Chemical Mechanisms in Toxicology

Grillo, Mark P.

doi:10.1002/9780470439265.ch23

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2011

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“…The conversion of substrate 1 to the lead platform 2 was done with removal of a nitro group, since nitro functionality can impart undesirable biological properties, [19] and the original function of this moiety as a chromophoric agent was no longer necessary. However, it was unclear what effects deletion of the nitro group had on the binding affinities of the final ligands ( 3a – 3d ).…”

Section: Resultsmentioning

confidence: 99%

Oxime‐Based Click Chemistry in the Development of 3‐Isoxazolecarboxylic Acid Containing Inhibitors of Yersinia pestis Protein Tyrosine Phosphatase, YopH

Bahta

Burke

2011

ChemMedChem

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Pathogenicity of Yersinia pestis (Y. pestis) relies on several effector proteins, including YopH, a protein-tyrosine phosphatase. Previously, we screened a library of analogues based on the ubiquitous PTP substrate, p-nitrophenylphosphate (pNPP) and found that incorporation of a 3-phenyl substituent (6-nitro-[1,1'-biphenyl]-3-yl dihydrogen phosphate (1)) enhanced affinity. The current study reports the conversion of 1 from a substrate to 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. As reported herein, this approach led to the identification of non-promiscuous low micromolar affinity bidentate YopH inhibitors.

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Section: Resultsmentioning

confidence: 99%