RESUMO
A full account of an asymmetric synthesis of reblastatin (1) and the first total synthesis of autolytimycin (2) and related structural compounds is described. The syntheses expand the utility of a highly regio- and diastereoselective hydrometalation aldehyde addition sequence to assemble the fully functionalized ansa chain of the natural products. Also documented is an intramolecular copper-mediated amidation reaction to close the 19-membered macrolactams. The amidation reaction was also employed for the generation of structural derivatives (6-9) of phenolic ansamycins. Ansamycin natural products and selected structural analogues were evaluated in a competitive binding assay to breast cancer cell lysate and a cytotoxicity assay. Both reblastatin (1) and autolytimycin (2) were shown to bind the heat shock protein 90 with enhanced binding activity (approximately 25 nM) than 17-allylamino-17-demethoxygeldanamycin (17-AAG, 4), a geldanamycin (3) derivative currently under evaluation for treatment of cancer (approximately 100 nM).
Assuntos
Antineoplásicos/síntese química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/síntese química , Quinonas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzoquinonas/química , Linhagem Celular Tumoral , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Estrutura Molecular , Fenóis/síntese química , Quinonas/química , Quinonas/farmacologia , Relação Estrutura-AtividadeRESUMO
Synthesis and preliminary biological evaluation of a 35-member library of bistramide A stereoisomers are reported. All eight stereoisomers of the C1-C13 tetrahydropyran fragment of the molecule were prepared utilizing crotylsilane reagents 9 and 10 in our [4+2]-annulation methodology. In addition, the four isomers of the C14-C18 gamma-amino acid unit were accessed via a Lewis acid mediated crotylation reaction with use of both enantiomers of organosilane 11. The spiroketal subunit of bistramide A was modified at the C39-alcohol to give another point of stereochemical diversification. The fragments were coupled by using a standard peptide coupling protocol to provide 35 stereoisomers of the natural product. These stereochemical analogues were screened for their effects on cellular actin and cytotoxicity against cancer cell lines (UO-31 renal and SF-295 CNS). The results of these assays identified one analogue, 1.21, with enhanced potency relative to the natural product, bistramide A.
Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Actinas/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Piranos/síntese química , Piranos/farmacologia , Acetamidas/química , Actinas/química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Conformação Molecular , Piranos/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
An asymmetric synthesis of the marine metabolite bistramide A is reported. The synthesis relies on the utility of three different organosilane reagents to construct all principle fragments and 8 of the 11 stereogenic centers of the natural product. [structure: see text].
Assuntos
Acetamidas/síntese química , Piranos/síntese química , Acetamidas/química , Conformação Molecular , Piranos/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , EstereoisomerismoRESUMO
Enantioselective total synthesis of reblastatin is described. The synthesis highlights hydrozirconation, transmetalation, aldehyde addition sequence to install E-trisubstituted olefin and C7 stereocenter, and the first use of an intramolecular Buchwald-like amidation reaction to close the 19-membered macrolactam.