Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
J Med Chem. 2011 Sep 22;54(18):6375-93. doi: 10.1021/jm200803d. Epub 2011 Aug 24.
Chemically diverse oxysterols were prepared and evaluated for cytotoxicity, aiming to push forward potency and selectivity. They were tested against seven cancer (HT-29, HepG2, A549, PC3, LAMA-84, MCF-7, and SH-SY5Y) and two noncancerous cell lines (ARPE-19 and BJ). The influence of the oxidation pattern on rings A and B was studied. Oxygen functionalities on ring B, such as oxo, oxime, acetamide, acetate, and alkoxy, were evaluated. Most oxysterols were cytotoxic in the low micromolar range, with emphasis to the tetrols 14 and 34, the 6β methoxy and acetoxy derivatives 21 and 45, and the oxime 28. In general, the oxysterols were more toxic to cancer cells and a set of compounds (9, 14, 21, 28, 45) with very high selectivity was identified. The cytotoxicity of 3β-acetates was lower than that of the parent alcohols, although incubation for a longer period rendered them equally cytotoxic, pointing them as potential prodrugs of oxysterols.
合成了具有化学多样性的氧化甾醇，并对其进行了细胞毒性评估，旨在提高其效力和选择性。这些化合物被测试了对七种癌细胞（HT-29、HepG2、A549、PC3、LAMA-84、MCF-7 和 SH-SY5Y）和两种非癌细胞系（ARPE-19 和 BJ）的作用。研究了甾醇环 A 和 B 上的氧化模式对其的影响。B 环上的含氧官能团，如酮、肟、乙酰胺、乙酸盐和烷氧基，也进行了评估。大多数氧化甾醇在低微摩尔范围内具有细胞毒性，其中特别关注四醇 14 和 34、6β 甲氧基和乙氧基衍生物 21 和 45 以及肟 28。总的来说，这些氧化甾醇对癌细胞的毒性更大，并且确定了一组具有非常高选择性的化合物（9、14、21、28、45）。3β-乙酸盐的细胞毒性低于其母体醇，尽管延长孵育时间会使它们具有同等的细胞毒性，这表明它们可能是氧化甾醇的潜在前药。
