Resveratrol analogues as selective cyclooxygenase-2 inhibitors: Synthesis and structure-activity relationship

Author(s)

Marek Murias, Norbert Handler, Thomas Erker, Karin Pleban, Gerhard Ecker, Philipp Saiko, Thomas Szekeres, Walter Jäger

Abstract

A series of hydroxylated and methoxylated trans-stilbenes were synthesized and evaluated for their ability to inhibit COX-1 and COX-2. Some of the hydroxylated derivatives are highly selective COX-2 inhibitor with potency comparable or better than clinically established drugs. Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is found in grapes and various medical plants. Among cytotoxic, antifungal, antibacterial cardioprotective activity resveratrol also demonstrates non-selective cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibition. In order to find more selective COX-2 inhibitors a series of methoxylated and hydroxylated resveratrol derivatives were synthesized and evaluated for their ability to inhibit both enzymes using in vitro inhibition assays for COX-1 and COX-2 by measuring PGE2 production. Hydroxylated but not methoxylated resveratrol derivatives showed a high rate of inhibition. The most potent resveratrol compounds were 3,3',4',5-tetra-trans-hydroxystilbene (COX-1: IC50 = 4.713, COX-2: IC50 = 0.0113 œM, selectivity index = 417.08) and 3,3',4,4',5,5'-hexa-hydroxy-trans-stilbene (COX-1: IC 50 = 0.748, COX-2: IC50 = 0.00104 œM, selectivity index = 719.23). Their selectivity index was in part higher than celecoxib, a selective COX-2 inhibitor already established on the market (COX-1: IC 50 = 19.026, COX-2: IC50 = 0.03482 œM, selectivity index = 546.41). Effect of structural parameters on COX-2 inhibition was evaluated by quantitative structure-activity relationship (QSAR) analysis and a high correlation was found with the topological surface area TPSA (r = 0.93). Docking studies on both COX-1 and COX-2 protein structures also revealed that hydroxylated but not methoxylated resveratrol analogues are able to bind to the previously identified binding sites of the enzymes. Hydroxylated resveratrol analogues therefore represent a novel class of highly selective COX-2 inhibitors and promising candidates for in vivo studies. Œ 2004 Elsevier Ltd. All rights reserved.

Organisation(s)

External organisation(s)

Medizinische Universität Wien

Journal

Bioorganic & Medicinal Chemistry

Volume

12

Pages

5571-5578

No. of pages

8

ISSN

0968-0896

Publication date

2004

Peer reviewed

Yes

Austrian Fields of Science 2012

3012 Pharmacy, Pharmacology, Toxicology

Portal url

https://ucris.univie.ac.at/portal/en/publications/resveratrol-analogues-as-selective-cyclooxygenase2-inhibitors-synthesis-and-structureactivity-relationship(500c6154-23bb-431f-8c3f-b041dbe112de).html