COX-2 inhibitory effects of naturally occurring and modified fatty acids

Ringbom, T Huss, U Stenholm, A Flock, S Skattebol, L Perera, P Bohlin, L

T. Ringbom et al., COX-2 inhibitory effects of naturally occurring and modified fatty acids, J NAT PROD, 64(6), 2001, pp. 745-749

33

INGLESE

Article

Agricultural Chemistry","Pharmacology & Toxicology

JOURNAL OF NATURAL PRODUCTS

0163-3864 → ACNP

64

6

2001

745 - 749

ISI

0163-3864(200106)64:6<745:CIEONO>2.0.ZU;2-J

In the search for new cyclooxygenase-2 (COX-2) selective inhibitors, the in hibitory effects of naturally occurring fatty acids and some of their struc tural derivatives on COX-2-catalyzed prostaglandin biosynthesis were invest igated, Among these fatty acids, linoleic acid (LA), a-linolenic acid (alph a -LNA), myristic acid, and palmitic acid were isolated from a CH2Cl2 extra ct of the plant Plantago major by bioassay-guided fractionation. Inhibitory effects of other natural, structurally related fatty acids were also inves tigated: stearic acid, oleic acid, pentadecanoic acid, eicosapentaenoic aci d (EPA), and docosahexaenoic acid (DHA). Further, the inhibitory effects of these compounds on COX-2- and COX-1-catalyzed prostaglandin biosynthesis w as compared with the inhibition of some synthesized analogues of EPA and DH A with ether or thioether functions. The most potent COX-2-catalyzed prosta glandin biosynthesis inhibitor was all-(Z)-5-thia-8,11,14,17-eicosatetraeno ic acid (2), followed by EPA, DHA, cx-LNA, LA, (7E, 11Z,14Z,17Z)-5-thiaeico sa-7, 11,14,17-tetraenoic acid, all-(Z)-3-thia-6,9,12,15-octadecatetraenoic acid, and (5E,9Z,12Z,15Z,18Z)-3-oxaheneicosa-5,9,12,15,18-pentaenoic acid, with IC50 values ranging from 3.9 to 180 muM. The modified compound 2 and alpha -LNA were most selective toward COX-2, with COX-2/ COX-1 ratios of 0. 2 and 0.1, respectively. This study shows that several of the natural fatty acids as well as all of the semisynthetic thioether-containing fatty acids inhibited COX-2-catalyzed prostaglandin biosynthesis, where alpha -LNA and compound 2 showed selectivity toward COX-2.