Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase

Human aldose reductase (AKR1B1, AR) is a key enzyme of the polyol pathway, catalyzing the reduction of glucose to sorbitol at high glucose concentrations, as those found in diabetic condition. Indeed, AKR1B1 overexpression is related to diabetes secondary complications and, in some cases, with cance...

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Autores: Crespo, Isidro|||0000-0001-7698-1720, Giménez-Dejoz, Joan, Porté, Sergio, Cousido-Siah, Alexandra, Mitschler, André, Podjarny, Alberto, Pratsinis, Harris, Kletsas, Dimitris, Parés i Casasampera, Xavier|||0000-0002-5071-9465, Ruiz, Francesc Xavier|||0000-0002-0457-0030, Metwally, Kamel, Farrés, Jaume|||0000-0001-9069-3987
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:288486
Acceso en línea:https://ddd.uab.cat/record/288486
https://dx.doi.org/urn:doi:10.1016/j.ejmech.2018.04.015
Access Level:acceso abierto
Palabra clave:1-Oxopyrimido[4,5-c]quinoline-2-acetic acids
AKR1B1
AKR1B10
Molecular modeling
X-ray crystallography
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spelling Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductaseCrespo, Isidro|||0000-0001-7698-1720Giménez-Dejoz, JoanPorté, SergioCousido-Siah, AlexandraMitschler, AndréPodjarny, AlbertoPratsinis, HarrisKletsas, DimitrisParés i Casasampera, Xavier|||0000-0002-5071-9465Ruiz, Francesc Xavier|||0000-0002-0457-0030Metwally, KamelFarrés, Jaume|||0000-0001-9069-39871-Oxopyrimido[4,5-c]quinoline-2-acetic acidsAKR1B1AKR1B10Molecular modelingX-ray crystallographyHuman aldose reductase (AKR1B1, AR) is a key enzyme of the polyol pathway, catalyzing the reduction of glucose to sorbitol at high glucose concentrations, as those found in diabetic condition. Indeed, AKR1B1 overexpression is related to diabetes secondary complications and, in some cases, with cancer. For many years, research has been focused on finding new AKR1B1 inhibitors (ARIs) to overcome these diseases. Despite the efforts, most of the new drug candidates failed because of their poor pharmacokinetic properties and/or unacceptable side effects. Here we report the synthesis of a series of 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as novel ARIs. IC50 assays and X-ray crystallographic studies proved that these compounds are promising hits for further drug development, with high potency and selectivity against AKR1B1. Based on the determined X-ray structures with hit-to-lead compounds, we designed and synthesized a second series that yielded lead compound 68 (Kiapp vs. AKR1B1 = 73 nM). These compounds are related to the previously reported 2-aminopyrimido[4,5-c]quinolin-1(2H)-ones, which exhibit antimitotic activity. Regardless of their similarity, the 2-amino compounds are unable to inhibit AKR1B1 while the 2-acetic acid derivatives are not cytotoxic against fibrosarcoma HT-1080 cells. Thus, the replacement of the amino group by an acetic acid moiety changes their biological activity, improving their potency as ARIs. 22018-01-0120182018-01-01Articlehttp://purl.org/coar/resource_type/c_6501AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/288486https://dx.doi.org/urn:doi:10.1016/j.ejmech.2018.04.015reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 BFU2011-24176Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 BIO2016-78057Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-1584open accesshttp://purl.org/coar/access_right/c_abf2Aquest material està protegit per drets d'autor i/o drets afins. Podeu utilitzar aquest material en funció del que permet la legislació de drets d'autor i drets afins d'aplicació al vostre cas. Per a d'altres usos heu d'obtenir permís del(s) titular(s) de drets.https://rightsstatements.org/vocab/InC/1.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2884862026-06-06T12:50:31Z
dc.title.none.fl_str_mv Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase
title Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase
spellingShingle Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase
Crespo, Isidro|||0000-0001-7698-1720
1-Oxopyrimido[4,5-c]quinoline-2-acetic acids
AKR1B1
AKR1B10
Molecular modeling
X-ray crystallography
title_short Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase
title_full Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase
title_fullStr Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase
title_full_unstemmed Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase
title_sort Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase
dc.creator.none.fl_str_mv Crespo, Isidro|||0000-0001-7698-1720
Giménez-Dejoz, Joan
Porté, Sergio
Cousido-Siah, Alexandra
Mitschler, André
Podjarny, Alberto
Pratsinis, Harris
Kletsas, Dimitris
Parés i Casasampera, Xavier|||0000-0002-5071-9465
Ruiz, Francesc Xavier|||0000-0002-0457-0030
Metwally, Kamel
Farrés, Jaume|||0000-0001-9069-3987
author Crespo, Isidro|||0000-0001-7698-1720
author_facet Crespo, Isidro|||0000-0001-7698-1720
Giménez-Dejoz, Joan
Porté, Sergio
Cousido-Siah, Alexandra
Mitschler, André
Podjarny, Alberto
Pratsinis, Harris
Kletsas, Dimitris
Parés i Casasampera, Xavier|||0000-0002-5071-9465
Ruiz, Francesc Xavier|||0000-0002-0457-0030
Metwally, Kamel
Farrés, Jaume|||0000-0001-9069-3987
author_role author
author2 Giménez-Dejoz, Joan
Porté, Sergio
Cousido-Siah, Alexandra
Mitschler, André
Podjarny, Alberto
Pratsinis, Harris
Kletsas, Dimitris
Parés i Casasampera, Xavier|||0000-0002-5071-9465
Ruiz, Francesc Xavier|||0000-0002-0457-0030
Metwally, Kamel
Farrés, Jaume|||0000-0001-9069-3987
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv 1-Oxopyrimido[4,5-c]quinoline-2-acetic acids
AKR1B1
AKR1B10
Molecular modeling
X-ray crystallography
topic 1-Oxopyrimido[4,5-c]quinoline-2-acetic acids
AKR1B1
AKR1B10
Molecular modeling
X-ray crystallography
description Human aldose reductase (AKR1B1, AR) is a key enzyme of the polyol pathway, catalyzing the reduction of glucose to sorbitol at high glucose concentrations, as those found in diabetic condition. Indeed, AKR1B1 overexpression is related to diabetes secondary complications and, in some cases, with cancer. For many years, research has been focused on finding new AKR1B1 inhibitors (ARIs) to overcome these diseases. Despite the efforts, most of the new drug candidates failed because of their poor pharmacokinetic properties and/or unacceptable side effects. Here we report the synthesis of a series of 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as novel ARIs. IC50 assays and X-ray crystallographic studies proved that these compounds are promising hits for further drug development, with high potency and selectivity against AKR1B1. Based on the determined X-ray structures with hit-to-lead compounds, we designed and synthesized a second series that yielded lead compound 68 (Kiapp vs. AKR1B1 = 73 nM). These compounds are related to the previously reported 2-aminopyrimido[4,5-c]quinolin-1(2H)-ones, which exhibit antimitotic activity. Regardless of their similarity, the 2-amino compounds are unable to inhibit AKR1B1 while the 2-acetic acid derivatives are not cytotoxic against fibrosarcoma HT-1080 cells. Thus, the replacement of the amino group by an acetic acid moiety changes their biological activity, improving their potency as ARIs.
publishDate 2018
dc.date.none.fl_str_mv 2
2018-01-01
2018
2018-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
AM
http://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/288486
https://dx.doi.org/urn:doi:10.1016/j.ejmech.2018.04.015
url https://ddd.uab.cat/record/288486
https://dx.doi.org/urn:doi:10.1016/j.ejmech.2018.04.015
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 BFU2011-24176
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 BIO2016-78057
Agència de Gestió d'Ajuts Universitaris i de Recerca https://doi.org/10.13039/501100003030 2017/SGR-1584
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://rightsstatements.org/vocab/InC/1.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://rightsstatements.org/vocab/InC/1.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
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repository.mail.fl_str_mv
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