Introduction: The continuous pursuit of novel chemotherapeutical agents with improved efficacy and reduced adverse effects remains a critical area of research despite advancements in chemotherapy. We have previously synthesized indolenine and barbituric acid zwitterion scaffolds 1–10 sustainably; however, their precise chemotherapeutical properties are still lacking. Methods: In this present work, we conducted in silico ADMET analyses, molecular docking calculations, DNA binding studies, and cytotoxicity assays on these zwitterions. Results and Discussion: Among the 10 zwitterions, zwitterion 3 bearing a methoxy group demonstrated the highest drug-likeness score, low toxicity, as well as no violation of Lipinski’s rule of five and Veber’s rule. Both molecular docking calculations and DNA binding studies suggested that the minor groove of DNA is the most probable molecular target of 3 among the others (i.e., topoisomerase and tubulin). In addition, zwitterion 3 exhibited selective cytotoxicity against a wide array of human cancer cell lines without noticeable effect against the normal human colon fibroblast CCD- 18Co. Conclusion: Overall, these preliminary findings from our combined computational and experimental strategy suggested that 3 remains promising for further elaboration as a chemotherapeutic agent.

中文翻译：

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假吲哚-巴比妥酸两性离子作为潜在化疗药物的计算和体外阐明

简介：尽管化疗取得了进步，但不断追求提高疗效和减少不良反应的新型化疗药物仍然是研究的关键领域。我们之前已经可持续地合成了假吲哚和巴比妥酸两性离子支架1-10；然而，它们的精确化疗特性仍然缺乏。方法：在这项目前的工作中，我们对这些两性离子进行了计算机 ADMET 分析、分子对接计算、DNA 结合研究和细胞毒性测定。结果与讨论：在10个两性离子中，带有甲氧基的两性离子3表现出最高的药物相似性评分，毒性低，并且不违反Lipinski的五法则和Veber的法则。分子对接计算和 DNA 结合研究均表明 DNA 小沟是 3 个分子靶标（即拓扑异构酶和微管蛋白）中最有可能的分子靶标。此外，两性离子 3 对多种人类癌细胞系表现出选择性细胞毒性，但对正常人结肠成纤维细胞 CCD-18Co 没有明显影响。结论：总体而言，我们结合计算和实验策略的初步结果表明，3 作为化疗药物仍有希望进一步阐述。