Tetronothiodin, a novel cholecystokinin type-B receptor antagonist produced by Streptomyces sp. NR0489. III. Structural elucidation.

Ohtsuka, Tatsuo; Nakayama, Noboru; Itezono, Yoshiko; Shimma, Nobuo; Kuwahara, Toshikazu; Yokose, Kazuteru

doi:10.7164/antibiotics.46.18

Cited by 17 publications

(9 citation statements)

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“…12,157 Examples of such spirotetronates and spirotetramates are shown in Figure 6 and include versipelostatin ( 74 ), 158–161 pyrroindomycin ( 75 ), 162–166 chlorothricin ( 76 ), 167–175 kijanimicin ( 77 ), 176–181 the quartromicins ( 78 ), 182–186 the abyssomicins ( 79 ), 187–192 tetrocarcin, 193–198 the lobophorins, 199–205 nomimicin, 206 maklamicin, 207–209 and tetronothiodin. 210–214 Furthermore, several of these compounds also possess a second, decalin ring system, the formation of which is highly reminiscent of the reactions catalyzed by LovB and solanapyrone synthase (see above). Therefore, the pathways responsible for the biosynthesis of the spirotetronates and spirotetramates are unique, because many may involve not one but two enzyme catalyzed Diels-Alder reactions.…”

Section: Spirotetronates and Spirotetramatesmentioning

confidence: 99%

Natural [4 + 2]-Cyclases

et al. 2016

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[4 + 2]-Cycloadditions are increasingly being recognized in the biosynthetic pathways of many structurally complex natural products. A relatively small collection of enzymes from these pathways have been demonstrated to increase rates of cyclization and impose stereochemical constraints on the reactions. While mechanistic investigation of these enzymes is just beginning, recent studies have provided new insights with implications for understanding their biosynthetic roles, mechanisms of catalysis and evolutionary origin.

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Section: Spirotetronates and Spirotetramatesmentioning

confidence: 99%

Natural [4 + 2]-Cyclases

et al. 2016

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“…Isolated from a Streptomyces species, tetronothiodin ( 62 ) was shown to inhibit brain-type cholecystokinin (CCK)-B receptor in rat cerebral cortex with an IC 50 value of 3.6 nM. 88 It is worth noting that CCK receptors are structurally similar to gastrin and are used throughout the central nervous system (CNS) and gastric tract. 89 Interestingly, 62 has 27 000 times higher affinity for CCK-B over CCK-A in rat models.…”

Section: Biology Of Spirotetronate Polyketidesmentioning

confidence: 99%

Spirotetronate Polyketides as Leads in Drug Discovery

Lacoske

Theodorakis

2014

J. Nat. Prod.

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The discovery of chlorothricin (1) defined a new family of microbial metabolites with potent antitumor antibiotic properties collectively referred to as spirotetronate polyketides. These microbial metabolites are structurally distinguished by the presence of a spirotetronate motif embedded within a macrocyclic core. Glycosylation at the periphery of this core contributes to the structural complexity and bioactivity of this motif. The spirotetronate family displays impressive chemical structures, potent bioactivities, and significant pharmacological potential. This review groups the family members based on structural and biosynthetic considerations and summarizes synthetic and biological studies that aim to elucidate their mode of action and explore their pharmacological potential.

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“…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.…”

Section: Tetronothiodinmentioning

confidence: 92%

Cholecystokinin antagonists: Pharmacological and therapeutic potential

Herranz

2003

Medicinal Research Reviews

168

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Cholecystokinin (CCK) is a regulatory peptide hormone, predominantly found in the gastrointestinal tract, and a neurotransmitter present throughout the nervous system. In the gastrointestinal system CCK regulates motility, pancreatic enzyme secretion, gastric emptying, and gastric acid secretion. In the nervous system CCK is involved in anxiogenesis, satiety, nociception, and memory and learning processes. Moreover, CCK interacts with other neurotransmitters in some areas of the CNS. The biological effects of CCK are mediated by two specific G protein coupled receptor subtypes, termed CCK(1) and CCK(2). Over the past fifteen years the search of CCK receptor ligands has evolved from the initial CCK structure derived peptides towards peptidomimetic or non-peptide agonists and antagonists with improved pharmacokinetic profile. This research has provided a broad assortment of potent and selective CCK(1) and CCK(2) antagonists of diverse chemical structure. These antagonists have been discovered through optimization programs of lead compounds which were designed based on the structures of the C-terminal tetrapeptide, CCK-4, or the non-peptide natural compound, asperlicin, or derived from random screening programs. This review covers the main pharmacological and therapeutic aspects of these CCK(1) and CCK(2) antagonist. CCK(1) antagonists might have therapeutic potential for the treatment of pancreatic disorders and as prokinetics for the treatment of gastroesophageal reflux disease, bowel disorders, and gastroparesis. On the other hand, CCK(2) antagonists might have application for the treatment of gastric acid secretion and anxiety disorders.

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Tetronothiodin, a novel cholecystokinin type-B receptor antagonist produced by Streptomyces sp. NR0489. III. Structural elucidation.

Cited by 17 publications

References 0 publications

Natural [4 + 2]-Cyclases

Natural [4 + 2]-Cyclases

Spirotetronate Polyketides as Leads in Drug Discovery

Cholecystokinin antagonists: Pharmacological and therapeutic potential

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