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

James E. Egleton, Cyrille C. Thinnes, Peter T. Seden, Nicola Laurieri, Siu Po Lee, Kate S. Hadavizadeh, Angelina R. Measures, Alan M. Jones, Sam Thompson, Amy Varney, Graham M. Wynne, Ali Ryan, Edith Sim, Angela J. Russell*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3030-3054
Number of pages25
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number11
DOIs
Publication statusPublished - 1 Jun 2014
Externally publishedYes

Fingerprint

Dive into the research topics of 'Structure-activity relationships and colorimetric properties of specific probes for the putative cancer biomarker human arylamine N-acetyltransferase 1'. Together they form a unique fingerprint.

Cite this