COX-2 Inhibitory Effects of Naturally Occurring and Modified Fatty Acids

Abstract

In the search for new cyclooxygenase-2 (COX-2) selective inhibitors, the inhibitory effects of naturally occurring fatty acids and some of their structural derivatives on COX-2-catalyzed prostaglandin biosynthesis were investigated. Among these fatty acids, linoleic acid (LA), alpha-linolenic acid (alpha-LNA), myristic acid, and palmitic acid were isolated from a CH(2)Cl(2) extract of the plant Plantago major by bioassay-guided fractionation. Inhibitory effects of other natural, structurally related fatty acids were also investigated: stearic acid, oleic acid, pentadecanoic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Further, the inhibitory effects of these compounds on COX-2- and COX-1-catalyzed prostaglandin biosynthesis was compared with the inhibition of some synthesized analogues of EPA and DHA with ether or thioether functions. The most potent COX-2-catalyzed prostaglandin biosynthesis inhibitor was all-(Z)-5-thia-8,11,14,17-eicosatetraenoic acid (2), followed by EPA, DHA, alpha-LNA, LA, (7E,11Z,14Z,17Z)-5-thiaeicosa-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 IC(50) values ranging from 3.9 to180 microM. 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.

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“…Based on our test results for the COX-1 and COX-2 inhibitory activities of pure linoleic, oleic and stearic acids [69], [78] as well as the values reported by other groups [104], [105], it appears that fatty acids with higher unsaturation values possess more potent activity against COX-1 and COX-2 than their saturated analogues. Furthermore, the unsaturated fatty acids are selectively active against COX-2 [69], [78], [104], [105]. For example, the initial petroleum ether extract of the stems of Macrococculus pomiferus was found to significantly inhibit COX-2 (the % inhibition was 86 for both extracts at 100 mg/mL) [75].…”

“…However, the methylation product of the fatty acid mixture was inactive in these assays [78]. Based on our test results for the COX-1 and COX-2 inhibitory activities of pure linoleic, oleic and stearic acids [69], [78] as well as the values reported by other groups [104], [105], it appears that fatty acids with higher unsaturation values possess more potent activity against COX-1 and COX-2 than their saturated analogues. Furthermore, the unsaturated fatty acids are selectively active against COX-2 [69], [78], [104], [105].…”

“…The inhibitory effects against both COX-1 and COX-2 of some naturally occurring and modified fatty acids have been reported recently [104], [105]. In our previous work, a fatty acid mixture of linoleic, oleic and stearic acids isolated from the seeds of Ziziphus jujuba was found to be active against both COX-1 and COX-2 [78].…”

Nutritional sub-fertility in the dairy cow: towards improved reproductive management through a better biological understanding

“…The production of endometrial series 2 prostaglandins is mainly governed by the rate-limiting enzyme cyclooxygenase (COX)-2, which mediates embryo implantation in the mouse (Lim et al, 1999;Huang, 2008). The most potent COX-2 inhibitor is an omega 3 FA, eicosapentanoic acid (Ringbom et al, 2001). In a recent study, we have shown that the expression of different genes involved in the establishment of pregnancy in embryo and endometrial tissue is strongly modified by the supply of omega 3 FA in the diet (Palin et al, 2005).…”

Analytical Characterization of Fatty Acids Composition of Datura alba Seed Oil by Gas Chromatography Mass Spectrometry

“…It has been shown to be a potent inhibitor of cyclooxiginase-2 (COX-2) catalyzed prostaglandin biosynthesis. 29,30 Among the other fatty acids with concentrations more than 1% are: Palmitic acid (6.59%), Oleic acid (5.41%) and Stearic acid (1.35%) were found. Amount of rest of the fatty acids were less than 1% (Table 1).…”