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

[Display omitted] 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 drug...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2020-06, Vol.28 (11), p.115507-115507, Article 115507
Main Authors: Mas Claret, Eduard, Al Yahyaei, Balqees, Chu, Shuyu, Elliott, Ruan M., Imperato, Manuel, Lopez, Arnaud, Meira, Lisiane B., Howlin, Brendan J., Whelligan, Daniel K.
Format: Article
Language:English
Subjects:
Alkyladenine DNA glycosylase (AAG)
Aza-nucleoside
Base excision DNA repair
Ischaemic reperfusion
Methylpurine DNA glycosylase (MPG)
Small molecule inhibitor
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Summary:[Display omitted] 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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2020.115507