Leukotrienes
Title: Leukotrienes
Additional Names: LTs
Literature References: A family of endogenous metabolites of arachidonic acid via the lipoxygenase pathway, chemically related to the prostaglandins and thromboxanes, q.q.v. The name leukotrienes was applied because of their origin in leukocytes and their conjugated triene structures. [For a description of the nomenclature of individual leukotrienes see B. Samuelsson, S. Hammarström, Prostaglandins 19, 645 (1980)]. Members of the group are potent bronchoconstrictors that play an important pathophysiological role in immediate hypersensitivity reactions; they have been proposed as mediators of the inflammatory process and some are potent chemotactic agents. Initial studies of novel arachidonate metabolites in rabbit polymorphonuclear leukocytes: P. Borgeat et al., J. Biol. Chem. 251, 7816 (1976); 252, 8772 (1977). Subsequent studies and structure of a dihydroxyeicosatetraenoic acid (leukotriene B, LTB4): P. Borgeat, B. Samuelsson, ibid. 254, 2643 (1979). LTB4 is formed from an unstable intermediate oxido-eicosatetraenoic acid, leukotriene A or LTA4: eidem, Proc. Natl. Acad. Sci. USA 76, 3213 (1979). Stereochemistry and enzymatic conversion of LTA4 to LTB4: O. Radmark et al., Biochem. Biophys. Res. Commun. 92, 954 (1980). Synthesis of the four optical isomers of LTA4: J. Rokach et al., Tetrahedron Lett. 22, 2759, 2763 (1981). Total synthesis of LTB4: E. J. Corey et al., J. Am. Chem. Soc. 102, 7984 (1980); Y. Guindon et al., Tetrahedron Lett. 23, 739 (1982). Formation of the 20-hydroxy and 20-carboxy metabolites of LTB4: G. Hansson et al., FEBS Lett. 130, 107 (1981); total synthesis: R. Zamboni, J. Rokach, Tetrahedron Lett. 23, 4751 (1982). Earlier studies had described a "slow-reacting substance of anaphylaxis" (SRS-A or SRS) released from guinea pig and cat lung by cobra venom and in guinea pig lung after anaphylactic shock, cf. W. S. Feldberg, C. H. Kellaway, J. Physiol. 94, 187 (1938); C. H. Kellaway, E. R. Trethewie, Q. J. Exp. Physiol. 30, 121 (1940). The relationship between SRS and members of the leukotriene family was established following publication of the uv spectrum of purified SRS-A, which showed the presence of the conjugated triene, cf. H. R. Morris et al., FEBS Lett. 87, 203 (1978). Purification and structure of LTC4, an SRS from mouse mastocytoma cells: R. C. Murphy et al., Proc. Natl. Acad. Sci. USA 76, 4275 (1979); S. Hammarström et al., Biochem. Biophys. Res. Commun. 91, 1266 (1979). Total synthesis of LTC4: E. J. Corey et al., J. Am. Chem. Soc. 102, 1436, 3663 (1980); J. Rokach et al., Tetrahedron Lett. 21, 1485 (1980). Identity of synthetic LTC4 with SRS from mouse mastocytoma cells: S. Hammarström et al., Biochem. Biophys. Res. Commun. 92, 946 (1980). Structure of the SRS from rat basophil leukemia cells (RBL-1) and identification as a leukotriene (LTD4): H. R. Morris et al., Prostaglandins 19, 185 (1980). It was subsequently proposed that LTC4 was an intermediate in the biosynthesis of LTD4. Identity of SRS-A released in sensitized guinea pig lung perfusates and LTD4: eidem, Nature 285, 104 (1980). Assignment of stereochemistry: eidem, Prostaglandins 20, 601 (1980). Detection of LTA4 as an intermediate in the biosynthesis of LTC4 and LTD4: S. Hammarström, B. Samuelsson, FEBS Lett. 122, 83 (1980). The sulfone of LTC4, which has also been proposed as a natural product, cf. H. Ohnishi et al., Prostaglandins 20, 655 (1980), has been found to be as potent as LTC4: T. Jones et al., ibid. 24, 279 (1982). Synthesis: Y. Girard et al., Tetrahedron Lett. 23, 1023 (1982). Discovery of LTF4: M. E. Anderson et al., Proc. Natl. Acad. Sci. USA 79, 1088 (1982). Synthesis: F. Ellis et al., Tetrahedron Lett. 23, 3735 (1982). It is now known that SRS-A is made up of varying amounts of cysteine-containing members of the leukotrienes, i.e. leukotrienes C4, D4, and E4. These three LTs are generally found to be 100 to 1000 times more potent, on a molar basis, than histamine or prostaglandins in their effects on pulmonary airways. Review of chemistry and structure elucidation: D. A. Clark, A. Marfat, Annu. Rep. Med. Chem. 17, 291-300 (1982). Comprehensive review of synthesis of leukotrienes and other lipoxygenase-derived products: J. G. Atkinson, J. Rokach, in Handbook of Eicosanoids: Prostaglandins and Related Lipids IB, A. L. Willis, Ed. (CRC Press, Boca Raton, 1987) pp 175-263. General reviews: P. Sirois, P. Borgeat, Int. J. Immunopharmacol. 2, 281-293 (1980); P. Borgeat, P. Sirois, J. Med. Chem. 24, 121-126 (1981); B. Samuelsson, Int. Arch. Allergy Appl. Immunol. 66, Suppl. 1, 98-106 (1981); L. S. Wolfe, J. Neurochem. 38, 1-14 (1982); J. L. Marx, Science 215, 1380-1384 (1982); B. Samuelsson, S. Hammarström, Vitam. Horm. 39, 1-30 (1982). Books: SRS-A and Leukotrienes, P. J. Piper, Ed. (Research Studies Press, London, 1981) 279 pp; Advances in Prostaglandin, Thromboxane, and Leukotriene Research vol. 9, B. Samuelsson, R. Paoletti, Eds. (Raven Press, New York, 1982) 341 pp.
 
Derivative Type: Leukotriene A4
CAS Registry Number: 72059-45-1
CAS Name: (2S,3S)-3-(1E,3E,5Z,8Z)-1,3,5,8-Tetradecatetraenyloxiranebutanoic acid
Additional Names: leukotriene A; LTA4
Molecular Formula: C20H30O3
Molecular Weight: 318.45
Percent Composition: C 75.43%, H 9.50%, O 15.07%
Properties: Unstable. Characterized as its methyl ester: mp 28-32°. [a]D25 -27° (hexane). uv max (methanol): 270, 278, 290 nm (e 43900, 56700, 43100), cf. J. Rokach et al., Tetrahedron Lett. 22, 2759 (1981); I. Ernest et al., ibid. 23, 167 (1982).
Melting point: mp 28-32°
Optical Rotation: [a]D25 -27° (hexane)
Absorption maximum: uv max (methanol): 270, 278, 290 nm (e 43900, 56700, 43100)
 
Derivative Type: Leukotriene B4
CAS Registry Number: 71160-24-2
CAS Name: (5S,6Z,8E,10E,12R,14Z)-5,12-Dihydroxy-6,8,10,14-eicosatetraenoic acid
Additional Names: leukotriene B; LTB4
Molecular Formula: C20H32O4
Molecular Weight: 336.47
Percent Composition: C 71.39%, H 9.59%, O 19.02%
Properties: uv max (methanol): 260, 270.5, 281 nm (e 38000, 50000, 39000).
Absorption maximum: uv max (methanol): 260, 270.5, 281 nm (e 38000, 50000, 39000)
 
Derivative Type: Leukotriene C4
CAS Registry Number: 72025-60-6
CAS Name: L-g-Glutamyl-S-[(1R,2E,4E,6Z,9Z)-1-[(1S)-4-carboxy-1-hydroxybutyl]-2,4,6,9-pentadecatetraenyl]-L-cysteinylglycine
Additional Names: leukotriene C; leukotriene C1; LTC4
Molecular Formula: C30H47N3O9S
Molecular Weight: 625.77
Percent Composition: C 57.58%, H 7.57%, N 6.71%, O 23.01%, S 5.12%
Properties: uv max (methanol): 270, 280, 290 nm (e 32000, 40000, 31000). Can be stored for several days without appreciable decomposition in frozen (-20°) pH 6.8 phosphate buffer under argon or as the tripotassium salt frozen in water. Biological activity destroyed after incubation with soybean lipoxygenase and uv max shifts to 308 nm.
Absorption maximum: uv max (methanol): 270, 280, 290 nm (e 32000, 40000, 31000); uv max shifts to 308 nm
 
Derivative Type: Leukotriene D4
CAS Registry Number: 73836-78-9
CAS Name: S-[(1R,2E,4E,6Z,9Z)-1-[(1S)-4-Carboxy-1-hydroxybutyl]-2,4,6,9-pentadecatetraenyl]-L-cysteinylglycine
Additional Names: leukotriene D; LTD4
Molecular Formula: C25H40N2O6S
Molecular Weight: 496.66
Percent Composition: C 60.46%, H 8.12%, N 5.64%, O 19.33%, S 6.46%
Properties: uv max (methanol): 270, 280, 290 nm (e 31000, 40000, 31000). Storage, destruction of biological activity, uv shift are the same as for LTC4.
Absorption maximum: uv max (methanol): 270, 280, 290 nm (e 31000, 40000, 31000)
 
Derivative Type: Leukotriene E4
CAS Registry Number: 75715-89-8
CAS Name: (5S,6R,7E,9E,11Z,14Z)-6-[[(2R)-2-Amino-2-carboxyethyl]thio]-5-hydroxy-7,9,11,14-eicosatetraenoic acid
Additional Names: leukotriene E; LTE4
Molecular Formula: C23H37NO5S
Molecular Weight: 439.61
Percent Composition: C 62.84%, H 8.48%, N 3.19%, O 18.20%, S 7.29%
Properties: uv max (ethanol) of methyl ester: 269, 280, 291 nm (e 28200, 35200, 28900).
Absorption maximum: uv max (ethanol) of methyl ester: 269, 280, 291 nm (e 28200, 35200, 28900)

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