Design, synthesis and evaluation of novel PEGylated curcumin analogs as potent Nrf2 activators in human bronchial epithelial cells

Mukesh K. Pandey, Sarvesh Kumar, Rajesh K. Thimmulappa, Virinder S. Parmar, Shyam Biswal, Arthur C. Watterson

Research output: Contribution to journalArticle

36 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)16-24
Number of pages9
JournalEuropean Journal of Pharmaceutical Sciences
Volume43
Issue number1-2
DOIs
StatePublished - May 18 2011

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Keywords

  • Novozym 435
  • Nrf2
  • PEGylated curcumin
  • chemo-Enzymatic synthesis

ASJC Scopus subject areas

  • Pharmaceutical Science

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