Tetronothiodin, a novel cholecystokinin type-B receptor antagonist produced by Streptomyces sp. NR0489. II. Isolation, characterization and biological activities.

Abstract

A novel cholecystokinin type-B receptor antagonist named tetronothiodin has been isolated by column chromatography and preparative HPLCfrom the fermentation broth of Streptomyces sp. NR0489. Tetronothiodin inhibited the binding of CCK8(C-terminal octapeptide of cholecystokinin) to rat cerebral cortex membranes (CCK type-B receptors) with an IC50 of 3.6nM, whereas it did not inhibit CCK8binding to rat pancreatic membranes (CCK type-A receptors). It also inhibited CCK8induced Ca2+ mobilization in GH3cells, a rat anterior pituitary cell line, but was without effect on the basal cytosolic Ca2+ concentration. This finding indicated tetronothiodin was an antagonist of CCKtype-B receptors. Cholecystokinin(CCK) is a hormonal regulator of pancreatic secretion1* as well as gallbladder contraction2* and gut motility3). It has also been proposed to act as a neurotransmitter in the central nervous system4*. CCKtype-B (CCK-B)receptors are suggested to be related to appetite5*, pain6'7* and anxiety8'9*. SomeCCK-Breceptor antagonists increased food intake5*, enhanced morphine analgesia6'7* and reduced anxiety8'9* in rats. However, physiological and pharmacological roles of CCK-Breceptorsare not yet fully understood in part because of the shortage of potent and specific CCK-B receptor antagonists. To obtain structurallv unique and specific CCK-Breceptor antagonists, we screened microbial metabolites by employing a binding assay method in which rat cerebral cortex membranesand 125I labeled Bolton-Hunter CCK8 ([125I]-CCK8) were used as the receptors and the radioligand, respectively. In this screening program, we discovered a novel CCK-B receptor antagonist named tetronothiodin (1) from the culture broth of Streptomyces sp. NR0489, and determined the structure to be a macrocyclic compound containing an aacyltetronic acid and a tetrahydrothiophene ring (Fig. 1). A preliminary communication of this work Fie. 1. Structure of tetronothiodin (1

Elucidation of the Kijanimicin Gene Cluster: Insights into the Biosynthesis of Spirotetronate Antibiotics and Nitrosugars

“…Yoshii and coworkers reported the chemical synthesis of (+)-tetronolide, the aglycone of tetrocarcin (5), in 1991. 25 Enantioselective synthesis of (−)-chlorothricolide, the aglycone of chlorothricin (4), was accomplished by Roush and Sciotti in 1994. 26 Both syntheses employed intramolecular DielsAlder cyclizations to construct the spirotetronate and octahydronaphthalene portions of the aglycones.…”

“…Kijanolide has not yet been chemically synthesized, but the preparation of an advanced seco-acid intermediate was recently reported. 27 Biosynthetic studies of chlorothricin (4) have been performed by Floss and coworkers. 28 Through feeding of labeled acetate and propionate, it was found that the chlorothricolide aglycone (6) is primarily polyketide-derived, except for C22-C24 which are uniformly labeled after feeding of [ 13 C 3 ]-glycerol ( Figure 1).…”

Cholecystokinin antagonists: Pharmacological and therapeutic potential

“…NR0489. 280,281 This compound inhibited the CCK-8 binding to rat cerebral cortex membranes with nanmolar binding affinity, whereas it did not showed affinity at rat pancreatic membranes. It also inhibited the CCK-8-induced Ca 2 þ mobilization in rat anterior pituitary cells GH3, but it did not inhibit the basal cytosolic Ca 2 þ concentration.…”

“…It also inhibited the CCK-8-induced Ca 2 þ mobilization in rat anterior pituitary cells GH3, but it did not inhibit the basal cytosolic Ca 2 þ concentration. 280 …”

Organocatalytic Asymmetric Synthesis of Tetrahydrothiophenes and Tetrahydrothiopyrans

“…Chiral tetrahydrothiophene‐based compounds include the water‐soluble B vitamin biotin ( 1 ), involved in important biological functions, and the potent α‐glucosidase inhibitors salacinol ( 2 ) and kotalanol ( 3 ), isolated from several Salacia species (Scheme ). Further typical compounds are the 4′‐thioadenosine derivative 4 , a highly effective and selective A3 adenosine receptor antagonist, the cholecystokinin type‐B receptor antagonist tetronothiodin ( 5 ), the 4′‐thiocytidine nucleoside 6 , active against HSV‐1 and HSV‐2, and ( R )‐tetrahydrothiophen‐3‐ol ( 7 ), an essential intermediate en route to the potent antibacterial Sulopenem ( 8 ; Scheme ) . Furthermore, tetrahydrothiophenes have also been employed as building blocks for new chiral ligands in various chemical transformations including asymmetric hydrogenation, catalytic asymmetric epoxidation and catalytic intramolecular cyclopropanation .…”