Elsevier

Bioorganic & Medicinal Chemistry

Volume 18, Issue 4, 15 February 2010, Pages 1428-1433
Bioorganic & Medicinal Chemistry

Synthesis and SAR of thiazolidinedione derivatives as 15-PGDH inhibitors

https://doi.org/10.1016/j.bmc.2010.01.016Get rights and content

Abstract

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.

Graphical abstract

Replacement of the cyclohexylethyl group of CT-8 with the hetero five-member ring increased the inhibitory potency. Compound 2 is a most potent 15-PGDH inhibitor that was effective in the nanomolar range.

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Introduction

Prostaglandins are derived from arachidonic acid through the cyclooxygenase (COX) pathway. Two COX isoforms have been recognized. COX-1 is expressed constitutively in various tissues, including the stomach, whereas COX-2 is induced by cytokines, growth factors, tumor promoters and other agents. Prostaglandins have a short life time in vivo because they are metabolized rapidly by oxidation to 15-ketoprostaglandins catalyzed by a cytosolic enzyme named NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH).1 This enzyme is present ubiquitously in mammalian tissues and is responsible for the biological inactivation of prostaglandins because 15-ketoprostaglandins possess significantly lower biological activities.2 Two different types of 15-PGDH have been recognized. Type I is NAD+ specific, while Type II is NADP+ preferred. Type I is more prostaglandin specific and exhibits a low Km for prostaglandins, whereas Type II has a much broader substrate specificity and shows a high Km for prostaglandins.3 Indeed, Type II was later found to be identical to carbonyl reductase.4 Therefore, Type I is considered to be the key enzyme responsible for the biological inactivation of prostaglandins. Studies on the prostaglandin catabolism have focused on the Type I enzyme (hereafter referred to as 15-PGDH).

Prostaglandins have been implicated in a wide variety of physiological and pathological processes. Prostaglandin E2 (PGE2) is a major mediator of inflammation and a key player in the control of various physiological functions. Recently, clinical studies demonstrated that PGE2 causes the growth of body hair and eyelashes in humans and animals.5 In humans, trials carried out on the scalp have shown that PGE2 could increase the hair density.6 Furthermore, 15-PGDH is also expressed in hair melanocytes. Inhibition of this enzyme as a target to reduce hair loss has been reported.7 PGE2 has also been identified as an important mediator of gastric ulcer healing,8, 9, 10, 11, 12, 13, 14, 15, 16 bone formation,17, 18, 19, 20, 21 and dermal wound healing.22, 23, 24, 25, 26, 27 Therefore, inhibitors of 15-PGDH will be valuable for the therapeutic management of such disorders.

Previously, it was reported that ciglitazone, an antidiabetic thiazolidinedione, is a potent antagonist of the 15-PGDH enzymatic activity with an IC50 of 2.7 μМ.28 In addition, the inhibitory potency of ciglitazone was higher than those of other thiazolidinediones, such as rosiglitazone (10 times) and troglitazone (127 times) (Fig. 1). Structure–activity analysis of thiazolidinediones also indicated that the nature of the moiety linking to benzylidenethiazolidine-2,4-dione through an ether linkage plays an important role in its inhibitory potency.29 Based on the structures of the thiazolidinediones analogues and inhibitory activity, various benzylidene thiazolidinedione derivatives with different substituents on the phenyl ring were synthesized using a series of reactions and tested for the 15-PGDH inhibitory activity.

Section snippets

Results and discussion

PGE2 is a major inflammatory product derived from arachidonic acid through the cyclooxygenase pathway, which is involved in pain and inflammatory responses and is a key player in controlling various physiological functions. Many studies have reported that PGE2 is an important mediator of dermal wound healing with specific effects on fibroblast behavior. Of particular interest is the work by Kolodsick et al.,30 who reported that PGE2 can inhibit the differentiation of fibroblasts into

Materials

PGE2, NAD+, NADH, Glutathione–Sepharose 4B, dithiothreitol (DTT), sodium dodecylsulfate (SDS), EDTA, and reduced glutathione were obtained from Sigma. The GST gene fusion pGEX-2T expression vector was purchased from Pharmacia Corp. The cDNA of human 15-PGDH was cloned from a human placenta cDNA library, as described previously.43 All chemical reagents were commercially available. The UV spectra were obtained using a UV–vis spectrophotometer (SHIMADZU). The TLC plates were prepared using

Acknowledgment

This work was supported by National Research Foundation of Korea (NRF) Grant funded by the Ministry of Education, Science and Technology (MEST) through the Research Center for Resistant Cells (R13-2003-009).

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