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.

Autor: Cherukupalli S; Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa., Chandrasekaran B; Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa., Kryštof V; Laboratory of Growth Regulators, Centre of the Region Hana for Biotechnological and Agricultural Research, Palacky University & Institute of Experimental Botany ASCR, Šlechtitelů 27, 78371 Olomouc, Czech Republic., Aleti RR; Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa., Sayyad N; Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa., Merugu SR; Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa., Kushwaha ND; Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa., Karpoormath R; Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa. Electronic address: karpoormath@ukzn.ac.za.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2018 Sep; Vol. 79, pp. 46-59. Date of Electronic Publication: 2018 Mar 17.
DOI: 10.1016/j.bioorg.2018.02.030
Abstrakt: 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 mono-substituted 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 IC 50 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 IC 50 values in a micromolar range. Thus, the synthesized compounds could be considered as new anticancer hits for further lead optimization.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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