Studies On Prodrug Design And Synthesis Of Bioactive Flavonoid Quercetin

Quercetin is a kind of flavonoid, which is widely distributed, in many dietary and medicinal plants including onion, apple, tea, ginkgo biloba and others. It is a strong natural antioxidant and so have lots of important pharmacological activities, such as prevention of cardiovascular diseases, anticancer and neurodegenerative inhibition. Voluminous animal studies and limited human studies show that it is the bad solubility in pharmaceutically acceptable solvents and bad pharmacokinetic properties that lead to the poor absorption/availability after oral administration of quercetin and so badly affected the clinic development of quercetin. Therefore it is significant to design and synthesize quercetin derivatives with enhanced water solubility and better pharmacokinetic properties by structure modification on quercetin. It is a pity few studies on this work were found in the literature so far. During our work aimed at synthesis of quercetin derivatives used as potential prodrug or drug candidates, a series of amino acid carbamates of quercetin were designed and synthesized from commercially available quercetin and endogenetic L-amino acid utilizing triphosgene (BTC) as an auxiliary reagent. Firstly, two strategies for construction of quercetin carbamates were comparatively researched to give a better one as final choice. The result shown that it was difficult to get chloroformate of quercetin by reaction with BTC and isocyanate can couple with quercetin easily. So the preferential strategy to synthesize quercetin carbamate with the help of BTC was to transform amino compound into corresponding isocyanate in the first step. Endogenetic L-amino acids were chosen as starting materials for their potential benefits on the improvement of pharmacokinetic properties of quercetin. The key intermediate products were obtained by sequential esterification, isocyanation of starting amino acids and coupling with the 3-OH of 3,7,4′-O-tribenzylquercetin. The following catalytic hydrogenolysis of the key intermediate products gave a series of objective products, which were especially suitable for use as biodegradable prodrugs. The key intermediate products and part of final objective products were fully characterized by IR, 1H NMR, ESI-MS and microanalysis. Based on above results, a novel and facile strategy for modification of quercetin was constructed. Amino acid was used to modify quercetin with BTC as isocyanation reagent in the strategy. The strategy has many advantages such as short reaction steps, mild reaction conditions, and commercially available not expensive reagent. So it has great practical significance for promoting clinical use of quercetin.