The University of Southampton
University of Southampton Institutional Repository

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

Structure–activity relationships and colorimetric properties of specific probes for the putative cancer biomarker human arylamine N-acetyltransferase 1
Structure–activity relationships and colorimetric properties of specific probes for the putative cancer biomarker human arylamine N-acetyltransferase 1
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.
0968-0896
3030-3054
Egleton, James E.
b6e7e09f-90e4-42c9-8123-34b3eb6448eb
Thinnes, Cyrille C.
3bfbbf02-e6b6-4935-af0d-f30ce487d0bd
Seden, Peter T.
4dd1082b-132c-4199-98f4-278b1aa06cb4
Laurieri, Nicola
83aa6a45-b081-4cb4-88ed-eee80ffb967c
Lee, Siu Po
69d102ce-1a06-4a8e-9391-a4d636451b4c
Hadavizadeh, Kate S.
57289445-d772-436a-826e-1e645918f8ff
Measures, Angelina R.
e5fbdd41-3e02-45d6-822b-2322518c0668
Jones, Alan M.
08075fc1-c0a7-4124-aa26-5e7dad1a32ea
Thompson, Sam
99b7e34e-fe24-401c-b7b0-64e56cbbbcb1
Varney, Amy
f2abc8bf-7b6d-43b5-b92b-20113be5ac18
Wynne, Graham M.
92caae94-3c44-46be-aeaf-516d2ca363ba
Ryan, Ali
9646d980-5648-49fc-9477-7d04dc104559
Sim, Edith
76b9b428-c005-44d0-972d-edbf3b169443
Russell, Angela J.
da250fde-2cb6-4f3f-971b-a9a66678e1d3
Egleton, James E.
b6e7e09f-90e4-42c9-8123-34b3eb6448eb
Thinnes, Cyrille C.
3bfbbf02-e6b6-4935-af0d-f30ce487d0bd
Seden, Peter T.
4dd1082b-132c-4199-98f4-278b1aa06cb4
Laurieri, Nicola
83aa6a45-b081-4cb4-88ed-eee80ffb967c
Lee, Siu Po
69d102ce-1a06-4a8e-9391-a4d636451b4c
Hadavizadeh, Kate S.
57289445-d772-436a-826e-1e645918f8ff
Measures, Angelina R.
e5fbdd41-3e02-45d6-822b-2322518c0668
Jones, Alan M.
08075fc1-c0a7-4124-aa26-5e7dad1a32ea
Thompson, Sam
99b7e34e-fe24-401c-b7b0-64e56cbbbcb1
Varney, Amy
f2abc8bf-7b6d-43b5-b92b-20113be5ac18
Wynne, Graham M.
92caae94-3c44-46be-aeaf-516d2ca363ba
Ryan, Ali
9646d980-5648-49fc-9477-7d04dc104559
Sim, Edith
76b9b428-c005-44d0-972d-edbf3b169443
Russell, Angela J.
da250fde-2cb6-4f3f-971b-a9a66678e1d3

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 N-acetyltransferase 1. Bioorganic & Medicinal Chemistry, 22 (11), 3030-3054. (doi:10.1016/j.bmc.2014.03.015).

Record type: Article

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.

Text
bmc 2014 3030.pdf - Version of Record
Restricted to Repository staff only
Request a copy

More information

Accepted/In Press date: 10 March 2014
e-pub ahead of print date: 28 March 2014
Published date: 1 June 2014
Organisations: Chemistry

Identifiers

Local EPrints ID: 403602
URI: http://eprints.soton.ac.uk/id/eprint/403602
ISSN: 0968-0896
PURE UUID: f04eeeeb-caeb-445f-a8e0-2e872067fde6
ORCID for Sam Thompson: ORCID iD orcid.org/0000-0001-6267-5693

Catalogue record

Date deposited: 07 Dec 2016 11:15
Last modified: 12 Nov 2019 01:33

Export record

Altmetrics

Contributors

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

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×