螺吲哚的独特结构及其具有各种药效团基序的能力使它们成为定制新型多靶点抗癌药物的特殊支架。在此，利用立体选择性多组分反应生成了一个小型的吡唑系螺环吲哚组合文库，该文库靶向 DNA 和 CDK2，并具有自由基清除潜力作为额外的好处。设计的螺吲哚旨在通过诱导细胞凋亡和减轻氧化应激来对抗非小细胞肺癌。该系列的绝对构型通过X射线衍射分析确定。与正常肺成纤维细胞 Wi-38 相比，开发的螺氧吲哚针对 NSCLC A549 和 H460 细胞的细胞毒性筛选揭示了 A549 细胞对化合物的敏感性，并随着研究命中而提高了 6e 和 6h（IC50 ∼ 0.09 μM 和 SI > 3）。它们以 24.6 和 35.3 nM 的浓度损伤 DNA，并且作为 CDK2 抑制剂超过了 roscovitine（IC50 = 75.6 和 80.2 nM）。对接和 MD 模拟假定了它们的受体结合模式。最有效的衍生物 6e 诱导 A549 凋亡，使细胞周期停滞在 G2/M 期 40.85%，并且与 Trolox 相比，如 DPPH 清除测定所示，表现出剂量依赖性的抗氧化活性。最后，计算机 ADMET 分析预测了 6e 的药物相似性。该期刊版权所有 © 英国皇家化学学会。

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.This journal is © The Royal Society of Chemistry.