Synthesis and SARs study of novel spiro-oxindoles as potent antiproliferative agents with CDK-2 inhibitory activities.

Autor: Al-Jassas RM; Department of Chemistry, King Saud University, Riyadh, Saudi Arabia., Islam MS; Department of Chemistry, King Saud University, Riyadh, Saudi Arabia., Al-Majid AM; Department of Chemistry, King Saud University, Riyadh, Saudi Arabia., Nafie MS; Department of Chemistry (Biochemistry program), Faculty of Science, Suez Canal University, Ismailia, Egypt., Haukka M; Department of Chemistry, University of Jyväskylä, Jyväskylä, Finland., Rahman AFMM; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia., Alayyaf AMA; Department of Chemistry, King Saud University, Riyadh, Saudi Arabia., Barakat A; Department of Chemistry, King Saud University, Riyadh, Saudi Arabia.
Jazyk: angličtina
Zdroj: Archiv der Pharmazie [Arch Pharm (Weinheim)] 2023 Aug; Vol. 356 (8), pp. e2300185. Date of Electronic Publication: 2023 May 30.
DOI: 10.1002/ardp.202300185
Abstrakt: 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.
(© 2023 Deutsche Pharmazeutische Gesellschaft.)
Databáze: MEDLINE
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