title: Chemoenzymatic synthesis of (2R,3R,4R)-dehydroxymethylepoxyquinomicin (DHMEQ), a new activator of antioxidant transcription factor Nrf2.
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.
authors.affiliation: Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Niitsu
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hakamata
authors.forename: Yuko
authors.initials: Y
authors.lastname: Goto
authors.forename: Toshinori
authors.initials: T
authors.lastname: Higashi
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shoji
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugai
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D001549:Benzamides / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D055162:Biocatalysis; D016956:Burkholderia cepacia / Q000737:chemistry / Q000201:enzymology; D045744:Cell Line, Tumor; D003512:Cyclohexanones / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006801:Humans; D008049:Lipase / Q000378:metabolism*; D008156:Luciferases / Q000032:analysis; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D001549:Benzamides; D003512:Cyclohexanones; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; C464444:dehydroxymethylepoxyquinomicin; D008156:Luciferases; D008049:Lipase