Exploiting spirooxindoles for dual DNA targeting/CDK2 inhibition and simultaneous mitigation of oxidative stress towards selective NSCLC therapy; synthesis, evaluation, and molecular modelling studies

Abstract

The unique structure of spirooxindoles and their ability to feature various pharmacophoric motifs render them privileged scaffolds for tailoring new multitarget anticancer agents. Herein, a stereoselective multicomponent reaction was utilized to generate a small combinatorial library of pyrazole-tethered spirooxindoles targeting DNA and CDK2 with free radical scavenging potential as an extra bonus. The designed spirooxindoles were directed to combat NSCLC via inducing apoptosis and alleviating oxidative stress. The series' absolute configuration was assigned by X-ray diffraction analysis. Cytotoxicity screening of the developed spirooxindoles against NSCLC A549 and H460 cells compared to normal lung fibroblasts Wi-38 revealed the sensitivity of A549 cells to the compounds and raised 6e and 6h as the study hits (IC₅₀ ∼ 0.09 μM and SI > 3). They damaged DNA at 24.6 and 35.3 nM, and surpassed roscovitine as CDK2 inhibitors (IC₅₀ = 75.6 and 80.2 nM). Docking and MDs simulations postulated their receptors binding modes. The most potent derivative, 6e, induced A549 apoptosis by 40.85% arresting cell cycle at G2/M phase, and exhibited antioxidant activity in a dose-dependent manner compared to Trolox as indicated by DPPH scavenging assay. Finally, in silico ADMET analysis predicted the drug-likeness properties of 6e.