RRC ID 18650
Author Niitsu Y, Hakamata M, Goto Y, Higashi T, Shoji M, Sugai T, Umezawa K.
Title Chemoenzymatic synthesis of (2R,3R,4R)-dehydroxymethylepoxyquinomicin (DHMEQ), a new activator of antioxidant transcription factor Nrf2.
Journal Org Biomol Chem
Abstract Dehydroxymethylepoxyquinomicin (DHMEQ, 1a) is a specific and potent inhibitor of NF-κB, and it is now being developed as an anti-inflammatory and anticancer agent. While previously only the (2S,3S,4S)-form had been available from the racemate by using lipase-catalyzed enantioselective resolution, in the present study a new route for production of the (2R,3R,4R)-form was established by use of a chemoenzymatic approach. (1R*,2R*,3R*)-2,3-Epoxy-5-N-[(2-hydroxybenzoyl)amino]-4,4-dimethoxycyclohex-5-en-1-ol (2a) was hexanoylated on both secondary and phenolic hydroxy groups, and subjected to Burkholderia cepacia lipase-catalyzed hydrolysis. The reaction proceeded in a highly enantioselective manner (E >500) to give (1S,2S,3S)-2a in an enantiomerically pure state. Several chemical steps of transformation from the enzyme reaction product gave (2R,3R,4R)-DHMEQ (1a) without any loss of stereochemical purity. Moreover, we newly found that (2R,3R,4R)-DHMEQ activated Nrf2, which is a transcription factor that induces the expression of multiple antioxidant enzymes. It activated Nrf2 in a promoter reporter assay. It also increased the expression of target antioxidant proteins and cancelled ROS-induced cell death in a neuronal cell line. Thus, (2R,3R,4R)-DHMEQ was efficiently prepared by a newly designed route using lipase, and it may be useful as a new anti-inflammatory agent.
Volume 9(12)
Pages 4635-41
Published 2011-6-21
DOI 10.1039/c1ob05205e
PMID 21541373
MeSH Antineoplastic Agents / chemical synthesis Antineoplastic Agents / metabolism* Antineoplastic Agents / pharmacology Antioxidants / metabolism Benzamides / chemical synthesis Benzamides / metabolism* Benzamides / pharmacology Biocatalysis Burkholderia cepacia / chemistry Burkholderia cepacia / enzymology Cell Line, Tumor Cyclohexanones / chemical synthesis Cyclohexanones / metabolism* Cyclohexanones / pharmacology Dose-Response Relationship, Drug Genes, Reporter Humans Lipase / metabolism* Luciferases / analysis NF-E2-Related Factor 2 / agonists* NF-E2-Related Factor 2 / metabolism NF-kappa B / antagonists & inhibitors* NF-kappa B / metabolism Neuroblastoma / drug therapy* Neuroblastoma / metabolism Reactive Oxygen Species / antagonists & inhibitors Reactive Oxygen Species / metabolism Stereoisomerism
IF 3.412
Times Cited 9
Human and Animal Cells SK-N-SH(RCB0426)