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

Jian Zhou; Arvind Negi; Styliana I Mirallai; Rolf Warta; Christel Herold-Mende; Michael P Carty; Xin-Shan Ye; Paul V Murphy

doi:10.1016/j.bioorg.2018.12.003

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

Bioorg Chem. 2019 Mar:84:418-433. doi: 10.1016/j.bioorg.2018.12.003. Epub 2018 Dec 4.

Authors

Jian Zhou¹, Arvind Negi², Styliana I Mirallai², Rolf Warta³, Christel Herold-Mende³, Michael P Carty⁴, Xin-Shan Ye⁵, Paul V Murphy⁶

Affiliations

¹ School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, D04 V1W8, Ireland.
² School of Chemistry, National University of Ireland Galway, University Road, Galway H91 TK33, Ireland.
³ Division of Experimental Neurosurgery, Department of Neurosurgery, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
⁴ School of Natural Sciences, Biochemistry and Centre for Chromosome Biology, National University of Ireland Galway, University Road, H91 TK33 Galway, Ireland.
⁵ State Key Laboratory of Natural and Biomimetic Drugs and School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No. 38, Beijing 100191, China.
⁶ School of Chemistry, National University of Ireland Galway, University Road, Galway H91 TK33, Ireland. Electronic address: paul.v.murphy@nuigalway.ie.

PMID: 30554081
DOI: 10.1016/j.bioorg.2018.12.003

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 α-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.

Keywords: 1-Deoxyfuconojirimycin; Anti-cancer activity; Fucosidase; Homology modelling; Iminosugar; N-alkylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Deoxynojirimycin / analogs & derivatives
1-Deoxynojirimycin / chemistry
1-Deoxynojirimycin / metabolism
Bacteria / enzymology
Bacterial Proteins / antagonists & inhibitors
Bacterial Proteins / metabolism
Binding Sites
Cell Line, Tumor
Cell Survival / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Humans
Immunoglobulin G / metabolism
Immunoglobulin G / pharmacology
Inhibitory Concentration 50
Melphalan / chemical synthesis
Melphalan / metabolism
Melphalan / pharmacology
Molecular Docking Simulation
Structure-Activity Relationship
Sugar Alcohols / chemistry*
Sugar Alcohols / metabolism
alpha-L-Fucosidase / antagonists & inhibitors*
alpha-L-Fucosidase / metabolism

Substances

Bacterial Proteins
Enzyme Inhibitors
Immunoglobulin G
Sugar Alcohols
antineoplastic agent K 18
fucitol
1-Deoxynojirimycin
deoxyfuconojirimycin
alpha-L-Fucosidase
Melphalan