Novel Polyphenol Conjugates: Design, Synthesis and Biological Evaluation
저자
발행사항
서울 : 건국대학교 대학원, 2013
학위논문사항
학위논문(박사)-- 건국대학교 대학원 : 생명공학과 2013. 8
발행연도
2013
작성언어
영어
주제어
발행국(도시)
서울
형태사항
222 ; 26 cm
일반주기명
지도교수: 정유훈
소장기관
In order to discover a quercetin prodrug with improved bioavailability, we synthesized nine quercetin-amion acid conjugates and estimated their pharmacokinetic properties including water solubility, stability against chemical or enzymatic hydrolysis, and cell permeability. Among the synthesized quercetin prodrugs, quercetin-glutamic acid conjugate Qu-E (4g/5g) showed remarkable increases in water solubility, stability, and cell permeability compared with quercetin, which warrants further development as a quercetin prodrug.
더보기Quercetin is a flavonoid with health promoting effects such as antioxidant, anti-inflammatory, antiviral, immunomodulatory and anticancer effect. However, quercetin has limited bioavailability due to low water solubility and fast metabolism as well as excretion. In order to discover a quercetin prodrug with improved bioavailability, we designed a dimethyl carbamate promoiety at the 3-O position of quercetin (3-N,N-dimethyl carbamoyl quercetin, DCQ) and its various pharmacokinetic properties including water solubility, stability against chemical or enzymatic hydrolysis, and cell permeability across the MDCK (Mardin-Darby canine kidney) cell were estimated. DCQ showed increased water solubility, stability, and cell permeability compared with quercetin. Particularly, DCQ was highly resistant against non-enzymatic hydrolysis but underwent facile hydrolysis by cellular hydrolyzing enzymes.
더보기Efficient intracellular localization of a bioactive compound is important for elicitation of its therapeutic effect, but chemical instability and fast metabolism of quercetin limit its intracellular accumulation. In this study, in order to increase stability of quercetin, the metabolically and chemically susceptible hydroxyl groups, 7-OH and 3-OH, respectively, were transiently blocked with a pivaloxymethyl (POM) promoiety to provide two novel quercetin conjugates [7-O-POM-Q (2) and 3-O-POM-Q (3)]. In the absence of stabilizer (ascorbic acid), the synthesized conjugates showed significantly increased stability in cell culture media [t½ = 4 h (2), 52 h (3)] compared with quercetin (t½ < 30 min) and the quercetin prodrug, QC12 (t½ = 0.8 h). In addition, confocal live-cell imaging as well as HPLC analysis of the extracellular and intracellular contents after incubation of cells with 7-O-POM-Q (2) revealed that the quercetin conjugate 2 undergoes efficient cellular uptake and the intracellular levels of its hydrolysis product, quercetin, are maintained up to 12 h. Extracellular stability and facile intracellular accumulation of the quercetin conjugate 2 were demonstrated by its stabilizer-independent cytostatic effect and induction of apoptotic cell death. On the other hand, the highly stable 3-O-POM-Q (3) was not transported into the cell. However, even though 3-O-POM-Q failed to localize inside the cell, its high solubility as well as remarkable stability in extracellular fluid warrants further investigation of quercetin conjugates with various promoieties at the 3-OH position.
더보기Two pivaloxymethyl (POM) groups were introduced at 3- and 7-OH position of quercetin to provide 3,7-bis-O-POM-Q which showed exceptional stability in cell culture media and efficient cellular uptake. In cytoplasm, 3,7-bis-O-POM-Q was hydrolyzed to 3-O-POM-Q and showed significant cytostatic effect against various cancer cells.
더보기The aim of this study was to investigate the role of the aromatic substituents of the curcumin scaffold on the antibacterial activity of the resulting curcumin analogues. Six curcumin analogues with different aromatic substituents were prepared and their antibacterial activities were evaluated against two Gram-positive and four Gram-negative bacteria. The structure-activity relationship study demonstrated that antibacterial activity of the curcumin analogues was critically dependent upon the aromatic hydroxyl group. Thus, hydroxycurcumin with an additional aromatic hydroxyl group on the curcumin scaffold showed antibacterial activity against all six pathogens tested and it remained effective even against ampicillin-resistant Enterobacter cloacae. The broad-spectrum antibacterial activity of the hydroxycurcumin warrants further investigation of its biological activity as well as extensive structure-activity relationship study of the curcumin analogues with various aromatic substituents
더보기For a compound to be a radical-trapping antioxidant, the antioxidant-derived radical must be sufficiently inert to molecular oxygen as this would generate harmful chain-propagating peroxyl radicals. Curcumin has a unique structure with phenolic hydroxyl group as well as β-diketone moiety in the same molecule, both of which are able to donate electrons to free radicals. However, due to the reactivity toward molecular oxygen, the carbon-centered radical derived from β-diketone moiety do not serve as radical-trapping antioxidants. In this study, we reasoned that stabilization of the carbon-centered radical through substitution with an electron-withdrawing group would enhance the radical scavenging antioxidative activity of the resulting curcuminoids. Thus, various substituents (methyl, allyl, methoxy, xanthate, and acetoxy) covering broad spectrum of the polar substituent effect were introduced to the central methylene position of both phenolic and non-phenolic curcuminoids. With the free phenolic hydroxyl groups present, the methylene-substituent did not exert significant effect on the antioxidant activity of the curcuminoids (EC50 = 23.2 ~ 30.3 μM) with the exception of the acetoxy-substituted derivative (EC50 = 8.7 μM) which showed more potent activity than curcumin (EC50 = 22.6 μM). When substituted to the non-phenolic curcumin scaffold, however, the methylene-substituent enhanced antioxidant activity of the otherwise inactive curcuminoids in the increasing order of methyl<allyl<methoxy<xanthate<<acetoxy, which is well correlated with the polar inductive effects of the substituents.
더보기A limiting factor to biological activity of curcumin is its low solubility in water. In this study, we evaluated aqueous solubility as well as antiproliferative effect of a series of curcuminoids and acetoxy-curcuminoids. The acetoxy group substituted at the central methylene unit provided remarkable water-solubility and antiproliferative effect to the corresponding acetoxy-curcuminoids. Among the series, compound 11 showed complete solubility up to 200 μM with potent antiproliferative effect.
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