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

Research output: Contribution to journalArticlepeer-review

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 α-methyl group oxidation protocol, which involves cyclopalladation of the C1 α-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 (US)
Pages (from-to)5540-5543
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number20
DOIs
StatePublished - Oct 15 2013

Keywords

  • Bioitin
  • Cyclopalladation
  • Diabetic nephropathy
  • Keap1/Nrf2/ARE pathway
  • Protein targets

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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