Reference : Structure-activity relationships and colorimetric properties of specific probes for t...
Scientific journals : Article
Physical, chemical, mathematical & earth Sciences : Chemistry
Structure-activity relationships and colorimetric properties of specific probes for the putative cancer biomarker human arylamine N-acetyltransferase 1.
Egleton, James E. [> >]
Thinnes, Cyrille [University of Oxford > Department of Chemistry]
Seden, Peter T. [> >]
Laurieri, Nicola [> >]
Lee, Siu Po [> >]
Hadavizadeh, Kate S. [> >]
Measures, Angelina R. [> >]
Jones, Alan M. [> >]
Thompson, Sam [> >]
Varney, Amy [> >]
Wynne, Graham M. [> >]
Ryan, Ali [> >]
Sim, Edith [> >]
Russell, Angela J. [> >]
Bioorganic & Medicinal Chemistry
Yes (verified by ORBilu)
[en] Arylamine N-Acetyltransferase/antagonists & inhibitors/metabolism ; Biomarkers, Tumor/antagonists & inhibitors/metabolism ; Cell Line, Tumor ; Colorimetry ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/chemical synthesis/chemistry/pharmacology ; Humans ; Isoenzymes/antagonists & inhibitors/metabolism ; Models, Molecular ; Molecular Structure ; Naphthoquinones/chemical synthesis/chemistry/pharmacology ; Structure-Activity Relationship ; Arylamine N-acetyltransferase ; Biomarker ; Breast cancer ; Colorimetric probe ; Naphthoquinone
[en] A naphthoquinone inhibitor of human arylamine N-acetyltransferase 1 (hNAT1), a potential cancer biomarker and therapeutic target, has been reported which undergoes a distinctive concomitant color change from red to blue upon binding to the enzyme. Here we describe the use of in silico modeling alongside structure-activity relationship studies to advance the hit compound towards a potential probe to quantify hNAT1 levels in tissues. Derivatives with both a fifty-fold higher potency against hNAT1 and a two-fold greater absorption coefficient compared to the initial hit have been synthesized; these compounds retain specificity for hNAT1 and its murine homologue mNat2 over the isoenzyme hNAT2. A relationship between pKa, inhibitor potency and colorimetric properties has also been uncovered. The high potency of representative examples against hNAT1 in ZR-75-1 cell extracts also paves the way for the development of inhibitors with improved intrinsic sensitivity which could enable detection of hNAT1 in tissue samples and potentially act as tools for elucidating the unknown role hNAT1 plays in ER+ breast cancer; this could in turn lead to a therapeutic use for such inhibitors.
Copyright (c) 2014. Published by Elsevier Ltd.

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