Synthesis, anticancer evaluation, and molecular docking studies of some novel 4,6-disubstituted pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 (CDK2) inhibitors

0492257 - ÚEB 2019 RIV US eng J - Článek v odborném periodiku
Cherukupalli, S. - Chandrasekaran, B. - Kryštof, Vladimír - Aleti, R.R. - Sayyad, N. - Merugu, S.R. - Kushwaha, N.D. - Karpoormath, R.
Synthesis, anticancer evaluation, and molecular docking studies of some novel 4,6-disubstituted pyrazolo[3,4-d]pyrimidines as cyclin-dependent kinase 2 (CDK2) inhibitors.
Bioorganic Chemistry. Roč. 79, SEP (2018), s. 46-59. ISSN 0045-2068. E-ISSN 1090-2120
Grant CEP: GA MŠMT(CZ) LO1204; GA ČR GA17-14007S
Institucionální podpora: RVO:61389030
Klíčová slova: cancer-therapy * cell-cycle * cyclin-dependent-kinase-2 * roscovitine * lethality * scaffold * targets * mice * Pyrazolo[3,4-d]pyrimidine * Cyclin dependent kinase inhibitor * Anti-proliferative activity * Molecular docking * glide
Obor OECD: Oncology
Impakt faktor: 3.926, rok: 2018

A novel series of 4,6-disubstituted pyrazolo[3,4-d]pyrimidines (7-43) bearing various anilines at C-4 position and thiophenethyl or thiopentane moieties at C-6 position have been designed and synthesized by molecular hybridization approach. All the synthesized compounds were evaluated for in vitro CDK2/cyclin E and Abl kinase inhibitory activity as well as anti-proliferative activity against K-562 (chronic myelogeneous leukemia), and MCF-7 (breast adenocarcinoma) cell lines. The structure-activity relationship (SAR) studies revealed that compounds with thiophenethyl group at C-6 with monosubstituted anilines at C-4 exhibited better CDK2 inhibitory activity compared to alkyl group (thiopentane) at C-6 and di-substituted anilines at C-4 of the scaffold. In particular, compounds having 2-chloro, 3-nitro and 4-methylthio aniline groups at C-4 displayed significant enzymatic inhibitory activity against CDK2 with single digit micromolar IC50 values. The in silico molecular docking studies suggested possible binding orientation and the binding energies were in agreement with the observed SAR as well as experimental results. In addition, some of the synthesized compounds showed anti-proliferative effects against K-562 and MCF-7 cancer cell lines with IC50 values in a micromolar range. Thus, the synthesized compounds could be considered as new anticancer hits for further lead optimization.
Trvalý link: http://hdl.handle.net/11104/0285792