RESUMO
The conformational properties of anticancer saponin OSW-1 were investigated by X-ray crystallography and by an integrated approach combining a conformational search and the evaluation of the computed conformational distribution by comparing the experimental and simulated spectroscopic data. Our results suggested that OSW-1 adopts two preferred conformations in solution at an approximately 2:1 ratio, of which the crystal structure is consistent with the major conformation. In the solution models, the arabinose residue of OSW-1 appears to serve as a molecular hinge by flipping from the standard 4C1 form in the major conformer to the unusual 1C4 form in the minor conformer. This results in different orientations of the biologically essential p-methoxybenzoyl group, thereby inducing a dramatic alteration of the three-dimensional shape and polarity of OSW-1.
Assuntos
Antineoplásicos Fitogênicos/química , Colestenonas/química , Química Computacional , Cristalografia por Raios X/métodos , Saponinas/química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Conformação Molecular , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
A strategy to site-selectively monoacylate an antitumor saponin OSW-1 was developed using an organotin reagent to rapidly access its derivatives that are useful as chemical probes. 4â³-O-Acylated OSW-1 derivatives bearing a fluorophore, an alkyne tag, or biotin were prepared in good yields and were shown to maintain highly cytotoxic activity.
Assuntos
Biotina/química , Colestenonas/química , Colestenonas/síntese química , Saponinas/química , Saponinas/síntese química , Acilação , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
OSW-1 is a steroidal saponin, which has emerged as an attractive anticancer agent with highly cancer cell selective activity. A fluorescent analog was prepared from the natural product to analyze its cellular uptake and localization. We found that the fluorescent analog is rapidly internalized into cells and is primarily distributed in endoplasmic reticulum and Golgi apparatus.