Cytotoxicity and enzymatic activity inhibition in cell lines treated with novel iminosugar derivatives

Abstract

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.

Perfluoroalkylation of Nitrones for the Synthesis of a Series of Fucosidase Inhibitors

“…[1][2][3][4][5][6] The strong electron-withdrawing capacity of fluorine and its marked hydrophobic character induce significant modifications to physicochemical properties, such as solubility, bioavailability, basicity, conformation, and binding properties to a biological target. [10][11][12][13][14][15][16] The latter behave as sugar mimetics by disrupting the natural biological event, mainly through inhibition of glycoenzymes such as glycosidases. [10][11][12][13][14][15][16] The latter behave as sugar mimetics by disrupting the natural biological event, mainly through inhibition of glycoenzymes such as glycosidases.…”

“…[7][8][9] Iminosugars belong to a family of compounds that exhibit therapeutic potential toward several metabolic disorders and act as antiviral, antidiabetic, and antitumor agents. [10][11][12][13][14][15][16] The latter behave as sugar mimetics by disrupting the natural biological event, mainly through inhibition of glycoenzymes such as glycosidases. Structural modification of natural iminosugars has led to "second-generation" drugs that are much more potent and selective, some of which are now on the market.…”

Rapid and practical synthesis of (−)-1-deoxyaltronojirimycin

“…11 Iminosugar derivatives have been reported to be active against the Flaviviridae viral family, 12 cytotoxic against several cancer cell lines 13 and to inhibit angiogenesis.…”

D(−)lentiginosine-induced apoptosis involves the intrinsic pathway and is p53-independent

“…6 Iminosugars were used in metabolic disorders characterized by the accumulation of glycosphingolipids in lysosomes, because of the deficient activity of glycosidases. 7 In particular N -butyl-1-deoxynojirimycin has been used to treat type 1 Gaucher diseases characterized by glucocerebroside accumulation, 8 whereas α-glucosidase inhibitors were used to treat type-2 diabetes mellitus. 9 However, inhibition of carbohydrate-processing enzymes by iminosugars also affects maturation, transport and secretion of glycoproteins involved in cell to cell contact.…”

“…The results showed that the cytotoxic effect of these compounds was dependent on the length of the alkyl groups attached to the iminosugars and paralleled the inhibitory activity of glycosidases. 7 Moreover, castanospermine, an iminosugar endowed with α-glucosidase inhibitor activity, was shown to inhibit the migration and invasion tendency of tumour cells, preventing them from binding to extracellular matrix. 12, 13 These lines of evidence suggest that iminosugars are endowed with a broad range of biological activity potentially useful in therapeutic treatment.…”