Synthesis and biological evaluation of biotin conjugates of (±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydro-phenanthrene-2,6-dicarbonitrile, an activator of the Keap1/Nrf2/ARE pathway, for the isolation of its protein targets

Akira Saito, Maureen Higgins, Suqing Zheng, Wei Li, Iwao Ojima, Albena T. Dinkova-Kostova, Tadashi Honda (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    4 Citations (Scopus)

    Abstract

    The tricycle 1 ((±)-(4bS,8aR,10aS))-10a-ethynyl-4b,8,8-trimethyl-3, 7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile), a potent activator of the Keap1/Nrf2/ARE pathway, has the potential to be a first in class drug for the treatment of diabetic nephropathy. To identify the protein targets for the development of 1, the (1:1)-diasteromeric mixture of biotinylated tricycles 3a and 3b were designed and synthesized. For the synthesis of 3a and 3b, a new important precursor, hydroxylated tricycle (±)-16 was synthesized from 4 by a C1 a-methyl group oxidation protocol, which involves cyclopalladation of the C1 a-methyl group from a C2-oxime. For the induction of the phase 2 cytoprotective enzyme NQO1 in Hepa1c1c7 murine hepatoma cells, the diasteromeric mixture 3a and 3b shows high potency (CD, 75 nM) although this potency is lower than that of 1 and 16. Thus, biotinylated tricycles 3a and 3b may be promising tools for the isolation of the protein targets of 1.
    Original languageEnglish
    Pages (from-to)5540-5543
    Number of pages4
    JournalBioorganic & Medicinal Chemistry Letters
    Volume23
    Issue number20
    DOIs
    Publication statusPublished - 15 Oct 2013

    Keywords

    • Adaptor Proteins, Signal Transducing
    • Animals
    • Biotin
    • Biotinylation
    • Carboxylic Ester Hydrolases
    • Cell Line, Tumor
    • Cytoskeletal Proteins
    • Liver
    • Mice
    • NAD(P)H Dehydrogenase (Quinone)
    • NF-E2-Related Factor 2
    • Phenanthrenes
    • Protective Agents
    • Signal Transduction
    • Stereoisomerism

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