Synthesis and SARs study of novel spiro‐oxindoles as potent antiproliferative agents with CDK‐2 inhibitory activities
Refaah M. Al-Jassas, Mohammad Shahidul Islam, Abdullah Mohammed Al‐Majid, Mohamed S. Nafie, Matti Haukka, A. F. M. Motiur Rahman, Abdulmajeed Abdullah Alayyaf, Assem Barakat
Abstract
Abstract A series of 16 novel spirooxindole analogs 8a–p were designed and constructed via cost‐effective single‐step multicomponent [3+2] cycloaddition reaction of azomethine ylide (AY) generated in situ from substituted isatin ( 6a–d ) with suitable amino acids ( 7a–c ) and ethylene‐engrafted pyrazole derivatives ( 5a,b ). The potency of all compounds was assayed against a human breast cancer cell line (MCF‐7) and a human liver cell line (HepG2). Spiro compound 8c was the most active member among the synthesized candidates, with exceptional cytotoxicity against the MCF‐7 and HepG2 cell lines, with IC 50 values of 0.189 ± 0.01 and 1.04 ± 0.21 µM, respectively. The candidate 8c exhibited more potent activity (10.10‐ and 2.27‐fold) than the standard drug roscovitine (IC 50 = 1.91 ± 0.17 µM (MCF‐7) and 2.36 ± 0.21 µM (HepG2)). Compound 8c was investigated for epidermal growth factor receptor (EGFR) inhibition; it exhibited promising IC 50 values of 96.6 nM compared with 67.3 nM for erlotinib. The IC 50 value of 8c (34.98 nM) exhibited cyclin‐dependent kinase 2 (CDK‐2) inhibition, being more active than roscovitine the (IC 50 = 140 nM) in targeting the CDK‐2 kinase enzyme. Additionally, for apoptosis induction of compound 8c in MCF‐7, it upregulated the expression levels of proapoptotic genes for P53, Bax, caspases‐3, 8, and 9 at up to 6.18, 4.8, 9.8, 4.6, 11.3 fold‐change, respectively, and downregualted the level of the antiapoptotic gene for Bcl‐2 by 0.14‐fold. Finally, a molecular docking study of the most active compound 8c highlighted a good binding affinity with Lys89 as the key amino acid for CDK‐2 inhibition.