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

Abstract

Despite the crucial role of CDK2 in tumorigenesis, few inhibitors reached clinical trials for managing lung cancer, the leading cause of cancer death. Herein, we report combinatorial stereoselective synthesis of rationally designed spiroindeno[1,2- b ]quinoxaline-based CDK2 inhibitors for NSCLC therapy. The design relied on merging pharmacophoric motifs and biomimetic scaffold hopping into this privileged skeleton via cost‐effective one-pot multicomponent [3 + 2] cycloaddition reaction. Absolute configuration was assigned by single crystal x-ray diffraction analysis and reaction mechanism was studied by Molecular Electron Density Theory. Initial MTT screening of the series against A549 cells and normal lung fibroblasts Wi-38 elected 6b as the study hit regarding potency (IC 50 = 54 nM) and safety (SI = 6.64). In vitro CDK2 inhibition assay revealed that 6b (IC 50 = 177 nM) was comparable to roscovitine (IC 50 = 141 nM). Docking and molecular dynamic simulations suggested that 6b was stabilised into CDK2 cavity by hydrophobic interactions with key aminoacids.

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 .…”

“…Barakat research group has reported a combinatorial stereoselective synthesis of rationally designed spiroindeno [1,2- b ]quinoxaline-based CDK2 inhibitors III for non-small cell lung cancer (NSCLC) therapy ( Barakat, et al, 2023 ). Among the derivatives tested, hit III emerged as the most promising, exhibiting potent inhibitory effects against A549 cells and normal lung fibroblasts Wi-38, with an IC 50 value of 54 nM and a selectivity index (SI) of 6.64.…”