Department of Polymer Science & Engineering, Chosun University, Gwangju 501-759, Republic of Korea.
Bioorg Med Chem. 2010 Feb 15;18(4):1428-33. doi: 10.1016/j.bmc.2010.01.016. Epub 2010 Jan 11.
Prostaglandins have a short life in vivo because they are metabolized rapidly by oxidation to 15-ketoprostaglandins catalyzed by a cytosolic enzyme known as NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Previously, CT-8, a thiazolidinedione analogue, was found to be a potent inhibitor of 15-PGDH. Structure-activity analysis indicated that the N-methylation of thiazolidine-2,4-dione, CT-8, abolished the inhibitory activity, whereas the introduction of an ethyl hydroxyl group at amine in CT-8 still had a good inhibitory effect. Based on the structures of the thiazolidinediones analogues and inhibitory activity, a range of benzylidene thiazolidinedione derivatives were synthesized with different substituents on the phenyl ring and their inhibitory activity was evaluated. Replacement of the cyclohexylethyl group of CT-8 with the hetero five-member ring increased the inhibitory potency. However, replacement of the cyclohexylethyl group with a hetero six-member ring decreased the inhibitory potency significantly. It was found that compound 2 (5-(4-(2-(thiophen-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione) was the most potent inhibitor that was effective in the nanomolar range.
前列腺素在体内的寿命很短，因为它们会被氧化迅速代谢为 15-酮前列腺素，这一过程由一种称为 NAD(+)依赖性 15-羟基前列腺素脱氢酶（15-PGDH）的胞质酶催化。此前，噻唑烷二酮类似物 CT-8 被发现是 15-PGDH 的一种有效抑制剂。结构-活性分析表明，噻唑烷-2,4-二酮（CT-8）的 N-甲基化会使抑制活性丧失，而在 CT-8 的氨基上引入乙基羟基仍具有良好的抑制效果。基于噻唑烷二酮类似物的结构和抑制活性，合成了一系列苯环上带有不同取代基的苯亚甲基噻唑烷二酮衍生物，并对其抑制活性进行了评价。用杂环五元环取代 CT-8 的环己基乙基会增加抑制效力。然而，用杂环六元环取代环己基乙基会显著降低抑制效力。结果发现，化合物 2（5-(4-(2-(噻吩-2-基)乙氧基)苯亚甲基)噻唑烷-2,4-二酮）是最有效的抑制剂，其抑制效力在纳摩尔范围内。
