Inhibition of Golgi mannosidase II with mannostatin A analogues: synthesis, biological evaluation, and structure-activity relationship studies

Chembiochem : a European Journal of Chemical Biology
Bing LiGeert-Jan Boons

Abstract

Mannostatin and aminocyclopentitetrol analogues with various substitutions at the amino function were synthesized. These compounds were tested as inhibitors of human Golgi and lysosomal alpha-mannosidases. Modification of the amine of mannostatin had only marginal effects, whereas similar modifications of aminocyclopentitetrol led to significantly improved inhibitors. Ab initio calculations and molecular docking studies were employed to rationalize the results. It was found that mannostatin and aminocyclopentitretrol could bind to Golgi alpha-mannosidase II in a similar mode to that of the known inhibitor swainsonine. However, due to the flexibility of the five-membered rings of these compounds, additional low-energy binding modes could be adopted. These binding modes may be relevant for the improved activities of the benzyl-substituted compounds. The thiomethyl moiety of mannostatin was predicted to make favorable hydrophobic interactions with Arg228 and Tyr727 that would possibly account for its greater inhibitory activity.

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Citations

Aug 28, 2013·Glycoconjugate Journal·Ivana NemčovičováIain B H Wilson
Apr 15, 2008·Nature Chemical Biology·Louise E TailfordGideon J Davies
Aug 24, 2005·The Journal of Biological Chemistry·Chaeho ParkKelley W Moremen
May 12, 2009·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Ji-Yuan SunQian Yang
Nov 14, 2006·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·J-Y SunJ-B Wang
Dec 23, 2008·Chembiochem : a European Journal of Chemical Biology·Douglas A KuntzGeert-Jan Boons
Jul 19, 2006·Angewandte Chemie·Jun GuoGeert-Jan Boons
Feb 8, 2011·European Journal of Medicinal Chemistry·Monika PolákováJuraj Kóňa
Jul 9, 2013·Bioorganic & Medicinal Chemistry·Daniel W WrightGideon J Davies

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