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Phosphonic acid-containing inhibitors of tyrosyl-DNA phosphodiesterase 1

Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs stalled type I topoisomerase (TOP1)-DNA complexes by hydrolyzing the phosphodiester bond between the TOP1 Y723 residue and the 3′-phosphate of its DNA substrate. Although TDP1 antagonists could potentially reduce the dose of TOP1 inhibitors needed to ac...

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Autores principales: Zhao, Xue Zhi, Wang, Wenjie, Lountos, George T., Tropea, Joseph E., Needle, Danielle, Pommier, Yves, Burke, Terrence R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9424690/
https://www.ncbi.nlm.nih.gov/pubmed/36051621
http://dx.doi.org/10.3389/fchem.2022.910953
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author Zhao, Xue Zhi
Wang, Wenjie
Lountos, George T.
Tropea, Joseph E.
Needle, Danielle
Pommier, Yves
Burke, Terrence R.
author_facet Zhao, Xue Zhi
Wang, Wenjie
Lountos, George T.
Tropea, Joseph E.
Needle, Danielle
Pommier, Yves
Burke, Terrence R.
author_sort Zhao, Xue Zhi
collection PubMed
description Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs stalled type I topoisomerase (TOP1)-DNA complexes by hydrolyzing the phosphodiester bond between the TOP1 Y723 residue and the 3′-phosphate of its DNA substrate. Although TDP1 antagonists could potentially reduce the dose of TOP1 inhibitors needed to achieve effective anticancer effects, the development of validated TDP1 inhibitors has proven to be challenging. This may, in part, be due to the open and extended nature of the TOP1 substrate binding region. We have previously reported imidazopyrazines and imidazopyridines that can inhibit TDP1 catalytic function in vitro. We solved the TDP1 crystal structures with bound inhibitors of this class and found that the dicarboxylic acid functionality within the N-(3,4-dicarboxyphenyl)-2-diphenylimidazo [1,2-a]pyridin-3-amine platform overlaps with aspects of phosphoryl substrate recognition. Yet phosphonic acids could potentially better-replicate cognate TOP1-DNA substrate binding interactions than carboxylic acids. As reported herein, we designed phosphonic acid-containing variants of our previously reported carboxylic acid-containing imidazopyrazine and imidazopyridine inhibitors and effected their synthesis using one-pot Groebke–Blackburn–Bienayme multicomponent reactions. We obtained crystal structures of TDP1 complexed with a subset of inhibitors. We discuss binding interactions of these inhibitors within the context of phosphate-containing substrate and carboxylic acid-based inhibitors. These compounds represent a new structural class of small molecule ligands that mimic aspects of the 3′-processed substrate that results from TDP1 catalysis.
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spelling pubmed-94246902022-08-31 Phosphonic acid-containing inhibitors of tyrosyl-DNA phosphodiesterase 1 Zhao, Xue Zhi Wang, Wenjie Lountos, George T. Tropea, Joseph E. Needle, Danielle Pommier, Yves Burke, Terrence R. Front Chem Chemistry Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs stalled type I topoisomerase (TOP1)-DNA complexes by hydrolyzing the phosphodiester bond between the TOP1 Y723 residue and the 3′-phosphate of its DNA substrate. Although TDP1 antagonists could potentially reduce the dose of TOP1 inhibitors needed to achieve effective anticancer effects, the development of validated TDP1 inhibitors has proven to be challenging. This may, in part, be due to the open and extended nature of the TOP1 substrate binding region. We have previously reported imidazopyrazines and imidazopyridines that can inhibit TDP1 catalytic function in vitro. We solved the TDP1 crystal structures with bound inhibitors of this class and found that the dicarboxylic acid functionality within the N-(3,4-dicarboxyphenyl)-2-diphenylimidazo [1,2-a]pyridin-3-amine platform overlaps with aspects of phosphoryl substrate recognition. Yet phosphonic acids could potentially better-replicate cognate TOP1-DNA substrate binding interactions than carboxylic acids. As reported herein, we designed phosphonic acid-containing variants of our previously reported carboxylic acid-containing imidazopyrazine and imidazopyridine inhibitors and effected their synthesis using one-pot Groebke–Blackburn–Bienayme multicomponent reactions. We obtained crystal structures of TDP1 complexed with a subset of inhibitors. We discuss binding interactions of these inhibitors within the context of phosphate-containing substrate and carboxylic acid-based inhibitors. These compounds represent a new structural class of small molecule ligands that mimic aspects of the 3′-processed substrate that results from TDP1 catalysis. Frontiers Media S.A. 2022-08-16 /pmc/articles/PMC9424690/ /pubmed/36051621 http://dx.doi.org/10.3389/fchem.2022.910953 Text en Copyright © 2022 Zhao, Wang, Lountos, Tropea, Needle, Pommier and Burke. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Chemistry
Zhao, Xue Zhi
Wang, Wenjie
Lountos, George T.
Tropea, Joseph E.
Needle, Danielle
Pommier, Yves
Burke, Terrence R.
Phosphonic acid-containing inhibitors of tyrosyl-DNA phosphodiesterase 1
title Phosphonic acid-containing inhibitors of tyrosyl-DNA phosphodiesterase 1
title_full Phosphonic acid-containing inhibitors of tyrosyl-DNA phosphodiesterase 1
title_fullStr Phosphonic acid-containing inhibitors of tyrosyl-DNA phosphodiesterase 1
title_full_unstemmed Phosphonic acid-containing inhibitors of tyrosyl-DNA phosphodiesterase 1
title_short Phosphonic acid-containing inhibitors of tyrosyl-DNA phosphodiesterase 1
title_sort phosphonic acid-containing inhibitors of tyrosyl-dna phosphodiesterase 1
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9424690/
https://www.ncbi.nlm.nih.gov/pubmed/36051621
http://dx.doi.org/10.3389/fchem.2022.910953
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