N-Alkyl-1,5-dideoxy-1,5-imino-l-fucitols as fucosidase inhibitors: Synthesis, molecular modelling and activity against cancer cell lines

Abstract

1,5-Dideoxy-1,5-imino-l-fucitol (1-deoxyfuconojirimycin, DFJ) is an iminosugar that inhibits fucosidases. Herein, N-alkyl DFJs have been synthesised and tested against the ¿-fucosidases of T. maritima (bacterial origin) and B. taurus (bovine origin). The N-alkyl derivatives were inactive against the bacterial fucosidase, while inhibiting the bovine enzyme. Docking of inhibitors to homology models, generated for the bovine and human fucosidases, was carried out. N-Decyl-DFJ was toxic to cancer cell lines and was more potent than the other N-alkyl DFJs studied.Research presented herein was supported by Science Foundation Ireland (07/IN.1/B966), the Irish Research Council (GOI PhD Scholarships to JZ, AN) and the European Commission through COST Action CM1106. The authors thank Guan-Nan Wang for recording NMR spectra and to Nadine Martinet for organization of the COST Action CM1106 screening library that led to identification of the activity for 16. The authors thank Dr. Stephen Rea and Dr. Helen Dodson for gifts of tumour cells