Tetronothiodin, a novel cholecystokinin type-B receptor antagonist produced by Streptomyces sp.

Natural [4 + 2]-Cyclases

“…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.…”

“…The tetronate antibiotics have been the focus of many recent biosynthetic research programs on account of their unusual polycyclic structures as well as their value as potential antimicrobial and antiproliferative agents. − A subclass of this family of natural products has drawn particular interest, because the tetronate or tetramate namesake appears to have undergone an intramolecular Diels–Alder reaction with a 1,3-diene to form a cyclohexene ring with a tertiary carbon joint. , Examples of such spirotetronates and spirotetramates are shown in Figure and include versipelostatin ( 74 ), − pyrroindomycin ( 75 ), − chlorothricin ( 76 ), − kijanimicin ( 77 ), − the quartromicins ( 78 ), − the abyssomicins ( 79 ), − tetrocarcin, − the lobophorins, − nomimicin, maklamicin, − and tetronothiodin. − 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.…”

Controlled Modification of Acidity in Cholecystokinin B Receptor Antagonists: N-(1,4-Benzodiazepin-3-yl)-N ‘-[3-(tetrazol-5-ylamino)phenyl]ureas

“…This wealth of potential therapeutic utilities for CCK receptor agonists and antagonists has provided the impetus for intensive research in the area, and over the past decade, a variety of selective nonpeptidic CCK-A and CCK-B receptor antagonists have been disclosed by several laboratories. , From a pioneering program of work at Merck, sparked by the isolation of the natural product asperlicin, series of benzodiazepine-based CCK-A and CCK-B receptor antagonists were developed, and first-generation compounds such as MK-329 (CCK-A) and L-365,260 (CCK-B) have been evaluated in the clinic. The latter compound, however, had to be specially formulated in order to achieve adequate levels of oral bioavailability, mainly as a consequence of the low aqueous solubility of its crystalline form (<0.002 mg/mL, pH 7.4) .…”