5-Lipoxygenase inhibitory activity

In 1993, Oki et al. isolated the novel carbazole antibiotics epocarbazolin A (258) and B (259) from the culture broth of Streptomyces anulatus T688-8 (230). They represent the first carbazole alkaloids with an epoxide moiety in a side chain, and are the epoxides corresponding to carbazomadurin A (256) and B (257). Epocarbazolin A (258) [oC + 75.0 (c 0.5, MeOH) and B (259) Mg -b 78.0 (c 0.5, MeOH) were obtained from Nature in optically active form. However, their absolute configuration is not known. These alkaloids showed potent 5-lipoxygenase inhibitory activity and weak antibacterial activity (230) (Scheme 2.63). 

A recent report describes the formation of benzo derivatives of the pyrimido[4,5- ][l,4]thiazine system by cyclization (Scheme 109) <2007BMC2120>. The compounds prepared have some 5-lipoxygenase inhibitory activity, the active inhibitor being the corresponding sulfoxide, which has been prepared by oxidation of the parent (Scheme 109). 

The overall modest yields achieved in these syntheses have recently been markedly improved by the use of the solid-phase copolymer of 4-vinylpyridine (P4-VP) (112) in the formation of the starting di-ynic esters. For example, when a suspension of P4-VP polymer in dichloromethane was stirred with the acid chloride from (1011 and then the propargyl alcohol (114), the ester (1151 was obtained excellent yield. By heating in xylene, (1151 underwent intramolecular cyclization to yield justicidin E(1041 and taiwanin C(1051 as the major products in addition, the isomers helioxanthin (1081 and retrohelioxanthin (1161 could also be isolated (Scheme 22) (113). Increased interest in these four lactone products has resulted from an assay which indicates 5-lipoxygenase inhibitory activity (114). 

Halicholactone 214, a marine metabolite with lipoxygenase inhibitory activity, belongs to the family of oxylipins which all contain a lactone moiety substituted by a /ra r-disubstituted cyclopropane subunit. Stereoselective RCM for the formation of the nine-membered lactone core in 214 was the penultimate step (212 —> 213) in a asymmetric... 

Loke WM, Proudfoot JM, Stewart S, McKinley AJ, Needs PW, Kroon PA, Hodgson JM, Croft KD. 2008c. Metabolic transformation has a profound effect on antiinflammatory activity of flavonoids such as quercetin Lack of association between antioxidant and lipoxygenase inhibitory activity. Biochem Pharmacol 75 1045-1053. 

Rational design could be pushed even further, employing 3D-QSAR studies to yield pharmacophore models, as is the case for 15-lipoxygenase inhibitory activity. For this purpose, 47 indolizines with anti-15-LOX activity were used to obtain a statistically significant model [70]. 

Ha, T. J. and K. Nihei, L Kubo. 2004. Lipoxygenase inhibitory activity of octyl gallate./. Agric. Food Chem. 52 3177-3181. 

The microbial transformation of glyc5a-rhetinic acid (83) by C. elegans afforded one metabolite, 3p,7p-dihydroxy-ll-oxo-olean-12-en-29-oic acid (84), while fermentation of 83 with F. Uni afforded 3,ll-dioxo-olean-12-en-29-oic acid (96) (Figure 28.26) which exhibited a potent lipoxygenase inhibitory activity [73]. 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

Halicholactone (25) was reported to exhibit weak inhibitory activity against the 5-lipoxygenase from guinea pig polymorphonuclear leukocytes (IC50 = 630 pM) [38], A subsequent report detailing the three-dimensional structure of the co3 unsaturated neohalicholactone (26) described it as a potent lipoxygenase inhibitor , however, no additional experimental data were provided [39],... 

Whatever the mechanism of action for the inhibition of 5-lipoxygenase by flavonoids, it appears to be distinct from the antioxidant properties of these compounds. The results comparing antioxidant activity with leukotriene inhibitory activity clearly demonstrate this distinction. The profound effects of metabolic transformation on the anti-inflammation activity of dietary flavonoids such as quercetin must also be considered in relation to in vitro studies, and further highlights the need to use actual metabolic forms of flavonoids rather than the free aglycone or glycosides occurring in the diet. 

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