Cytotoxicity and enzymatic activity inhibition in cell lines treated with novel iminosugar derivatives.
Iminosugars are monosaccharide analogues that have been demonstrated to be specific inhibitors for glycosidases and are currently used therapeutically in several human disorders. N-alkylated derivatives of D-fagomine and (2R,3S,4R,5S)-2-(hydroxymethyl)-5-methylpyrrolidine-3,4-diol with aliphatic chains were tested in eight human cancer cell lines to analyze their cytotoxicity and the inhibitory effect in the activities of specific glycosidases. Results indicate that these compounds were more cytotoxic as the length of the alkyl chain increases. N-dodecyl-D-fagomine inhibited specifically the alpha-D-glucosidase activity in cell lysates, whereas no effect was detected in other glycosidases. The N-dodecyl derivative of (2R,3S,4R,5S)-2-(Hydroxymethyl)-5-methylpyrrolidine-3,4-diol induced specific inhibition against alpha-L-fucosidase in cell lysates. Our results indicated that the length of the alkyl chain linked to the iminosugars determine their cytotoxicity as well as the inhibitory effect on the enzymatic activities of specific glycosidases, in human cancer cell lines.
Padró
Mercè
M
Programa de Recerca en Càncer, IMIM-Hospital del Mar (PRBB), Dr. Aiguader, 88, 08003 Barcelona, Spain.
Castillo
José A
JA
Gómez
Livia
L
Joglar
Jesús
J
Clapés
Pere
P
de Bolós
Carme
C
D016923:Cell Death / Q000187:drug effects; D002457:Cell Extracts; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005960:Glucosides / Q000378:metabolism; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors*; D006027:Glycosides / Q000378:metabolism; D006801:Humans; D050112:Imino Pyranoses / Q000737:chemistry / Q000494:pharmacology*; D010641:Phenotype; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*
C517931:(2S,3S,4R,5S)-5-methylpyrrolidine-3,4-diol; D002457:Cell Extracts; D005960:Glucosides; D006027:Glycosides; D050112:Imino Pyranoses; D011759:Pyrrolidines; C014125:4-nitrophenylfucoside; C019502:4-nitrophenyl alpha-glucoside; C105643:fagomine; D006026:Glycoside Hydrolases