RESUMO
The secondary metabolites platensimycin and platencin, isolated from the bacterial strain Streptomyces platensis, represent a novel class of natural products exhibiting unique and potent antibacterial activity. Platencin, though structurally similar to platensimycin, has been found to operate through a slightly different mechanism of action involving the dual inhibition of lipid elongation enzymes FabF and FabH. Both natural products exhibit strong, broad-spectrum, gram-positive antibacterial activity to key antibiotic resistant strains, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, and vancomycin-resistant Enterococcus faecium. Described herein are our synthetic efforts toward platencin, culminating in both racemic and asymmetric preparation of the natural product. The syntheses demonstrate the power of the cobalt-catalyzed asymmetric Diels-Alder reaction and the one-pot reductive rearrangement of [3.2.1] bicyclic ketones to [2.2.2] bicyclic olefins.
Assuntos
Aminofenóis/síntese química , Antibacterianos/síntese química , Compostos Policíclicos/síntese química , Aminofenóis/química , Aminofenóis/isolamento & purificação , Aminofenóis/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Catálise , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Compostos Policíclicos/química , Compostos Policíclicos/isolamento & purificação , Compostos Policíclicos/farmacologia , Estereoisomerismo , Streptomyces/químicaRESUMO
Platensimycin is the flagship member of a new and growing class of antibiotics with promising antibacterial properties against drug-resistant bacteria. The total syntheses of platensimycin and its congeners, platensimycins B(1) and B(3), platensic acid, methyl platensinoate, platensimide A, homoplatensimide A, and homoplatensimide A methyl ester, are described. The convergent strategy developed toward these target molecules involved construction of their cage-like core followed by attachment of the various side chains through amide bond formation. In addition to a racemic synthesis, two asymmetric routes to the core structure are described: one exploiting a rhodium-catalyzed asymmetric cycloisomerization, and another employing a hypervalent iodine-mediated de-aromatizing cyclization of an enantiopure substrate. The final two bonds of the core structure were forged through a samarium diiodide-mediated ketyl radical cyclization and an acid-catalyzed etherification. The rhodium-catalyzed asymmetric reaction involving a terminal acetylene was developed as a general method for the asymmetric cycloisomerization of terminal enynes.
Assuntos
Adamantano/síntese química , Aminobenzoatos/síntese química , Anilidas/síntese química , Antibacterianos/síntese química , Produtos Biológicos/síntese química , Adamantano/química , Aldeídos/síntese química , Aminobenzoatos/química , Anilidas/química , Antibacterianos/química , Produtos Biológicos/química , Catálise , Ciclização , Isomerismo , Ródio/químicaRESUMO
The molecular design, chemical synthesis, and biological evaluation of two distinct series of platensimycin analogues with varying degrees of complexity are described. The first series of compounds probes the biological importance of the benzoic acid subunit of the molecule, while the second series explores the tetracyclic cage domain. The biological data obtained reveal that, while the substituted benzoic acid domain of platensimycin is a highly conserved structural motif within the active compounds with strict functional group requirements, the cage domain of the molecule can tolerate considerable structural modifications without losing biological action. These findings refine our present understanding of the platensimycin pharmacophore and establish certain structure-activity relationships from which the next generation of designed analogues of this new antibiotic may emerge.
Assuntos
Adamantano/química , Adamantano/farmacologia , Aminobenzoatos/química , Aminobenzoatos/farmacologia , Anilidas/química , Anilidas/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Adamantano/análogos & derivados , Adamantano/síntese química , Aminobenzoatos/síntese química , Anilidas/síntese química , Compostos de Anilina/síntese química , Compostos de Anilina/química , Anti-Infecciosos/síntese química , Benzaldeídos/química , Benzoatos/síntese química , Benzoatos/química , Benzoatos/farmacologia , Benzodioxóis/química , Cicloexenos/síntese química , Cicloexenos/química , Desenho de Fármacos , Compostos de Epóxi/síntese química , Compostos de Epóxi/química , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Piranos/síntese química , Piranos/química , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and biological activity of a series of cycloalkene acid-based niacin receptor agonists are described. This led to the discovery that tetrahydro anthranilic acid is an excellent surrogate for anthranilic acid. Several compounds were identified that were potent against the niacin receptor, had enhanced cytochrome P450 selectivity against subtypes CYP2C8 and CYP2C9, and improved oral exposure in mice.