Stereospecific total synthesis of a "slow reacting substance" of anaphylaxis, leukotriene C-1

Corey, E. J.; Clark, David A.; Goto, Giichi; Marfat, Anthony; Mioskowski, Charles; Samuelsson, Bengt; Hammarstroem, Sven

doi:10.1021/ja00524a045

Cited by 386 publications

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“…METHODS Materials. LTC4, LTD4, LTE4 and the structural leukotriene analogues of LTC4-5(R),6(S )-LTC4, Cl-monoamide-LTC4, deamino-LTC4, and 1 1-trans-LTC4-were prepared as described (4,6,8,9) (Fig. 1 a).…”

Section: Introductionmentioning

confidence: 99%

Specific receptors for leukotriene C4 on a smooth muscle cell line.

Krilis¹,

Lewis²,

Corey³

et al. 1983

J. Clin. Invest.

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Cl-monoamide-LTC4, competed effectively with radiolabeled LTC4 such that the relative Kd values of these heteroligands were within one log of that of the homoligand. In contrast, the other native sulfidopeptide leukotrienes, leukotriene D4 and leukotriene E4, exhibited relative Kd values that were 2-3 logs less than that of LTC4. Thus, the high affinity receptor on the DDT1 smooth muscle cell line is specific for a single Dr.

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Section: Introductionmentioning

confidence: 99%

Specific receptors for leukotriene C4 on a smooth muscle cell line.

Krilis¹,

Lewis²,

Corey³

et al. 1983

J. Clin. Invest.

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“…1) were synthesized as previously described [8,27,281. Compounds I, I1 and I11 were eluted as single peaks after reverse-phase HPLC using a 5-pm Spherisorb C,, column (4.6 mm X 250 mm) (Hichrom Ltd) with retention times of 18, 28 and 12 min, respectively.…”

Section: Synthesis Of Ltb and Its Structural Analoguesmentioning

confidence: 99%

Structure/activity relationship of leukotriene B₄ and its structural analogues in chemotactic, lysosomal‐enzyme release and receptor‐binding assays

Soyombo

Spur

Soh

et al. 1993

European Journal of Biochemistry

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The biological activities of chemically synthesized leukotriene B, and eight structural analogues have been studied using chemotaxis, lysosomal-enzyme release and receptor-binding assays on human neutrophils. The results show that increasing the number of double bonds between C14 and C20, having triple bonds at C6 or C14, substitution of the primary carboxyl group at C1, changing the geometry of the double bond at C6 from the cis to trans configuration and changing the chirality of the hydroxyl group at C12 from the R to the S configuration result in substantial loss of both biological activity and the capacity to bind to the LTB, recognition site in parallel. We suggest that the functional epitopes of 5S, 12R-dihydroxy-6,14-cis-8,lO-truns-icosatetraenoic acid (LTB,) are either the same, or reside in the same domain as the binding site for the LTB, receptor. Development of LTB, antagonists to the high-affinity LTB, receptor, based on the structure of LTB,, is unlikely to be successful.Arachidonic acid is released from membrane phospholipids upon stimulation and is transformed via 5-hydroperoxy-6,8,11,14-icosatetraenoic acid (5-HPETE) by the 5-lipoxygenase enzyme [l-31 into an unstable epoxide, leukotriene A, (LTA,; 5,6-oxido-7,9,11,14-icosatetraenoic acid) [4]. LTA, is formed from 5-HPETE by abstraction of a hydrogen at ClO and elimination of a hydroxyl anion from the hydroperoxy group. LTA, undergoes either spontaneous, non-enzymic hydrolysis to form several stereochemically distinct 5,12-dihydroxy-icosatetraenoic acids (5,12-diHETE) or is enzymically catalyzed by the hydrolase enzyme to form leukotriene B, (LTB, ; 5S, 12R-dihydroxy-6,14-cis-8,1 O-trunsicosatetraenoic acid), a specific form of 5,12-diHETE [5, 61. Conjugation of LTA, with glutathione at the C6 position, by the glutathione-S-transferase enzyme LTC, synthetase, leads to the formation of LTC, (5S-hydroxy-GR-glutathionyl-7,9-truns-ll,14-cis-icosatetraenoic acid) [7, 81. LTC, is metabolically altered by successive elimination of a y-glutamyl residue, then glycine, to form its 6-cysteinylglycyl analogue, LTD, [9] and its 6-cysteinyl analogue, LTE, [lo] respectively. The structure of LTB, is 5S,12R-dihydroxy-6,14-cis-8,1O-truns-icosatetraenoic acid (compound I) [ll]. It is synthesized by human neutrophils, monocytes and alveolar macrophages in response to a wide variety of stimuli Abbreviations. PMN, polymorphonuclear cells ; HPETE, hydroperoxyicosatetraenoic acid; LTA,, 5,6-oxido-7,9,11,14-icosatetraenoic acid; diHETE, dihydroxyicosatetraenoic acids ; DMA, dimethylamide; LTB,, 5s. 12R-dihydroxy-6,14-cis-8,lO-trunL~-icosatetraenoic acid (compound 1); LTC,, SS-hydroxy-6R-glutathionyl-7,9-trans-11,14-cis-icosatetraenoic acid; IC,,, concentration at which half of the response is inhibited; fmet, formylmethionyl; HBSS, Hanks' balanced-salt solution; HPF, High-power field; compounds I-IX, the structures and chemical formulae are shown in Fig. 1. and is a potent chemotactic agent for neutrophils [12]. It induces aggregation of polymorphonuclear cells (P...

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“…This research has now been well reviewed (7)(8)(9)(10)(11). The geometrical assignments of the double bonds of the different leukotrienes as well as the stereochemical assignments have been made possible by total syntheses and subsequent comparison of synthetic and natural products (12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Section: Ltdmentioning

confidence: 99%

The conformational analysis of leukotriene D₄ in aqueous solution based on high-field nuclear magnetic resonance measurements

Sugiura¹,

Beierbeck²,

Kotovych³

et al. 1984

Can. J. Chem.

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. Can. J. Chem. 62, 1640 ( 1984). The conformational analysis of LTD, in D20 was carried out based on the analysis of vicinal proton-proton coupling constants, nonselective proton longitudinal relaxation times, and nuclear Overhauser effect data. The H6-C6 to C12 region of the molecule is transoid, the predominant rotamer about C5-C6 is gauche, and two rotamers can be used to describe the rotation about C12-C13. There are three rotamers that can be used to describe the rotation about the C21-C22 bond of cysteine. Finally, chelation between an ~b " , shift reagents and LTD, was not observed.MAKIKO SUGIURA, HELMUT BEIERBECK, GEORGE KOTOVYCH et PATRICE C. BELANGER. Can. J. Chem. 62, 1640 (1984). Faisant appel h une analyse des constantes de couplage proton-proton vicinales, des temps de relaxation longitudinaux non-selectifs des protons et de donnCes d'effet Overhauser nuclkaire, on a rCalisC une analyse conformationnelle du LTD, dans le D20. La region H6-C6 2 1 C12 de la molCcule est transoide, le rotamkre predominant autour de la liaison C5-C6 est gauche et deux rotameres peuvent &tre utilisCs pour decrire la rotation autour de la liaison C12-C13. On peut utiliser trois rotameres pour dtcrire la rotation autour de la liaison C21-C22 de la cystkine. Finalement, on n'a pas pu observe de chelation entre le Yb3', un reactif de contact, et le LTD,.[Traduit par le journal]

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Stereospecific total synthesis of a "slow reacting substance" of anaphylaxis, leukotriene C-1

Cited by 386 publications

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Specific receptors for leukotriene C4 on a smooth muscle cell line.

Specific receptors for leukotriene C4 on a smooth muscle cell line.

Structure/activity relationship of leukotriene B₄ and its structural analogues in chemotactic, lysosomal‐enzyme release and receptor‐binding assays

The conformational analysis of leukotriene D₄ in aqueous solution based on high-field nuclear magnetic resonance measurements

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Stereospecific total synthesis of a "slow reacting substance" of anaphylaxis, leukotriene C-1

Cited by 386 publications

References 0 publications

Specific receptors for leukotriene C4 on a smooth muscle cell line.

Specific receptors for leukotriene C4 on a smooth muscle cell line.

Structure/activity relationship of leukotriene B4 and its structural analogues in chemotactic, lysosomal‐enzyme release and receptor‐binding assays

The conformational analysis of leukotriene D4 in aqueous solution based on high-field nuclear magnetic resonance measurements

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Structure/activity relationship of leukotriene B₄ and its structural analogues in chemotactic, lysosomal‐enzyme release and receptor‐binding assays

The conformational analysis of leukotriene D₄ in aqueous solution based on high-field nuclear magnetic resonance measurements