title: Synthesis and biological assessment of novel N-(hydroxy/methoxy)alkyl β-enaminone curcuminoids.
abstract: Curcumin, a natural compound extracted from the rhizomes of Curcuma Longa, is known to display pronounced anticancer activity but lacks good pharmacokinetic properties. In that respect, augmenting the water solubility by structural modification of the curcumin scaffold may result in improved bioavailability and pharmacokinetics. A possible scaffold modification, especially important for this study, concerns the imination of the labile β-diketone moiety in curcumin. Previous work revealed that novel N-alkyl β-enaminones showed a similar water solubility as compared to curcumin, accompanied by a stronger anti-proliferative activity. To extend this β-enaminone compound library, new analogues were prepared in this work using more polar amines (hydroxyalkylamines and methoxyalkylamines instead of alkylamines) with the main purpose to improve the water solubility without compromising the biological activity of the resulting curcuminoids. Compared to their respective parent compounds, i.e. curcumin and bisdemethoxycurcumin, the bisdemethoxycurcumin N-(hydroxy/methoxy)alkyl enaminone analogues showed better water solubility, antioxidant and anti-proliferative activities. In addition, the curcumin enaminones displayed activities comparable to or better than curcumin, and the water solubility was improved significantly. The constructed new analogues may thus be of interest for further exploration concerning their impact on oxidative stress related diseases such as cancer.
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
authors.forename: Atiruj
authors.initials: A
authors.lastname: Theppawong
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
authors.forename: Rob
authors.initials: R
authors.lastname: De Vreese
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
authors.forename: Lore
authors.initials: L
authors.lastname: Vannecke
authors.affiliation: Department of Food Safety and Food Quality, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Grootaert
authors.affiliation: Department of Food Safety and Food Quality, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium. Electronic address: John.VanCamp@UGent.be.
authors.forename: John
authors.initials: J
authors.lastname: Van Camp
authors.affiliation: SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium. Electronic address: matthias.dhooghe@Ugent.be.
authors.forename: Matthias
authors.initials: M
authors.lastname: D'hooghe
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D030024:Curcuma / Q000737:chemistry*; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D036381:Diarylheptanoids; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D000975:Antioxidants; D036381:Diarylheptanoids; D014867:Water; C034786:bisdemethoxycurcumin; D003474:Curcumin
keywords: Curcumin; Cytotoxicity; Dihydropyridin-4-ones; Oxidative stress; Synthesis; β-Enaminones