Joshua Rokach

The synthesis of a leukotriene with SRS-like activity

Abstract The synthesis and biological characteristics of an SRS-like leukotriene are described.

The stereospecific synthesis of leukotriene A4 (LTA4), 5-epi-LTA4, 6-epi-LTA4 and 5-epi,6-epi-LTA4

The stereospecific syntheses of the four isomers of 6-formyl-5,6-epoxy hexanoic acid methyl ester 8, 15, 23 and 30 from Z-deoxy-D-ribose have allowed the preparation of methyl esters of LTA4, 1, and its three unnatural isomers.

5-Methyltetrahydrofolic Acid as a Mediator in the Formation of Pyridoindoles

Enzymes from chick and rat tissues catalyze the reaction of N-methyl tryptamine with 5-methyltetrahydrofolic acid to form 2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4b] indole. N,N-Dimethyltryptamine was not formed. With tryptamine as substrate the product is 2,3,4,9-tetrahydro-1H-pyrido[3,4b] indole and not N-methyltryptamine. These pyridoindoles were not formed when S-adenosylmethionine was cosubstrare.

Comparative biological activities of synthetic leukotriene b4 and its ω-oxidation products

Abstract Synthetic leukotriene B4 (LTB4) and its ω-oxidation products, 20 OH-LT4 and 20 COOH-LTB4, were tested for their ability to induce the aggregation of rat neutrophils in vitro , to contract the guinea pig parenchymal strip in vitro and to cause vascular permeability changes in rabbit skin in vivo . 20 OH-LTB4 had 10, 100 and 20% of the activity of LTB4 in the neutrophil aggregation, parenchymal strip and vascular permeability assays respectively. 20 C00H-LTB4 was inactive in vivo and showed in vitro . These results show that while ω-oxidation is a route for biological inactivation of LTB4, 20 OH-LTB4 still retains significant biological activity.

The development of sensitive and specific radioimmunoassays for leukotrienes

Radioimmunoassays for leukotriene C4 (LTC4) and for leukotriene B4 (LTB4) have been developed. LTC4 was conjugated with thiolated hemocyanin (Keyhole Limpet) (KLH) using 6-(N-maleimido)hexanoic acid chloride as coupling agent. LTB4 was converted to its hydrazide derivative, via the delta-lactone and the hydrazide was similarly coupled with thiolated KLH using 6-(N-maleimido)hexanoic acid chloride as coupling agent. These conjugates were used to consistently raise high titres of anti-leukotriene antibodies in rabbits. 14,15-[3H]-LTC4 was prepared by total synthesis via two routes. 14,15-[3H]-LTB4 was prepared by total synthesis. The assay for LTC4 recognizes LTC4, LTD4 and LTF4, and to a lesser extent, LTE4 with a detection limit of ca. 0.1 pmoles LTC4 per mL of sample. The assay for LTB4 is highly specific and has a similar detection limit.

A simple and efficient route to β-substituted pyrroles

Abstract N -Phenylsulfonylpyrrole undergoes Friedel-Crafts acylation exclusively at the β-position of the pyrrole ring, thus allowing a simple and efficient synthesis of β-acylated pyrroles.

Biological activity of leukotriene sulfones on respiratory tissues.

The biological activity of synthetic leukotriene C4, D4 and E4 sulfone has been determined in respiratory smooth muscle in vitro and in vivo. The sulfones of LTC4, LTD4 and LTE4 were potent contractile agonists on indomethacin-treated guinea pig tracheal chains with respective pD2-values of 8.2, 8.0 and 7.9. Contractions were submaximal (75–85% of the cholinergic maximum), slow in onset, prolonged in duration, slowly reversed by washing (compared to acetylcholine or histamine) and were partially reversed by 2μM FPL-55712. The sulfones of LTC4, LTD4 and LTD4 also contracted indomethacin-treated guinea pig parenchyma (respective pD2′s of 7.9 8.2 and 7.8) and rat parenchyma (respective pD2′s of 7.1, 7.2 and 7.2) but were inactive on rat trachea (0.01–2.0 gmM). When administered intravenously to anaesthetized guinea pigs, the sulfones of LTD4, LTE4 and to a lesser degree LTC4 (respective ED50′s - 0.5; 2.0 and 4.6 μg/kg) elicited dose-dependent increases in inflation pressure which were antagonized by FPL-55712 and indomethacin. Leukotriene C4, D4 and E4 sulfones display a qualitatively similar profile of biological activity to that of their corresponding sulfides.

Stereospecific synthesis of leukotriene B4 (LTB4)

Abstract A stereospecific and chirally economical synthesis of LTB 4 starting from 2-deoxy-D-ribose is reported as part of a comprehensive and efficient approach to the Leukotrienes (A, B, C, D, E). The process includes a novel approach to chiral dienic synthons.

Simple efficient synthesis of LTB4 and 12-epi-LTB4

Abstract Using L-and D-arabinose respectively as the source of chirality at C-12 in LTB 4 , efficient new syntheses of LTB 4 and 12-epi-LTB 4 have been realized.

A C-glycoside route to leukotrienes

Abstract The stereospecific syntheses of three isomers of 7-hydroxy-5,6-epoxy heptanoic acid methyl ester, 7 , 12b and 19 , have been achieved via a C -glycoside route.