RESUMO
Photochemistry of mycolactone A/B and related unsaturated fatty acid esters is reported. On exposure to visible light, mycolactone A/B gave a mixture of four photomycolactones. Pentaenoates and tetraenoates, representing the unsaturated fatty acid portion of mycolactone A/B, were found to show the reactivity profile parallel with that of mycolactone A/B. The structure of the four photomycolactones was elucidated via (1) structure determination of the four photoproducts in the tetraenoate series; (2) their transformation to the photoproducts in the pentaenoate and then mycolactone series. Triplet quenchers did not affect the photochemical transformation, thereby indicating an event at the singlet state. A concerted, photochemically allowed [4πs + 2πa] cycloaddition was suggested to account for the observed result. This study provided the structurally defined and homogeneous material, which allowed demonstration that photomycolactones exhibit significantly reduced cytotoxicity, compared with mycolactone A/B.
Assuntos
Úlcera de Buruli/induzido quimicamente , Macrolídeos/química , Macrolídeos/toxicidade , Processos Fotoquímicos , Humanos , Estrutura Molecular , EstereoisomerismoRESUMO
Mycolactones are complex macrolides responsible for a severe necrotizing skin disease called Buruli ulcer. Deciphering their functional interactions is of fundamental importance for the understanding, and ultimately, the control of this devastating mycobacterial infection. We report herein a diverted total synthesis approach of mycolactones analogues and provide the first insights into their structure-activity relationship based on cytopathic assays on L929 fibroblasts. The lowest concentration inducing a cytopathic effect was determined for selected analogues, allowing a clear picture to emerge by comparison with the natural toxins.
Assuntos
Toxinas Bacterianas/síntese química , Úlcera de Buruli/induzido quimicamente , Macrolídeos/síntese química , Animais , Toxinas Bacterianas/química , Toxinas Bacterianas/farmacologia , Úlcera de Buruli/microbiologia , Úlcera de Buruli/patologia , Fibroblastos/efeitos dos fármacos , Macrolídeos/química , Macrolídeos/farmacologia , Camundongos , Estrutura Molecular , Infecções por Mycobacterium/patologia , Mycobacterium ulcerans/química , Relação Estrutura-AtividadeRESUMO
Buruli ulcer is a severe and devastating skin disease caused by Mycobacterium ulcerans infection, yet it is one of the most neglected diseases. The causative toxin, referred to as mycolactone A/B, was isolated and characterized as a polyketide-derived macrolide in 1999. The current status of the mycolactone chemistry is described, highlighting the stereochemistry assignment of mycolactone A/B; total synthesis; the structure determination of mycolactone congeners from the human pathogen M. ulcerans, the frog pathogen Mycobacterium liflandii, and the fish pathogen Mycobacterium marinum; the structural diversity in the mycolactone class of natural products; the highly sensitive detection/structure-analysis of mycolactones; and some biological activity.