalytic site of cyclin-dependent kinases (CDKs). Since CDKs, a group of serine/threonine kinases forming active heterodimeric complexes with cyclins, are key regulators of the cell cycle regulation, therapeutic interventions targeting CDKs have been stimulated for the treatment of proliferative diseases, such as cancer, psoriasis, and for the prevention of chemotherapy-associated side effects, such as alopecia. A series of novel indirubin analogs was synthesized and evaluated for anti-proliferative and CDK2 inhibitory activities. Among the indirubin derivatives tested in the growth inhibitions against several human cancer cell lines, 5-nitro, halide, and bulky group containing acylamino substituted analogs showed high anti-proliferative effects. Selected analogs showing potent anti-proliferative activities were evaluated further in the CDK2 enzyme assay, which resulted in the discovery of potent CDK2 inhibitors.
authors.affiliation: Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
authors.forename: Myoung Ju
authors.initials: MJ
authors.lastname: Moon
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
authors.forename: Jong-Won
authors.initials: JW
authors.lastname: Lee
authors.forename: Woo Keun
authors.initials: WK
authors.lastname: Song
authors.forename: Si Wouk
authors.initials: SW
authors.lastname: Kim
authors.forename: Jae Il
authors.initials: JI
authors.lastname: Kim
authors.forename: Chunghee
authors.initials: C
authors.lastname: Cho
authors.forename: Soo Jeong
authors.initials: SJ
authors.lastname: Choi
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
mesh_terms: D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D016160:Retinoblastoma Protein; D051357:Cyclin-Dependent Kinase 2; C027185:indirubin