Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, Thailand.
Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand; Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
Eur J Med Chem. 2015 Oct 20;103:446-59. doi: 10.1016/j.ejmech.2015.09.001. Epub 2015 Sep 5.
A novel series of 1,4-naphthoquinones (33-44) tethered by open and closed chain sulfonamide moieties were designed, synthesized and evaluated for their cytotoxic and antimalarial activities. All quinone-sulfonamide derivatives displayed a broad spectrum of cytotoxic activities against all of the tested cancer cell lines including HuCCA-1, HepG2, A549 and MOLT-3. Most quinones (33-36 and 38-43) exerted higher anticancer activity against HepG2 cell than that of the etoposide. The open chain analogs 36 and 42 were shown to be the most potent compounds. Notably, the restricted sulfonamide analog 38 with 6,7-dimethoxy groups exhibited the most potent antimalarial activity (IC₅₀ = 2.8 μM). Quantitative structure-activity relationships (QSAR) study was performed to reveal important chemical features governing the biological activities. Five constructed QSAR models provided acceptable predictive performance (Rcv 0.5647-0.9317 and RMSEcv 0.1231-0.2825). Four additional sets of structurally modified compounds were generated in silico (34a-34d, 36a-36k, 40a-40d and 42a-42k) in which their activities were predicted using the constructed QSAR models. A comprehensive discussion of the structure-activity relationships was made and a set of promising compounds (i.e., 33, 36, 38, 42, 36d, 36f, 42e, 42g and 42f) was suggested for further development as anticancer and antimalarial agents.
设计、合成了一系列新型的 1,4-萘醌（33-44）衍生物，这些衍生物通过开链和闭环磺酰胺部分连接，并对其细胞毒性和抗疟活性进行了评价。所有醌-磺酰胺衍生物均表现出广谱的细胞毒性活性，对所有测试的癌细胞系（包括 HuCCA-1、HepG2、A549 和 MOLT-3）均有作用。大多数醌（33-36 和 38-43）对 HepG2 细胞的抗癌活性均高于依托泊苷。开链类似物 36 和 42 表现出最强的活性。值得注意的是，带有 6,7-二甲氧基的受限磺酰胺类似物 38 表现出最强的抗疟活性（IC₅₀ = 2.8 μM）。进行了定量构效关系（QSAR）研究，以揭示控制生物活性的重要化学特征。五个构建的 QSAR 模型提供了可接受的预测性能（Rcv 0.5647-0.9317 和 RMSEcv 0.1231-0.2825）。在计算机中生成了另外四组结构修饰的化合物（34a-34d、36a-36k、40a-40d 和 42a-42k），并使用构建的 QSAR 模型预测了它们的活性。对构效关系进行了全面讨论，并提出了一组有前途的化合物（即 33、36、38、42、36d、36f、42e、42g 和 42f），建议进一步开发作为抗癌和抗疟药物。
