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 (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Giménez-Dejoz, Joan (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Porté, Sergio (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Cousido-Siah, Alexandra (Institut de Génétique et de Biologie Moléculaire et Cellulaire, France)
Mitschler, André (Institut de Génétique et de Biologie Moléculaire et Cellulaire, France)
Podjarny, Alberto (Institut de Génétique et de Biologie Moléculaire et Cellulaire, France)
Pratsinis, Harris (Institute of Biosciences and Applications, National Centre of Scientific Research "Demokritos", Athens, Greece)
Kletsas, Dimitris (Institute of Biosciences and Applications, National Centre of Scientific Research "Demokritos", Athens, Greece)
Parés i Casasampera, Xavier (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Ruiz, Francesc Xavier (Institut de Génétique et de Biologie Moléculaire et Cellulaire, France)
Metwally, Kamel (Zagazig University, Egypt)
Farrés, Jaume (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2018
Abstract:	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.
Grants:	Agencia Estatal de Investigación BFU2011-24176 Agencia Estatal de Investigación BIO2016-78057 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017SGR1584
Rights:	Tots els drets reservats.
Language:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Subject:	1-Oxopyrimido[4,5-c]quinoline-2-acetic acids ; AKR1B1 ; AKR1B10 ; Molecular modeling ; X-ray crystallography
Published in:	European Journal of Medicinal Chemistry, Vol. 152 (2018) , p. 160-174, ISSN 1768-3254

DOI: 10.1016/j.ejmech.2018.04.015

52 p, 1.9 MB

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