Premium
Oxime‐Based Click Chemistry in the Development of 3‐Isoxazolecarboxylic Acid Containing Inhibitors of Yersinia pestis Protein Tyrosine Phosphatase, YopH
Author(s) -
Bahta Medhanit,
Burke Terrence R.
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100200
Subject(s) - yersinia pestis , chemistry , protein tyrosine phosphatase , click chemistry , moiety , stereochemistry , hapten , biochemistry , effector , oxime , tyrosine , combinatorial chemistry , biology , virulence , antibody , immunology , gene
The pathogenicity of Yersinia pestis relies on several effector proteins including YopH, a protein tyrosine phosphatase (PTP). We previously screened a library of analogues based on the ubiquitous PTP substrate para ‐nitrophenylphosphate ( p NPP) and found that incorporation of a 3‐phenyl substituent to give 6‐nitro‐[1,1′‐biphenyl]‐3‐yldihydrogen phosphate ( 1 ) enhanced affinity. Herein we report the conversion of 1 from a substrate into an inhibitor by replacing the hydrolysable phosphoryl group with a 3‐isoxazolecarboxylic acid moiety and by introduction of an aminooxy group and subsequent diversification using oxime‐based click chemistry. This approach led to the identification of non‐promiscuous bidentate YopH inhibitors with affinity in the low micromolar range.