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An aza-nucleoside, fragment-like inhibitor of the DNA repair enzyme alkyladenine glycosylase (AAG)

Mas Claret, Eduard, Al Yahyaei, Balqees, Chu, Shuyu, Elliott, Ruan M., Imperato, Manuel, Lopez, Arnaud, Meira, Lisiane B., Howlin, Brendan J. and Whelligan, Daniel K. (2020) An aza-nucleoside, fragment-like inhibitor of the DNA repair enzyme alkyladenine glycosylase (AAG) Bioorganic & Medicinal Chemistry, 28 (11), 115507.

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Abstract

The DNA repair enzyme AAG has been shown in mice to promote tissue necrosis in response to ischaemic reperfusion or treatment with alkylating agents. A chemical probe inhibitor is required for investigations of the biological mechanism causing this phenomenon and as a lead for drugs that are potentially protective against tissue damage from organ failure and transplantation, and alkylative chemotherapy. Herein, we describe the rationale behind the choice of arylmethylpyrrolidines as appropriate aza-nucleoside mimics for an inhibitor followed by their synthesis and the first use of a microplate-based assay for quantification of their inhibition of AAG. We finally report the discovery of an imidazol-4-ylmethylpyrrolidine as a fragment-sized, weak inhibitor of AAG.

Item Type: Article
Divisions : Faculty of Engineering and Physical Sciences > Chemistry
Authors :
NameEmailORCID
Mas Claret, Eduarde.masclaret@surrey.ac.uk
Al Yahyaei, Balqeesb.alyahyaei@surrey.ac.uk
Chu, Shuyu
Elliott, Ruan M.R.M.Elliott@surrey.ac.uk
Imperato, Manuel
Lopez, Arnaud
Meira, Lisiane B.
Howlin, Brendan J.B.Howlin@surrey.ac.uk
Whelligan, Daniel K.D.Whelligan@surrey.ac.uk
Date : 1 June 2020
Funders : Royal Society, Engineering and Physical Sciences Research Council (EPSRC)
DOI : 10.1016/j.bmc.2020.115507
Copyright Disclaimer : © 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).T
Uncontrolled Keywords : Methylpurine DNA glycosylase (MPG); Alkyladenine DNA glycosylase (AAG); Base excision DNA repair; Ischaemic reperfusion; Small molecule inhibitor; Aza-nucleoside
Depositing User : Diane Maxfield
Date Deposited : 27 May 2020 16:03
Last Modified : 10 Jun 2020 09:20
URI: http://epubs.surrey.ac.uk/id/eprint/856986

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