Structure of leukotriene

The leukotrienes are molecules that contribute to the asthmatic response. A typical example, leukotriene C4, is shown. Although its biological activity was first observed in the 1930s. the chemical structure of leukotriene C4 was not determined until 1979. Structure determination and chemical synthesis were difficult because leukotrienes are highly unstable and extremely potent, and are therefore present in tissues in exceedingly small amounts. 

Structures of leukotriene receptor antagonists, (a) Zafirlukast and (b) montelukast. 

Hammarstrom, S, Murphy, RC, Samuelsson, B, Clark, DA, Mioskowski, C and Corey, EJ (1979) Structure of leukotriene C. Identification of the amino acid part. Biochem Biophys Res Commun, 91, 1266-1272. 

Soon after, the complete structure of SRS-A was finally determined by total synthesis. SRS-A turned out to be a mixture of 3 substances now known as leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4) in which LTD4 was predominant. The jump from a biological observation in 1938 to a molecular structure of LTD4 opened the door to a novel and selective treatment for asthma. The theory was that if one... 

Fig. 8.2 Alignment of the protein structure of the cysteinyl leukotriene 1 (CysLTj) and 2 (CysLT ) receptors in relation to rhodopsin. The amino acids conserved between these family A receptors are shown. The consensus is greater than 50%. These data formed the basis of the model predicting the CysLTj and CysLT transmembrane domains (helices 1-7), the four [3-sheets, and the putative cysteinyl leukotiiene-binding domain. The amino acid variants that are associated with atopy or asthma, the G300S CysLTj variant, and the M201V CysLT variant are each boxed and noted with arrows...

D. A. Clark, A. Marfat (1982). Structure elucidation and the total synthesis of leukotrienes. Annu. Rep. Med. Chem. 17 291-300. 

The structure of the leukotrienes receptor antagonist cinalukast (58-9) bears only the vaguest resemblance to its predecessor, or, for that matter, to a leukotriene. Reaction of the cyanomethylphosphonate (58-1) with hydrogen sulfide converts the nitrile to a thioamide (58-2). Treatment of that intermediate with the bromoketone... 

Lipids are made up of many classes of very different molecules that all show solubility properties in organic solvents. Mass spectrometry plays a key role in the biochemistry of lipids. Indeed, mass spectrometry allows not only the detection and determination of the structure of these molecules but also their quantification. For practical reasons, only the fatty acids, acylglycerols and bile acids are discussed here, although other types of lipids such as phospholipids, [253-256] steroids, [257-259] prostaglandins, [260] ceramides, [261,262] sphingolipids [263,264] and leukotrienes [265,266] have been analysed successfully by mass spectrometry. Moreover, the described methods will be limited to those that are based only on mass spectrometry, even if the majority of these methods generally are coupled directly or indirectly with separation techniques such as GC or HPLC. A book on the mass spectrometry of lipids was published in 1993. [267]... 

Thiol-5-nitrobenzoxazole, the structural material for the preparation of potential enantioselective inhibitors of leukotriene biosynthesis, has been synthesized by condensation of nitro-orf/ioaminophenole with CS2 [506],... 

Because GS can be seen as a congener of PCN, it is not surprising that it can bind to PXR in addition to FXR. In contrast, its affinity to PPARa, whose natural ligand is leukotriene B4 (39, Scheme 14.10), is quite surprising. This cross-reactivity indicates that combinatorial variation of the structure of a ligand for one NR, irrespective of its scaffold (for example, steroidal or not), also leads to ligands for other NRs. 

In a similar biochemically oriented vein, several papers were published during 2003 in the journal Chemical Research in Toxicology, representing yet another area of applicability of 3 mm NMR probe capabilities. In the first of these reports, Hankin et al.159 described the results of an investigation into the covalent binding of leukotriene A4 to DNA and RNA. Later in 2003, Blair and co-workers160 reported on the characterization of 2 -deoxycytidine adducts derived from 4-oxo-2-nonenal, a novel lipid peroxidation product. Two of the adducts characterized, Ai and A2, were consistent with substituted ethano-deoxycytidine structures. The third adduct, B, was characterized as a 7-heptanone-etheno-deoxycytidine adduct (78). 

Figure 12.14. Structures of Zileuton, an inhibitor of 5-lipoxygenase, and of montelukast, an leukotriene receptor antagonist.

Figure 12.15. Increased leukotriene formation as an indirect consequence of cyclooxygenase inhibition by, e g., acetylsalicylic acid (ASS a), and structure of the 5-Lox/Cox-2 dual inhibitor tepoxalin (b).

Enzyme-catalyzed epoxide ring opening including discussion of convergent families of epoxide hydrolases, the catalytic mechanism of microsomal epoxide hydrolases, epoxide hydrolases in metabolism, and the synthesis, structure, and mechanism of leukotriene A4 hydrolase, and glutathione transferase has been reviewed by Armstrong <1999CONAP(5)51>. 

Figure 1 Chemical structures of representative eicosanoid molecules (a) leukotriene, (b) prostaglandin, (c) prostacyclin, and (d) thromboxane. Common names, chemical formulas, and molecular weights (g/mol) are shown.

Indicator variables (/) are often used to highlight a structural feature present in some of the molecules in a data set that confers unusual activity or lack of it to these particular members. Their use could be beneficial in cases where the data set is heterogeneous and includes large numbers of members with unusual features that may or may not impact a biological response. QSAR for the inhibition of trypsin by X-benzamidines used indicator variables to denote the presence of unusual features such as positional isomers and vinyl/ carbonyl-containing substituents (170). A recent study on the inhibition of lipoxygenase catalyzed production of leukotriene B4 and 5-hydroxyeicosatetraenoic from arachidonic... 

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