Liu Wei, Chen Shuqiang, Zhang Fan, He Shipeng, Wang Shengzheng, Sheng Chunquan
School of Food and Biological Engineering, Shaanxi University of Science & Technology, Weiyang College Park, Xi'an 710021, People's Republic of China.
Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
Bioorg Med Chem Lett. 2019 Jul 1;29(13):1636-1642. doi: 10.1016/j.bmcl.2019.04.037. Epub 2019 Apr 26.
Sulfur containing spiroheterocyclic oxindoles are promising privileged scaffolds in medicinal chemistry and drug discovery. Previously, we identified a new class of spirodihydrothiopyran-oxindoles with good in vitro antitumor activity against A549 lung cancer cell line. Herein, various spirooxindole-dihydrothiopyrans with diverse substitutions were synthesized and assayed to investigate the structure-activity relationships. Among the derivatives, compounds 4b, 4i, 4m, 4n and 4q displayed superior or comparable antitumor activity than nutlin-3. Molecular mechanism study revealed this scaffold displayed moderate MDM2 inhibitory activity, significantly induced cancer cell apoptosis and arrested cell cycle at G0/G1 phase, which represented a good lead compound for antitumor drug discovery.
含硫螺杂环氧化吲哚是药物化学和药物发现中很有前景的优势骨架。此前，我们鉴定出一类新型的螺二氢噻喃-氧化吲哚，对A549肺癌细胞系具有良好的体外抗肿瘤活性。在此，合成并测定了具有不同取代基的各种螺氧化吲哚-二氢噻喃，以研究构效关系。在这些衍生物中，化合物4b、4i、4m、4n和4q表现出比nutlin-3更高或相当的抗肿瘤活性。分子机制研究表明，该骨架具有中等的MDM2抑制活性，能显著诱导癌细胞凋亡并使细胞周期停滞在G0/G1期，这使其成为抗肿瘤药物发现的良好先导化合物。
