Chemoenzymatic synthesis of (2R,3R,4R)-Dehydroxymethylepoxyquinomicin (DHMEQ), a new activator of antioxidant transcription factor Nrf2

Yukihiro Niitsu, Masatoshi Hakamata, Yuko Goto, Toshinori Higashi, Mitsuru Shoji, Takeshi Sugai, Kazuo Umezawa

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4635-4641
Number of pages7
JournalOrganic and Biomolecular Chemistry
Volume9
Issue number12
DOIs
Publication statusPublished - 2011 Jun 21

Fingerprint

antioxidants
enzymes
Transcription Factors
Antioxidants
routes
Lipase
synthesis
cultured cells
death
reaction products
inhibitors
hydrolysis
purity
proteins
Anti-Inflammatory Agents
Burkholderia cepacia
Cell death
Enzymes
Reaction products
Antineoplastic Agents

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Biochemistry

Cite this

Chemoenzymatic synthesis of (2R,3R,4R)-Dehydroxymethylepoxyquinomicin (DHMEQ), a new activator of antioxidant transcription factor Nrf2. / Niitsu, Yukihiro; Hakamata, Masatoshi; Goto, Yuko; Higashi, Toshinori; Shoji, Mitsuru; Sugai, Takeshi; Umezawa, Kazuo.

In: Organic and Biomolecular Chemistry, Vol. 9, No. 12, 21.06.2011, p. 4635-4641.

Research output: Contribution to journalArticle

Niitsu, Yukihiro ; Hakamata, Masatoshi ; Goto, Yuko ; Higashi, Toshinori ; Shoji, Mitsuru ; Sugai, Takeshi ; Umezawa, Kazuo. / Chemoenzymatic synthesis of (2R,3R,4R)-Dehydroxymethylepoxyquinomicin (DHMEQ), a new activator of antioxidant transcription factor Nrf2. In: Organic and Biomolecular Chemistry. 2011 ; Vol. 9, No. 12. pp. 4635-4641.
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AU - Shoji, Mitsuru

AU - Sugai, Takeshi

AU - Umezawa, Kazuo

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