新型二硫胺含有双二醇部分,具有选择性碳酸酶抑制和抗癌活性
Aida Buza1, Cüneyt Türkeş2, Mustafa Arslan3
1Department of Chemistry, Faculty of Mathematical and Natural Sciences, University of Prishtina Prishtina 1000 Republic of Kosova arleta.rifati@uni-pr.edu.
RSC medicinal chemistry
|November 4, 2024
概括
新的硫胺化合物被合成为人类碳酸酶 (hCA) 抑制剂. 几种化合物显示出对与瘤相关的hCA IX和XII的强大和选择性抑制,其中一些也显示出选择性癌细胞细胞毒性.
科学领域:
- 药用化学 医学化学
- 生物化学 生物化学
- 化学生物学 化学生物学
背景情况:
- 人类碳酸无水酶 (hCA) 是参与各种生理过程的关键酶.
- 异常的hCA活性与癌症的发展有关,使它们成为有吸引力的治疗点.
- 开发针对瘤相关的hCA异型的选择性抑制剂是制药研究的一个关键领域.
研究的目的:
- 设计和合成新型硫胺衍生物,其中包含1,2,3-triazolyloxime替代的1,2,3-triazolyl部分.
- 评估这些化合物的抑制潜力和选择性,以对抗各种人类碳酸酶异型 (hCA I,II,IX和XII).
- 评估合成化合物对癌症和正常细胞系的体外细胞毒性和选择性.
主要方法:
- 一系列硫胺化合物 (7a-7o) 的合成.
- 在体外酶分析测试以确定对hCA I,II,IX和XII的抑制常数 (KI).
- 使用癌细胞系 (Hep3B,A549) 和正常细胞系 (L929) 的细胞毒性测定.
- 分子对接研究,以调查hCA活性部位内的结合相互作用.
主要成果:
- 化合物7a-o对与瘤相关的hCA IX和XII进行了适度的抑制,对细胞质hCA I和II进行了强有力的选择性抑制.
- 化合物7a,7d和7o被确定为最强效和选择性的抑制剂,具有纳米分子抑制常量.
- 化合物7d,7g,7k和7j对分别Hep3B和A549癌细胞系表现出选择性细胞毒性.
- 分子对接揭示了对观察到的活动和选择性负责的关键相互作用.
结论:
- 合成的硫胺是hCA抑制剂的有希望的候选者,特别是针对与瘤相关的异型.
- 化合物7a,7d和7o由于它们的强大和选择性抑制特征,显示出显著的潜力.
- 对癌细胞的选择性细胞毒性表明治疗潜力,需要进一步调查.
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