设计,合成和抗癌活动的N-aryl英多硫胺:强效和选择性抗癌剂的识别
Monika Malik1, Dinesh Kumar2, Humphrey Lotana2
1Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031, India; Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States.
Bioorganic & medicinal chemistry
|September 2, 2023
概括
一种新的铜催化反应有效地合成了N-arylated 醇硫胺. 几种化合物通过诱导细胞亡和抑制细胞入侵,表现出强有力的选择性抗癌活性,具有作为新型癌症治疗药物的潜力.
科学领域:
- 药用化学 医学化学
- 有机合成 有机合成
- 癌症生物学 癌症生物学
背景情况:
- 印醇衍生物是药物化学中普遍存在的支架,具有抗癌应用的潜力.
- 开发高效的合成路径,用于新型的基于醇的化合物,对于药物发现至关重要.
- 了解潜在抗癌剂的作用机制是优化其疗效的关键.
研究的目的:
- 开发一种简单高效的铜催化交叉合方法,用于合成N-arylated 酸硫胺.
- 评估合成化合物对各种癌症细胞系的细胞毒性和选择性抗癌活性.
- 为了研究最强大的N-arylated印度硫胺衍生物的作用机制.
主要方法:
- 铜介导的N-boc-3-indolylsulfoximines与酸的交叉合.
- 从N-boc-3-methylthioindoles中合成关键的NH硫胺前体.
- 对人类癌细胞系 (22Rv1,C4-2,MCF7) 和正常HEK293细胞进行细胞毒性测定.
- 细胞测试分析反应性氧物种 (ROS) 水平,亡标记物 (p-53,c-jun),线粒体功能,细胞侵入性和蛋白动态.
主要成果:
- 综合了各种各样的N-arylated 印度硫胺 (11a-m) 在优异的产量 (高达91%) 中.
- 化合物11f-k对测试的癌细胞系表现出强烈和选择性的细胞毒性,对正常的HEK293细胞没有显著的毒性.
- 化合物11l表现出广泛的抗癌活性,并通过ROS生成,p-53和c-jun上调和线粒体功能障碍诱导了亡.
- 化合物11l还抑制了细胞的侵入性,并降低了聚合蛋白水平,这表明它具有抗转移潜力,并破坏了微管动力学.
结论:
- 开发的铜催化反应提供了一条有效的途径,以获得具有显著抗癌潜力的N-arylated 醇硫胺.
- 合成的化合物,特别是11l,表现出有前途的选择性细胞毒性和多向的作用机制,包括亡诱导和抗转移效应.
- N-aryl英多硫胺是开发新型抗癌剂的一类有前途的化合物.
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