Synthesis of 4,6-disubstituted pyrazolo[3,4-d]pyrimidine analogues: Cyclin-dependent kinase 2 (CDK2) inhibition, molecular docking and anticancer evaluation

• Published in: Journal of molecular structure Vol. 1176; pp. 538 - 551
• Main Authors: Cherukupalli, Srinivasulu, Chandrasekaran, Balakumar, Aleti, Rajeshwar Reddy, Sayyad, Nisar, Hampannavar, Girish A., Merugu, Srinivas Reddy, Rachamalla, Harikrishna Reddy, Banerjee, Rajkumar, Karpoormath, Rajshekhar
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15.01.2019
• Subjects: Anti-proliferative activity; Cyclin-dependent kinase inhibitor; GLIDE; Molecular docking; Pyrazolo[3,4-d]pyrimidine; GLIDE; Pyrazolo[3,4-d]pyrimidine; Cyclin-dependent kinase inhibitor; Anti-proliferative activity; Molecular docking
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2018.08.104

The cyclin-dependent kinases (CDKs) play a crucial role in cell cycle progression and are validated targets of cancer therapy. Pyrazolopyrimidines are versatile scaffolds, which have been exploited for developing potential anticancer agents. We herein report the synthesis and in vitro CDK2/cyclin E kinase inhibitory activity of 34 novel 4,6-disubstituted pyrazolo [3,4-d]pyrimidines (9a-9s, 13a-13h, 14a-14d, 15a-15c). The structure-activity relationship (SAR) studies revealed that compounds with thiopentane/thiophenethyl group at C-6 and heteroatom-containing bicyclic moiety (benzofuran) at C-4 exhibited good CDK2 inhibitory activity. Further, the binding energies obtained for the active compounds from in silico molecular docking studies with CDK2 were found to be in consonance with the observed SAR and experimental results. In addition, some of the synthesized compounds showed anti-proliferative activity against K-562 (chronic myelogenous leukaemia) and MCF-7 (breast adenocarcinoma) cell lines in micromolar ranges. Further, the cytotoxicity studies on CHO cell line revealed that all the compounds are non-toxic to normal cells and are safe. Thus, the research findings revealed the anticancer potential of 4,6-disubstituted pyrazolo [3,4-d]pyrimidine derivatives which could be further considered for lead optimization. [Display omitted] •A novel series of mono and di-substituted pyrazolo [3,4-d]pyrimidine analogues.•All compounds were screened for their anticancer (CDK2 & Abl) and anti-proliferative (K-562 & MCF-7) activity.•Compounds 13a, 13c, 14c, 15a and 15b displayed significant CDK2 inhibitory activity.•The structure-activity relationship was discussed.