Lipoxygenases

Most of the drugs such as epinephrine and albuterol used to treat asthma attacks are bronchodilators—substances that expand the bronchial passages Newer drugs are designed to either inhibit the enzyme 5 lipoxygenase which acts on arachidomc acid m the first stage of leukotriene biosynthesis or to block leukotriene receptors... 

Lipostabil Lipoteichoic acid b-lipotropic hormone b-Lipotropin [12584-99-5] Lipoadase Lipoadases 5-lipoxygenase Lipoxygenase... 

Lipoxygenase-Catalyzed Oxidations. Lipoxygenase-1 catalyzes the incorporation of dioxygen into polyunsaturated fatty acids possessing a l(Z),4(Z)-pentadienyi moiety to yield ( ),(Z)-conjugated hydroperoxides. A highly active preparation of the enzyme from soybean is commercially available in purified form. From a practical standpoint it is important to mention that the substrate does not need to be in solution to undergo the oxidation. Indeed, the treatment of 28 g/L of linoleic acid [60-33-3] with 2 mg of the enzyme results in (135)-hydroperoxide of linoleic acid in 80% yield... 

Synthesis of a Class of Sulfur-Containing Lipoxygenase Inhibitors.351... 

Fluormated agents such as flurbiprofen (II), flunisal(i2), diflunisal (13), and sulindac (14), acting as prostaglandin synthesis mhibitors, have been available for some time [5] The recent introduction of flunoxaprafen (15), a lipoxygenase inhibitor, is notable It reportedly produces considerably less severe gastric disturbance [75]... 

Schewe, T, and Kuhn, H., 1991. Do 15-lipoxygenases have a common biological role. Trends in Biochemical Sciences 16 369—373. 

The wide applicability of the PK reaction is apparent in the synthesis of pyrroles, for example, 45, en route to novel chiral guanidine bases, levuglandin-derived pyrrole 46, lipoxygenase inhibitor precursors such as 47, pyrrole-containing zirconium complexesand iV-aminopyrroles 48 from 1,4-dicarbonyl compounds and hydrazine derivatives. The latter study also utilized Yb(OTf)3 and acetic acid as pyrrole-forming catalysts, in addition to pyridinium p-toluenesulfonate (PPTS). 

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). 

Di-tert-butyl-4-hydroxyphenyl)-7//-triazolo [3,2-b][l, 2,4]triazin-7-one (HWA-131)is anon-immunosuppressive drug that effectively inhibited carrageenan-induced paw edema, attenuated the active Arthus reaction, and demonstrated antierythema as well as antipyretic activity. Part of the antiinflammatory effect of this new compound is most probably related to its antioxidative activity as well as inhibition of lipoxygenase... 

Any of the collection of oxygenated metabolites of arachidonic acid that are the product of cyclooxygenase, cytochrome P450, or lipoxygenase pathways. 

In cell free systems or isolated cells, some enzymes of the arachidonate cascade can also recognize AEA and 2-AG as substrates, thereby producing the corresponding lipoxygenase and cyclooxygenase-2 derivatives. However, these metabolites have not yet been isolated from tissues and their biological relevance is still unknown. 

Triggering of asthma attacks in asthmatics. This side effect is a pseudo-allergic reaction where COX-inhibition increases the availability of substrates for lipoxygenase, which are converted to broncho-constrictive leukotriens... 

Lipoxygenase AVNTR polymorphism in 100 bp upstream from the ATG start codon is associated with transcription efficiency. Differences in response to 5-lipoxygenase inhibitors and leucotriene receptor antagonists. 

Genes involved in the uptake and degradation of tocopherols - Genes implicated with lipid uptake and. Mi / °f J - Protein kinase C (PKC) - Cyclooxygenase - 5-Lipoxygenase - Cytokine release (IL-1P)... 

Lipoprotein Metabolism Lipoproteins Liposomes 5-Lipoxygenase Lipoxygenases Lithocholic Acid Local Anaesthetics Locus... 

Applications of peroxide formation are underrepresented in chiral synthetic chemistry, most likely owing to the limited stability of such intermediates. Lipoxygenases, as prototype biocatalysts for such reactions, display rather limited substrate specificity. However, interesting functionalizations at allylic positions of unsaturated fatty acids can be realized in high regio- and stereoselectivity, when the enzymatic oxidation is coupled to a chemical or enzymatic reduction process. While early work focused on derivatives of arachidonic acid chemical modifications to the carboxylate moiety are possible, provided that a sufficiently hydrophilic functionality remained. By means of this strategy, chiral diendiols are accessible after hydroperoxide reduction (Scheme 9.12) [103,104]. 

Scheme 9.12 Soybean lipoxygenase (SBLO)-mediated oxygenation of fatty acid derivatives.

JP04 321 624 (Hisamitsu Pharm. appl. 19.4.1991 J-prior. 19.4.1991). combination with 5-lipoxygenase inhibitors ... 

Peroxidation is also catalyzed in vivo by heme compounds and by lipoxygenases found in platelets and leukocytes. Other products of auto-oxidation or enzymic oxidation of physiologic significance include oxysterols (formed from cholesterol) and isoprostanes (prostanoids). 

There are three groups of eicosanoids that are synthesized from C20 eicosanoic acids derived from the essential fatty acids linoleate and a-linolenate, or directly from dietary arachidonate and eicosapentaenoate (Figure 23-5). Arachidonate, usually derived from the 2 position of phospholipids in the plasma membrane by the action of phospholipase Aj (Figure 24-6)—but also from the diet—is the substrate for the synthesis of the PG2, 1X2 series (prostanoids) by the cyclooxygenase pathway, or the LT4 and LX4 series by the lipoxygenase pathway, with the two pathways competing for the arachidonate substrate (Figure 23-5). 

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