Structure-activity relationships and colorimetric properties of specific probes for the putative cancer biomarker human arylamine [Nu]-acetyltransferase 1

Egleton, James E., Thinnes, Cyrille C., 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 and Russell, Angela J. (2014) Structure-activity relationships and colorimetric properties of specific probes for the putative cancer biomarker human arylamine [Nu]-acetyltransferase 1. Bioorganic & Medicinal Chemistry, 22(11), pp. 3030-3054. ISSN (print) 0968-0896

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Abstract

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.

Item Type: Article
Additional Information: This work was supported by Cancer Research UK [C383202/A12450], Cancer Medicinal Chemistry Studentship, Small Molecule Cancer Drug Discovery Award [C17468/A9332] and Research Councils United Kingdom.
Uncontrolled Keywords: Arylamine [Nu]-acetyltransferase, breast cancer, biomarker, colorimetric probe, naphthoquinone
Research Area: Cancer studies
Chemistry
Faculty, School or Research Centre: Faculty of Science, Engineering and Computing > School of Life Sciences
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Depositing User: Ali Ryan
Date Deposited: 06 Nov 2014 11:29
Last Modified: 06 Nov 2014 11:29
URI: http://eprints.kingston.ac.uk/id/eprint/29068

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