Studies on lipoxygenase inhibitors. II KF8940 (2-n-heptyl-4-hydroxyquinoline-N-oxide), a potent and selective inhibitor of 5-lipoxygenase, produced by Pseudomonas methanica.

Abstract

Pseudomonas methanica KY4634 was found to produce 5-lipoxygenase inhibitor designated KF8940, MY12-62a and MY12-62c. The inhibitors were purified by solvent extraction, silica gel column chromatography, reversed-phase low pressure liquid chromatography and crystallization. The chemical structures of KF8940, MY12-62a and MY12-62c were determined to be 2-n-heptyl-4-hydroxyquinoline-N-oxide, 2-n-heptyl-4-hydroxyquinoline and 3-n-heptyl-3-hydroxy-1,2,3,4-tetrahydroquinoline-2,4-diore, respectively, on the basis of their physico-chemical properties. Among them, KF8940 was the most potent inhibitor. The compound inhibited 5-lipoxygenase of rat basophilic leukemia cells in a dose-dependent manner and the half maximal inhibitory concentration (IC,0) was 1.5 x 10 M. At this concentration, KF8940 did not inhibit bovine platelet 12-lipoxygenase and cyclooxygenase, and the IC,,0 values for these enzyme were 3.5 x 10-5 M and 1.7 x 10-4 M, respectively. The results indicated that KF8940 is a potent and selective inhibitor of 5-lipoxygenase. The IC50 value of MY12-62c for 5-lipoxygenase was 1.9 x 10 M and that of MY12-62a was 1.9 x 10-5M.Much attention has been focused on 5-lipoxygenase inhibitors as anti-asthmatic and anti-inflammatory agents since SAMUELSSON and co-workersl,2) showed that slow reacting substances of anaphylaxis (SRS-A), potent mediators generated during anaphylactic reaction, were oxidative products of arachidonate 5-lipoxygenase. The enzyme is mainly distributed in leukocytes3) and catalizes the oxygenation of arachidonic acid at C-5 position to produce 5-HPETE. The product can be either reduced enzymatically to its hydroxy derivative, 5-HETE, or transformed to the peptide LTs and LTB4. LTB4 was proposed to be implicated in inflammatory reactions because of its potent chemotactic activity4).Many compounds have recently been reported as 5-lipoxygenase inhibitors5-9) and some of them exhibited anti-asthmatic activities10,11). In the course of screening for lipoxygenase inhibitors from microbial origin, we found that Pseudomonas methanica KY4634 produced potent 5-lipoxygenase inhibitors. The compounds, designated KF8940, MY12-62a and MY12-62c, were isolated from the culture broth and their structures were determined. Among them, KF8940, 2-n-heptyl-4-hydroxyquinoline-N-oxide, was a potent and selective inhibitor of the enzyme. This manuscript describes the fermentation, isolation and purification, structural identification, and some biological properties of the inhibitors.

Two new 2-alkylquinolones, inhibitory to the fish skin ulcer pathogen Tenacibaculum maritimum, produced by a rhizobacterium of the genus Burkholderia sp.

“…A series of chemoecological studies of P. aeruginosa has uncovered multifunctional roles of this quinolone class as antibacterial, antifungal, iron-chelating, and autoinducer agents to assist the survival of the producing organisms [ 32 ]. Additionally, drug discovery attempts have revealed 5-lipoxygenase inhibitory activity [ 33 ], plant-growth promoting activity [ 32 , 34 ], and IGF-dependent cell-specific cytotoxicity [ 14 ].…”

Metabolomic profiling of regulatory lipid mediators in sputum from adult cystic fibrosis patients

“…Moreover, P. aeruginosa express a number of fatty acid metabolizing enzymes including dioxygenases, hydroperoxide isomerases, and arachidonate 15-lipoxygenase (LoxA; contribution to the formation of 15-HETE) [76, 77] that may directly contribute to the oxygenation of fatty acids in the CF airway [76, 78] and contribute to the virulence and airway persistence of the organism [79]. One report has revealed that P. aeruginosa may be a source of secreted inhibitors of 5-lipoxygenase [80]. Moreover, a recent study has identified an epoxide hydrolase produced by P. aeruginosa [81] that could potentially metabolize epoxide-based oxylipins to the corresponding diols which compromise the functions of these anti-inflammatory oxylipins in the CF RT.…”

Secondary metabolites from fluorescent pseudomonads

“…In the Russian literature, these compounds are named psevdans; Roman numerals indicating the chain lengths [138]. Spectroscopic and degradation studies established the presence of several 2-alk(en)yl-quinolones-4 (23) [69][70][71] and of their N-hydroxy derivatives (24) (also formulated in the tautomeric forms as 4-hydroxy quinoline (Noxides) [69,71,72] all of which show pronounced antibacterial activity. Pseudomonas aeruginosa seems also to produce 2-n-heptyl-3-hydroxy quinolone-4 [139].…”

“…Pseudomonas aeruginosa seems also to produce 2-n-heptyl-3-hydroxy quinolone-4 [139]. In addition, 3-n-heptyl-and 3-n-nonyl-3-hydroxy-1,2,3,4-tetra-hydroquinoline-2,4-dione was found (25) [71,74]. From the data given in [68], a mixture of them could be Pyo IV.…”