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
Autor: | Dimitris Kletsas, Sergio Porté, F.X. Ruiz, Jaume Farrés, Joan Gimenez-Dejoz, Harris Pratsinis, Isidro Crespo, Alberto Podjarny, Kamel Metwally, Alexandra Cousido-Siah, Andre Mitschler, Xavier Parés |
---|---|
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Models Molecular Stereochemistry Cell Survival Aldo-Keto Reductases Crystallography X-Ray 03 medical and health sciences chemistry.chemical_compound Acetic acid Structure-Activity Relationship 0302 clinical medicine Polyol pathway Aldehyde Reductase Cell Line Tumor Drug Discovery Humans Enzyme Inhibitors Pharmacology chemistry.chemical_classification Aldose reductase Dose-Response Relationship Drug Molecular Structure Organic Chemistry Quinoline Biological activity General Medicine 030104 developmental biology Enzyme chemistry 030220 oncology & carcinogenesis Drug Design Quinolines Sorbitol Lead compound |
Zdroj: | European journal of medicinal chemistry. 152 |
ISSN: | 1768-3254 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |