TY - JOUR
T1 - Design, synthesis and evaluation of novel PEGylated curcumin analogs as potent Nrf2 activators in human bronchial epithelial cells
AU - Pandey, Mukesh K.
AU - Kumar, Sarvesh
AU - Thimmulappa, Rajesh K.
AU - Parmar, Virinder S.
AU - Biswal, Shyam
AU - Watterson, Arthur C.
N1 - Funding Information:
This work was supported by National Institutes of Health Grant HL081205 (S.B.), National Heart, Lung, and Blood Institute Specialized Centers of Clinically Oriented Research Grant P50HL084945 , the Flight Attendant Medical Research Institute (S.B. and R.K.T) and National Institute on Environmental Health Sciences Grants P50ES015903 , P01 ES018176 and ES03819 (S.B.). M.K.P. and A.C.W. are thankful to University of Massachusetts at Lowell for the financial assistance. VSP is thankful to the Department of Biotechnology (DBT, New Delhi, India) and the University of Delhi under the DU-DST Purse Grant.
PY - 2011/5/18
Y1 - 2011/5/18
N2 - 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.
AB - 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.
KW - Novozym 435
KW - Nrf2
KW - PEGylated curcumin
KW - chemo-Enzymatic synthesis
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U2 - 10.1016/j.ejps.2011.03.003
DO - 10.1016/j.ejps.2011.03.003
M3 - Article
C2 - 21426935
AN - SCOPUS:79955701862
SN - 0928-0987
VL - 43
SP - 16
EP - 24
JO - European Journal of Pharmaceutical Sciences
JF - European Journal of Pharmaceutical Sciences
IS - 1-2
ER -