TY - JOUR
T1 - α-L-fucosidase inhibition by pyrrolidine-ferrocene hybrids
T2 - Rationalization of ligand-binding properties by structural studies
AU - Hottin, A.
AU - Wright, D.W.
AU - Steenackers, A.
AU - Delannoy, P.
AU - Dubar, F.
AU - Biot, C.
AU - Davies, G.J.
AU - Behr, J.-B.
PY - 2013/7/15
Y1 - 2013/7/15
N2 - Enhanced metabolism of fucose through fucosidase overexpression is a signature of some cancer types, thus suggesting that fucosidase-targetted ligands could play the role of drug-delivery vectors. Herein, we describe the synthesis of a new series of pyrrolidine-ferrocene conjugates, consisting of a L-fuco-configured dihydroxypyrrolidine as the fucosidase ligand armed with a cytotoxic ferrocenylamine moeity. Three-dimensional structures of several of these fucosidase inhibitors reveal transition-state-mimicking E conformations. Elaboration with the ferrocenyl moiety results in sub-micromolar inhibitors of both bovine and bacterial fucosidases, with the 3D structure of the latter revealing electron density indicative of highly mobile alkylferrocene compounds. The best compounds show a strong antiproliferative effect, with up to 100 % inhibition of the proliferation of MDA-MB-231 cancer cells at 50 μM. Transition-state-mimicking E conformations (see picture) are evident from the three-dimensional structures of ferrocenyl iminosugar/ fucosidase complexes. Novel pyrrolidine-ferrocene conjugates show strong anti-fucosidase and antiproliferative action, with up to 100 % inhibition of proliferation of an MDA-MB-231 cancer-cell line at 50 μM.
AB - Enhanced metabolism of fucose through fucosidase overexpression is a signature of some cancer types, thus suggesting that fucosidase-targetted ligands could play the role of drug-delivery vectors. Herein, we describe the synthesis of a new series of pyrrolidine-ferrocene conjugates, consisting of a L-fuco-configured dihydroxypyrrolidine as the fucosidase ligand armed with a cytotoxic ferrocenylamine moeity. Three-dimensional structures of several of these fucosidase inhibitors reveal transition-state-mimicking E conformations. Elaboration with the ferrocenyl moiety results in sub-micromolar inhibitors of both bovine and bacterial fucosidases, with the 3D structure of the latter revealing electron density indicative of highly mobile alkylferrocene compounds. The best compounds show a strong antiproliferative effect, with up to 100 % inhibition of the proliferation of MDA-MB-231 cancer cells at 50 μM. Transition-state-mimicking E conformations (see picture) are evident from the three-dimensional structures of ferrocenyl iminosugar/ fucosidase complexes. Novel pyrrolidine-ferrocene conjugates show strong anti-fucosidase and antiproliferative action, with up to 100 % inhibition of proliferation of an MDA-MB-231 cancer-cell line at 50 μM.
UR - http://www.scopus.com/inward/record.url?scp=84879981885&partnerID=8YFLogxK
U2 - 10.1002/chem.201301001
DO - 10.1002/chem.201301001
M3 - Article
AN - SCOPUS:84879981885
SN - 0947-6539
VL - 19
SP - 9526
EP - 9533
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
IS - 29
ER -