Synthesis, biological evaluation and molecular docking studies of pyrazole derivatives coupling with a thiourea moiety as novel CDKs inhibitors.
It was discovered that a number of cyclin dependent kinase inhibitors containing the pyrazole core structure exhibited high inhibitory potency against broad-range CDKs and corresponding anti-proliferative activities. This information guided us to design and synthesize a series of 1,3-diphenyl-N-(phenylcarbamothioyl)-1H-pyrazole-4-carboxamide derivatives (5a-10d), and evaluate their biological activities as CDKs inhibitors. Among all the synthesized compounds, compound 10b inhibited CDK2 with an IC50 value of 25 nM, counteracting tumor cell proliferation of three cancer cell lines (H460, MCF-7, A549) in the micromolar range (from 0.75 μM to 4.21 μM), In addition, flow cytometry indicated that compound 10b could induce cycle G0/G1 phase arrest in A549 cells with a dose dependent. Taken together, compound 10b could be selected for further preclinical evaluation.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Jian
J
Sun
Xian-Hai
XH
Lv
Han-Yue
HY
Qiu
Yan-Ting
YT
Wang
Qian-Ru
QR
Du
Dong-Dong
DD
Li
Yong-Hua
YH
Yang
Hai-Liang
HL
Zhu
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry*; D013890:Thiourea / Q000737:chemistry* / Q000494:pharmacology
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D018844:Cyclin-Dependent Kinases; D013890:Thiourea
CDK2; Cell cycle profile; Cyclin-dependent kinases; Molecular docking; Structure–activity relationship