Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal.
Eur J Med Chem. 2013 Feb;60:254-62. doi: 10.1016/j.ejmech.2012.11.036. Epub 2012 Nov 30.
The synthesis and biological evaluation of 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles as anticancer agents against MCF7 breast cancer cell lines is reported. The design of the new compounds has been guided considering (3R)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole as the lead compound due to its good performance against MCF7 breast cancer cell lines (IC(50) = 1.0 μM). The structural changes included the removal of the phenyl group at C-3, the replacement of this group by a 3,4,5-trimethoxyphenyl group, the removal of the methyl group at C-5 from the lead scaffold and the replacement of this group by a phenyl substituent. Overall, these studies showed that the combined presence of a phenyl group at C-3 and a methyl group at C-5 in the 1H,3H-pyrrolo[1,2-c]thiazole ring system is essential to ensure high cytotoxicty against MCF7 breast cancer cell lines. To probe whether the absolute configuration of the lead compound might affect the anticancer activity, its enantiomer was prepared and the activity against MCF7 cells was evaluated. (3S)-6,7-Bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole proved to be the most active compound so far studied, with IC(50) value of 0.5 μM.
报道了作为 MCF7 乳腺癌细胞系抗癌剂的 6,7-双（羟甲基）-1H,3H-吡咯并[1,2-c]噻唑的合成和生物评价。新化合物的设计考虑了（3R）-6,7-双（羟甲基）-5-甲基-3-苯基-1H,3H-吡咯并[1,2-c]噻唑作为先导化合物，因为它对 MCF7 乳腺癌细胞系具有良好的活性（IC50=1.0 μM）。结构变化包括去除 C-3 上的苯基，用 3,4,5-三甲氧基苯基取代该基团，去除先导支架上 C-5 上的甲基并用苯基取代该基团。总的来说，这些研究表明，1H,3H-吡咯并[1,2-c]噻唑环系统中 C-3 上的苯基和 C-5 上的甲基的组合存在对于确保对 MCF7 乳腺癌细胞系的高细胞毒性是必不可少的。为了探究先导化合物的绝对构型是否会影响抗癌活性，制备了其对映异构体并评估了其对 MCF7 细胞的活性。（3S）-6,7-双（羟甲基）-5-甲基-3-苯基-1H,3H-吡咯并[1,2-c]噻唑被证明是迄今为止研究过的最活性化合物，IC50 值为 0.5 μM。
