RESUMO
Here, we report an enantioselective synthesis of the monomeric nes product (-)-nenestatin A, via the intermediary diazofluorene "diazonenestatin A." Our route features a convergent, aldol-based fragment coupling to assemble the carbon skeleton and a diazotransfer to a highly conjugated tetracyclic fulvene. We find that diazonenestatin A is transformed to nenestatin A under conditions that mimic the bacterial fermentation, suggesting that the nes pathway may produce unstable diazofluorene products that have eluded isolation.
Assuntos
Aldeídos , Fermentação , Estrutura Molecular , EstereoisomerismoRESUMO
Myrocins are a family of antiproliferative antibiotic fungal metabolites possessing a masked electrophilic cyclopropane. Preliminary chemical reactivity studies imputed the bioactivity of these natural products to a DNA cross-linking mechanism, but this hypothesis was not confirmed by studies with native DNA. We recently reported a total synthesis of (-)-myrocin G (4), the putative active form of the metabolite myrocin C (1), that featured a carefully orchestrated tandem fragment coupling-annulation cascade. Herein, we describe the evolution of our synthetic strategy toward 4 and report the series of discoveries that prompted the design of this cascade coupling. Efforts to convert the diosphenol (-)-myrocin G (4) to the corresponding 5-hydroxy-γ-lactone isomer myrocin C (1) are also detailed. We present a preliminary evaluation of the antiproliferative activities of (-)-myrocin G (4) and related structures, as well as DNA cross-linking studies. These studies indicate that myrocins do not cross-link DNA, suggesting an alternative mode of action potentially involving a protein target.
Assuntos
Produtos Biológicos , Lactonas , DNA , Fungos , EstereoisomerismoRESUMO
Colibactin is a complex secondary metabolite produced by some genotoxic gut Escherichia coli strains. The presence of colibactin-producing bacteria correlates with the frequency and severity of colorectal cancer in humans. However, because colibactin has not been isolated or structurally characterized, studying the physiological effects of colibactin-producing bacteria in the human gut has been difficult. We used a combination of genetics, isotope labeling, tandem mass spectrometry, and chemical synthesis to deduce the structure of colibactin. Our structural assignment accounts for all known biosynthetic and cell biology data and suggests roles for the final unaccounted enzymes in the colibactin gene cluster.
Assuntos
Adutos de DNA/química , Peptídeos/química , Policetídeos/química , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Marcação por Isótopo , Mutação , Peptídeo Hidrolases/genética , Peptídeos/genética , Peptídeos/metabolismo , Policetídeos/metabolismo , Conformação Proteica , Metabolismo Secundário , Espectrometria de Massas em TandemRESUMO
A new multi-component condensation was discovered during the reaction of a urea, ß-keto ester, and formaldehyde. In the presence of catalytic indium bromide, a Biginelli dihydropyrimidinone intermediate was further converted to a five-component condensation product through a formal hetero Diels-Alder reaction. The product structure was confirmed by NMR and NOE analysis, and the proposed stepwise mechanism was supported by the reaction of the Biginelli intermediate with ethyl 2-methylene-3-oxobutanoate.