对第二代富含关尼迪尼的转运体进行以多样性为导向的合成,以实现细胞选择性透
Duc Tai Nguyen1, Michael Desgagné1, Andréanne Laniel1
1Department of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.
研究人员使用以多样性为导向的合成开发了新的细胞透 (CPPs). 这些新型类仿制药对癌细胞具有增强的选择性,改善了向细胞内传递潜力.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药物运输 药物运输 药物运输
背景情况:
- 细胞透 (CPPs) 对细胞内传递有希望,但缺乏选择性,阻碍了临床使用.
- 针对癌细胞的向传递需要提高CPP的特异性.
研究的目的:
- 设计和合成一个用于增强癌细胞选择性的皮多米米特库.
- 为了识别具有高细胞吸收和癌细胞选择性的特定化合物.
主要方法:
- 一个256个成员的多样性导向型模拟图书馆的自动合成.
- 加入脂性 (Phe,2Nal) 和pH敏感 (His) 氨基酸.
- 在HeLa (癌症) 和HEK293 (非癌症) 细胞中评估细胞内化和选择性指数 (SI).
主要成果:
- 图书馆对HeLa细胞的平均SI值为1.49,比HEK293细胞的平均SI值为1.49.
- 化合物155和187表现出高HeLa细胞吸收率 (64.6%和75.7%),SI分别为2.7和2.9.
- 化合物155和187含有三个His残留物和Phe或2Nal.
结论:
- 以多样性为导向的库合成对于识别细胞透性候选者是有效的.
- 开发的类仿制药显示了具有增强特异性的向细胞输送的潜力.
- 敏感pH的氨基酸有助于改善癌细胞的选择性.
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