Thiazolidinediones as a novel class of NAD+-dependent 15-hydroxyprostaglandin dehydrogenase inhibitors

NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes NAD+-dependent oxidation of prostaglandins and other nonprostanoid compounds. This enzyme was found to be dramatically induced in hormone-responsive human prostate cancer cells by androgens [M. Tong, and H. H. Tai, 2000, Biochem. Biophys. Res. Commun. 276, 77–81] and could be involved in prostate tumorigenesis. Inhibitors of this enzyme may be of value in determining the utility of these compounds in cancer chemoprevention. Previously, ciglitazone, an antidiabetic thiazolidinedione, was found to be a potent inhibitor of 15-PGDH. Structure–activity analysis of available thiazolidinediones indicated that the nature of the moiety linking to phenyl ring through ether linkage and benzylidene configuration play important roles in inhibitory potency. Furthermore, N-methylation of 2,4-thiazolidinedione abolished the inhibitory activity. A series of benzylidene thiazolidinediones with varied ring structure and methylene bridge to phenyl ring through ether linkage were synthesized and assayed for inhibitory activity. It was found that compound CT-8 (5-[4-(cyclohexylethoxy)benzylidene]-2,4-thiazolidinedione) was the most potent inhibitor effective at nanomolar range. Kinetic studies revealed that inhibition by this compound was noncompetitive with respect to NAD+ and uncompetitive with respect to prostaglandin E2, indicating that the inhibitor interacts with the enzyme at a site distinct from the substrate binding site. This regulatory site appears to overlap with the activator site occupied by imipramine since activation of the enzyme by this activator is competitively inhibited by compound CT-8.