Details

Autor(en) / Beteiligte

• Pavlović, Nebojša
• Milošević, Nastasija
• Đjanić, Maja
• Goločorbin-Kon, Svetlana
• Stanimirov, Bojan
• Stankov, Karmen
• Mikov, Momir

Titel

Antimetastatic Potential of Quercetin Analogues with Improved Pharmacokinetic Profile: A Pharmacoinformatic Preliminary Study

Ist Teil von

• Anti-cancer agents in medicinal chemistry, 2022-04, Vol.22 (7), p.1407

Ort / Verlag

Netherlands

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Urokinase-type plasminogen activator (uPA) system is a crucial pathway for tumor invasion and metastasis. Recently, multiple anticancer effects of quercetin have been described, including inhibitory activity against uPA. However, the clinical use of this flavonoid has been limited due to its low oral bioavailability. The objectives of the study were to assess the antimetastatic potential of quercetin analogues by analyzing their binding affinity for uPA, and to select the compounds with improved pharmacological profiles. Binding affinities of structural analogues of quercetin to uPA receptor were determined by molecular docking analysis using Molegro Virtual Docker software, and molecular descriptors relevant for estimating pharmacological profile were calculated from ligand structures using computational models. Among 44 quercetin analogues, only one quercetin analogue (3,6,2',4',5'-pentahydroxyflavone) was found to possess higher aqueous solubility and membrane permeability, and stronger affinity for uPA than quercetin, which makes it a potential lead compound for anticancer drug development. Like quercetin, this compound has five hydroxyl groups, but arranged differently, which contributes to the higher aqueous solubility and higher amphiphilic moment in comparison to quercetin. Since membrane permeability is not recognized as the limiting factor for quercetin absorption, analogues with higher aqueous solubility and retained or stronger uPA inhibitory activity should also be further experimentally validated for potential therapeutic use. Identified quercetin analogues with better physicochemical and pharmacological properties have a high potential to succeed in later stages of research in biological systems as potential anticancer agents with antimetastatic activity.