Title:Fluorinated Mechanism-Based Inhibitors: Common Themes and Recent Developments
VOLUME: 14 ISSUE: 7
Author(s):Christina Tysoe and Stephen G. Withers
Affiliation:Department of Chemistry, University of British Columbia, 2036, Main Mall, Vancouver, British Columbia, V6T 1Z1, Canada.
Keywords:Amine oxidases, drug design, enzyme inhibition, enzyme mechanisms, fluorine, glycosidases, mechanism-based
inhibition.
Abstract:Mechanism-based inhibitors are relatively chemically inert compounds that become activated when processed
by their target enzyme, leading to covalent enzyme inactivation. Fluorine substitution confers a number of properties that
are beneficial to the chemistry of such inhibitors and to their potential use as pharmaceuticals, and indeed several fluorinated
mechanism-based inhibitors have made it to clinical usage over the past 50 years. Well-known examples are the 5-
fluorouracil metabolite, 5-fluoro-2’-deoxyuridine-5’-monophosphate, which is used in the treatment of cancer, and α-
difluoromethylornithine for the treatment of African sleeping sickness. As the prevalence of fluorine in medicinal chemistry
continues to rise, more and more medically relevant fluorinated mechanism-based inhibitors are being developed with
a variety of interesting properties and uses.
