RESUMO
The amphimedosides, discovered in 2006, are the first examples of naturally occurring glycosylated alkoxyamines. We report syntheses of amphimedosides A-C that feature a stereoselective oxyamine neoglycosylation and found that these alkaloids display modest cytotoxicity toward seven diverse human cancer cell lines, exhibiting IC(50) values ranging from 3.0 µM to greater than 100 µM.
Assuntos
Alcaloides/química , Amino Açúcares/síntese química , Antineoplásicos/síntese química , Alcaloides/farmacologia , Alcaloides/toxicidade , Amino Açúcares/química , Amino Açúcares/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Glicosilação , Humanos , Concentração Inibidora 50 , EstereoisomerismoRESUMO
Cardenolides such as digitoxin have been shown to inhibit cancer cell growth, to reduce cancer metastasis, and to induce apoptosis in tumor cells. Among the most potent digitoxin-based cytotoxins identified to date are MeON-neoglycosides generated via oxyamine neoglycosylation. Here, we report our studies of oxyamine neoglycosylation aimed at facilitating the elucidation of linkage-diversified digitoxin neoglycoside structure-activity relationships. We identified conditions suitable for the convenient synthesis of digitoxin neoglycosides and found that sugar structure, rather than RON-glycosidic linkage, exerts the strongest influence on neoglycoside yield and stereochemistry. We synthesized a library of digitoxin neoglycosides and assessed their cytotoxicity against eight human cancer cell lines. Consistent with previous findings, our data show that the structure of RON-neoglycosidic linkages influences both the potency and selectivity of digitoxin neoglycosides.
