benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone and lentiginosine

D-(-)-Lentiginosine [(-)-4], the nonnatural enantiomer of the iminosugar indolizidine alkaloid L-(+)-lentiginosine, acts as apoptosis inducer on tumor cells of different origin, in contrast to its natural enantiomer. Although D-(-)-4 exhibited a proapoptotic activity towards tumor cells at level lower than the chemotherapeutic agent, SN38, it was less proapoptotic towards normal cells and less cytotoxic. Apoptosis induced by D-(-)-4 was caspase-dependent, as shown by the increased expression and activity of caspase-3 and -8 in treated cells, and by inhibition following treatment with the pan caspase inhibitor, ZVAD-FMK. This study highlighted how a natural iminosugar alkaloid and its synthetic enantiomer, which were simply known for their inhibition against a fungal glucoamylase, could behave in a complete different way when tested towards cell growth and death of cells of different origin.

Topics: Alkaloids; Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Apoptosis; Camptothecin; Caspase 3; Caspase 8; Caspase Inhibitors; Cell Proliferation; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Inhibitors; Glucan 1,4-alpha-Glucosidase; Humans; Molecular Conformation; Stereoisomerism; Structure-Activity Relationship