RESUMO
Buruli ulcer, classified as a neglected tropical disease by the World Health Organization, is caused by a mycobacterium which secretes a macrolidic exotoxin called mycolactone A/B. In this article, several synthetic strategies for the preparation of this toxin are discussed, highlighting the importance of total synthesis for the exploration of biological mechanism underpinning relevant human diseases.
Assuntos
Úlcera de Buruli/etiologia , Macrolídeos/síntese química , HumanosRESUMO
Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of skin lesions called Buruli ulcers. Mycolactone-mediated activation of neural (N) Wiskott-Aldrich syndrome proteins (WASP) induces defects in cell adhesion underpinning cytotoxicity and disease pathogenesis. We describe the chemical synthesis of 23 novel mycolactone analogues that differ in structure and modular assembly of the lactone core with its northern and southern polyketide side chains. The lactone core linked to southern chain was the minimal structure binding N-WASP and hematopoietic homolog WASP, where the number and configuration of hydroxyl groups on the acyl side chain impacted the degree of binding. A fluorescent derivative of this compound showed time-dependent accumulation in target cells. Furthermore, a simplified version of mycolactone mimicked the natural toxin for activation of WASP in vitro and induced comparable alterations of epithelial cell adhesion. Therefore, it constitutes a structural and functional surrogate of mycolactone for WASP/N-WASP-dependent effects.
Assuntos
Toxinas Bacterianas/química , Macrolídeos/química , Proteína da Síndrome de Wiskott-Aldrich/química , Toxinas Bacterianas/metabolismo , Toxinas Bacterianas/farmacologia , Adesão Celular/efeitos dos fármacos , Células HeLa , Humanos , Cinética , Macrolídeos/metabolismo , Macrolídeos/farmacologia , Modelos Químicos , Estrutura Molecular , Mycobacterium ulcerans/química , Ligação Proteica , Proteína da Síndrome de Wiskott-Aldrich/metabolismoRESUMO
Mycobacterium ulcerans infections (Buruli ulcer disease) have a long history that can be traced back 150 years. The successive discoveries of the mycobacteria in 1948 and of mycolactone A/B in 1999, the toxin responsible for this dramatic necrotic skin disease, resulted in a paradigm shift concerning the disease itself and in a broader sense, delineated an entirely new role for bioactive polyketides as virulence factors. The fascinating history, biology and chemistry of M. ulcerans infections are discussed in this review.
Assuntos
Úlcera de Buruli , Macrolídeos/síntese química , Úlcera de Buruli/história , História do Século XX , Humanos , Macrolídeos/química , Estrutura MolecularRESUMO
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
Covalent attachment of quinine to a salen framework through a racemic linker gave a new mixed ligand in a 1:1 diastereomeric mixture, from which an active Lewis acid-Lewis base (LA*-LB*) bifunctional catalyst derived from Co(II) was discovered by the screening of metal complexes. The remarkable intramolecular bifunctional catalytic activity (1 mol % catalyst loading) of the new catalyst was demonstrated using a proof-of-principle reaction. [reaction: see text].