4JFV

Crystal structure of a bacterial fucosidase with iminosugar inhibitor (2S,3S,4R,5S)-2-[N-(methylferrocene)]aminoethyl-5-methylpyrrolidine-3,4-diol

Summary for 4JFV

• Entry DOI: 10.2210/pdb4jfv/pdb
• Related: 2WVV 4J27 4J28 4JFS 4JFT 4JFU 4JFW
• Descriptor: alpha-L-fucosidase, SULFATE ION, IMIDAZOLE, ... (5 entities in total)
• Functional Keywords: alpha-l-fucosidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Bacteroides thetaiotaomicron
• Total number of polymer chains: 4
• Total formula weight: 210996.99

Authors

Wright, D.W.,Davies, G.J. (deposition date: 2013-02-28, release date: 2013-09-18, Last modification date: 2023-09-20)

Primary citation

Hottin, A.,Wright, D.W.,Steenackers, A.,Delannoy, P.,Dubar, F.,Biot, C.,Davies, G.J.,Behr, J.B.
alpha-L-fucosidase inhibition by pyrrolidine-ferrocene hybrids: rationalization of ligand-binding properties by structural studies.
Chemistry, 19:9526-9533, 2013

PubMed Abstract: 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 (3)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.

PubMed: 23740878
DOI: 10.1002/chem.201301001

Experimental method

X-RAY DIFFRACTION (1.88 Å)