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

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,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.

Exploring pyrrolidinyl-spirooxindole natural products as promising platforms for the synthesis of novel spirooxindoles as EGFR/CDK2 inhibitors for halting breast cancer cells

“…Targeting CDK2 offers a strategic approach to impede cancer cell division, and ongoing research aims to optimize CDK2 inhibitors for enhanced efficacy and reduced side effects, highlighting its potential as an innovative avenue in cancer therapy. We built upon the groundwork established by benchmark oxindole-based CDK2 inhibitors ( I ) ( Luk, 2004 ; Venkanna, et al, 2020 ; Bramson, et al, 2001 ) and spiro ( Al-Jassas, et al, 2023 ; Barakat, et al, 2023 ) anti-cancer agents recognized for their kinase inhibition, specifically those aimed at CDK2. This rational study involved a detailed exploration of the CDK2 inhibitory potential within the investigated series, as depicted in Figure 2 .…”

“…Al-Jassas ( Al-Jassas, et al, 2023 ) designed, synthesized, and assessed a novel spirooxindole scaffold for its dual inhibitory properties against CDK2 and EGFR. Compound II exhibited notable inhibition, with IC 50 values of 0.189 ± 0.01 µM (MCF-7) and 1.04 ± 0.21 µM (HepG2).…”

Exploring the mechanism of action of spirooxindoles as a class of CDK2 inhibitors: a structure-based computational approach

“…20 In recent years, drug discovery in cancer research has required the utilization of spirooxindole scaffold against cancer while focusing CDK2 enzyme as a therapeutic target. 21,22 Previous research has succeeded in synthesizing spirooxindole derivatives that work well in inhibiting the development of cancer cell lines, namely 6d (IC 50 4.3 AE 0.18 mM (MCF-7) and IC 50 6.9 AE 0.23 mM (HepG2)) and 6f (IC 50 10.33 AE 0.40 mM (MCF-7) and IC 50 : 3.5 AE 0.11 mM (HepG2)). 21 These findings lead us to several fragments that have a good potential in CDK2 inhibition, such as spirooxindole, isatin/ indole, pyrazole, and acetophenone (Fig.…”

“…Recent research provides significant results from the combination of these fragments for CDK2 inhibitory activity. 22 Recently, three compounds from a series of 16 novel spirooxindoles showed substantial inhibitory activity compared to roscovitine, taken as a control (Fig. 2).…”

New spiro-indeno[1,2- b ]quinoxalines clubbed with benzimidazole scaffold as CDK2 inhibitors for halting non-small cell lung cancer; stereoselective synthesis, molecular dynamics and structural insights

“…Most recently, our group has introduced series of spirooxindole-based CDK2 inhibitors surpassing roscovitine, via cost‐effective single‐step multicomponent [3 + 2] cycloaddition (32CA) reaction allowing easy access to combinatorial libraries. These leads exhibited efficient tumour-selective cytotoxic activities against breast and liver cancers 27 . Inspired by these findings, we speculated that combination of CDK2 inhibitors pharmacophores as well as motifs from efficient anti-lung cancer agents into this multifunctionalized privileged skeleton could facilitate the discovery of new lead molecules for targeting NSCLC.…”