Bjedov Srđan, Jakimov Dimitar, Pilipović Ana, Poša Mihalj, Sakač Marija
Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg D. Obradovića 3, 21000 Novi Sad, Serbia.
Oncology Institute of Vojvodina, Faculty of Medicine, University of Novi Sad, Institutski put 4, 21204 Sremska Kamenica, Serbia.
Steroids. 2017 Apr;120:19-25. doi: 10.1016/j.steroids.2017.01.008. Epub 2017 Feb 10.
Bile acid derivatives with modifications in side chain and modifications on steroid skeleton were synthetized and their antitumor activity against five human cancer cell lines was investigated. Modifications in side chain include amid group, formed in reaction with 2-amino-2-methylpropanol, and 4,4-dimethyloxazoline group, obtained after cyclization of amides. In the steroid skeleton oxo groups were introduced in position 7 (2, 2a, 2b) and 7,12 (3, 3a, 3b). Ethylidene groups were introduced regio- and stereoselectively on C-7, and/or without stereoselectivity on C-3 by Wittig reaction. By combination of these modifications, a series of 19 bile acid derivatives were synthesized. Compounds containing both C-7 ethylidene and C-12 carbonyl groups (6, 6a, 6b) shown very good antitumor activity with IC<5µM. Altering carboxylic group to amide or oxazoline group has positive effect on cytotoxicity. Different molecular descriptors were determined in silico and after principal component analysis was found that molecular descriptor BLTF96 can be used for fast assessment of experimental cytotoxicity of bile acid derivatives.
合成了侧链和甾体骨架有修饰的胆汁酸衍生物，并研究了它们对五种人类癌细胞系的抗肿瘤活性。侧链修饰包括与2-氨基-2-甲基丙醇反应形成的酰胺基，以及酰胺环化后得到的4,4-二甲基恶唑啉基。在甾体骨架中，氧代基团引入到7位（2, 2a, 2b）和7,12位（3, 3a, 3b）。通过维蒂希反应，亚乙基在C-7位区域和立体选择性地引入，和/或在C-3位无立体选择性地引入。通过这些修饰的组合，合成了一系列19种胆汁酸衍生物。含有C-7亚乙基和C-12羰基的化合物（6, 6a, 6b）显示出非常好的抗肿瘤活性，IC<5µM。将羧基改变为酰胺基或恶唑啉基对细胞毒性有积极影响。在计算机上确定了不同的分子描述符，主成分分析后发现分子描述符BLTF96可用于快速评估胆汁酸衍生物的实验细胞毒性。
