title: Design, synthesis and evaluation of novel PEGylated curcumin analogs as potent Nrf2 activators in human bronchial epithelial cells.
abstract: Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a central transcription factor that regulates the anti-oxidant defense system and is considered as a modifier for several inflammatory diseases. Thus, activation of Nrf2 provides pivotal therapeutic target for developing therapy against these diseases. Herein, a chemo-enzymatic methodology is designed and developed to make PEGylated curcumins as water soluble drug candidates with enhanced aqueous solubility and bioavailability. For this, curcumin was judiciously converted to diester (1) using ethyl α-bromoacetate and potassium carbonate. The diester 1 in subsequent step was copolymerized with poly(ethylene glycol) using Candida antarctica lipase [CAL-B, Novozym 435] under solventless condition. C. antarctica selectively does trans-esterification and only catalyses reaction of the primary hydroxyls of poly(ethylene glycol). It does not affect the secondary enolic hydroxyls of curcumin, thus leaving behind the active group unaltered. A luciferase based reporter gene assay was used for primary screening for identifying a novel Nrf2 activator. Most of the PEGylated curcumin analogs strongly activate Nrf2 several folds higher than the free curcumin but copolymer 3a was identified as the most potent Nrf2 activator. Copolymer 3a induces Nrf2-driven NQO1 expression in a concentration dependent manner. Furthermore, a plausible mechanism for quantitative structure-activity relationship is also discussed.
authors.affiliation: Institute of Nano-science and Engineering Technology, University of Massachusetts Lowell, One University Avenue, Lowell, MA 01854, USA. mpandey1@partners.org
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Pandey
authors.forename: Sarvesh
authors.initials: S
authors.lastname: Kumar
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Thimmulappa
authors.forename: Virinder S
authors.initials: VS
authors.lastname: Parmar
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
authors.forename: Arthur C
authors.initials: AC
authors.lastname: Watterson
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D018929:Cell Culture Techniques; D003474:Curcumin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D004800:Enzymes, Immobilized; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004951:Esterification; D005656:Fungal Proteins; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008049:Lipase / Q000737:chemistry; D008156:Luciferases / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000187:drug effects / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D004800:Enzymes, Immobilized; D005656:Fungal Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011092:Polyethylene Glycols; D008156:Luciferases; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C093667:Novozyme 435; D008049:Lipase; D003474:Curcumin