Novel quercetin conjugates : synthesis, pharmacokinetic properties, and biological activities

다국어 초록 (Multilingual Abstract)

Low bioavailability of quercetin has been tackled by conjugation with various promoieties. In this study, novel quercein conjugates with pivaloxymethyl (POM) promoieties attached at non-catecholic 7-O and/or 3-O position [7-O-POM-Q (2), 3-O-POM-Q (3), 3,7-bis-O-POM-Q (4)] were prepared, which, depending upon the position where the POM promoiety is introduced, showed characteristic physicochemical as well as biological properties. HPLC analysis of the cell lysates as well as fluorescence staining of the intracellular quercetin and its conjugates confirmed that a POM group attached on 7-O position enhanced cellular uptake of the corresponding conjugate (2) followed by sustained intracellular release of quercetin whereas 3-O-POM promoiety provided 3 with low intracellular localization and high stability. The characteristic physicochemical properties of the POM promoieties at 7-O and 3-O positions were combined in 4 to result in accumulation of the conjugate inside the cell followed by selective hydrolysis to 3. Cell viability assay and cell cycle distribution analysis showed that cellular uptake followed by hydrolysis into quercetin and 3-O-POM is responsible for the observed cytostatic effects as well as cell cycle modulation activities of the conjugates 2 and 4, respectively. Taken together, through positional scanning of a POM promoiety on non-catecholic hydroxyl groups of quercetin, we demonstrated that conjugation of naturally occurring flavonol with a POM promoiety at non-catecholic hydroxyl groups can enhance stability and intracellular accumulation of the corresponding quercetin conjugate to result in sustained release of the active ingredients inside the cell.

목차 (Table of Contents)

• 1. INTRODUCTION = 1
• 2. MATERIALS AND METHODS = 5
• 2.1 Materials and general method = 5
• 2.2 Chemistry = 6
• 2.3 Stability studies = 12
• 2.4 Solubility test = 13
• 2.5 Cellular uptake and intracellular stability = 13
• 2.6 Intracellular localization test (Confocal microscopy) = 14
• 2.7 Cell viability study = 14
• 2.8 Cell cycle distribution analysis by FACS = 14
• 3. Results & Discussion = 16
• 3.1 Synthesis = 16
• 3.2 Stability = 20
• 3.3 Solubility = 24
• 3.4 Cellular ptake and intracellular stability = 27
• 3.5 Intracellular localization of the quercetin conjugates = 34
• 3.6 Cell viability = 38
• 3.7 Cell Cycle Analysis = 42
• 4. Conclusion = 44
• 5. Reference = 46
• 국문초록 = 53