RESUMO
Covering: 2013 up to the end of 2015This review covers the isolation and structure of new pyrrolizidines; pyrrolizidine biosynthesis; biological activity, including the occurrence of pyrrolizidines as toxic components or contaminants in foods and beverages; and formal and total syntheses of naturally-occurring pyrrolizidine alkaloids and closely related non-natural analogues.
Assuntos
Alcaloides de Pirrolizidina , Estrutura Molecular , Alcaloides de Pirrolizidina/síntese química , Alcaloides de Pirrolizidina/química , Alcaloides de Pirrolizidina/farmacologiaRESUMO
This review covers pyrrolizidine alkaloids isolated from natural sources. Topics include: aspects of structure, isolation, and biological/pharmacological studies; total syntheses of necic acids, necine bases and closely-related non-natural analogues.
Assuntos
Plantas Medicinais/química , Alcaloides de Pirrolizidina , Estrutura Molecular , Alcaloides de Pirrolizidina/síntese química , Alcaloides de Pirrolizidina/química , Alcaloides de Pirrolizidina/farmacologiaRESUMO
OBJECTIVES: To identify and to characterize small-molecule inhibitors that target the subunit polymerization of the type 1 pilus assembly in uropathogenic Escherichia coli (UPEC). METHODS: Using an SDS-PAGE-based assay, in silico pre-filtered small-molecule compounds were screened for specific inhibitory activity against the critical subunit polymerization step of the chaperone-usher pathway during pilus biogenesis. The biological activity of one of the compounds was validated in assays monitoring UPEC type 1 pilus biogenesis, type 1 pilus-dependent biofilm formation and adherence to human bladder epithelial cells. The time dependence of the in vivo inhibitory activity and the overall effect of the compound on UPEC growth were determined. RESULTS: N-(4-chloro-phenyl)-2-{5-[4-(pyrrolidine-1-sulfonyl)-phenyl]-[1,3,4]oxadiazol-2-yl sulfanyl}-acetamide (AL1) inhibited in vitro pilus subunit polymerization. In bacterial cultures, AL1 disrupted UPEC type 1 pilus biogenesis and pilus-dependent biofilm formation, and resulted in the reduction of bacterial adherence to human bladder epithelial cells, without affecting bacterial cell growth. Bacterial exposure to the inhibitor led to an almost instantaneous loss of type 1 pili. CONCLUSIONS: We have identified and characterized a small molecule that interferes with the assembly of type 1 pili. The molecule targets the polymerization step during the subunit incorporation cycle of the chaperone-usher pathway. Our discovery provides new insight into the design and development of novel anti-virulence therapies targeting key virulence factors of bacterial pathogens.
Assuntos
Antibacterianos/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Fímbrias Bacterianas/efeitos dos fármacos , Substâncias Macromoleculares/metabolismo , Multimerização Proteica/efeitos dos fármacos , Subunidades Proteicas/metabolismo , Escherichia coli Uropatogênica/efeitos dos fármacos , Animais , Biofilmes/efeitos dos fármacos , Linhagem Celular , Células Epiteliais/microbiologia , Humanos , Escherichia coli Uropatogênica/fisiologiaRESUMO
Aziridines formed upon treatment of allylic carbamates and homoallylic sulfamates with Rh(II) carboxylate catalysts under oxidative conditions are trapped by suitably-disposed hydroxyl groups to give functionalised tetrahydrofurans.
Assuntos
Aziridinas/química , Furanos/síntese química , Ródio/química , Alcenos/química , Catálise , Radical Hidroxila/química , Estereoisomerismo , Difração de Raios XRESUMO
An efficient synthesis of NP25302 is presented that relies on 5-endo-dig N-cyclization to establish the bicyclic core and Curtius rearrangement to install the N-acyl vinylogous urea functionality.
Assuntos
Alcaloides de Pirrolizidina/síntese química , Ciclização , Modelos Moleculares , Estrutura Molecular , Ureia/química , Compostos de Vinila/químicaRESUMO
We describe a concise synthesis of (+)-isoaltholactone via a Au-catalysed cyclisation of a monoallylic diol to form the tetrahydrofuranyl ring. Analogous cyclisations show that the stereochemical outcome is dictated by the stereochemistry of the diol substrate.