2. Academic Validation
  3. New Monocyclic, Bicyclic, and Tricyclic Ethynylcyanodienones as Activators of the Keap1/Nrf2/ARE Pathway and Inhibitors of Inducible Nitric Oxide Synthase

New Monocyclic, Bicyclic, and Tricyclic Ethynylcyanodienones as Activators of the Keap1/Nrf2/ARE Pathway and Inhibitors of Inducible Nitric Oxide Synthase

  • J Med Chem. 2015 Jun 11;58(11):4738-48. doi: 10.1021/acs.jmedchem.5b00393.
Wei Li 1,  Suqing Zheng 1,  Maureen Higgins 2,  Rocco P Morra Jr 1,  Anne T Mendis 1,  Chih-Wei Chien 1,  Iwao Ojima 1 3,  Dale F Mierke 4,  Albena T Dinkova-Kostova 2 5,  Tadashi Honda 1 3
Affiliations

Affiliations

  • 1 †Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, New York 11794, United States.
  • 2 ‡Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee DD1 9SY, Scotland United Kingdom.
  • 3 §Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, United States.
  • 4 ∥Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755, United States.
  • 5 ⊥Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.
PMID: 25965897 DOI: 10.1021/acs.jmedchem.5b00393
Abstract

A monocyclic compound 3 (3-ethynyl-3-methyl-6-oxocyclohexa-1,4-dienecarbonitrile) is a highly reactive Michael acceptor leading to reversible adducts with nucleophiles, which displays equal or greater potency than the pentacyclic triterpenoid CDDO in inflammation and carcinogenesis related assays. Recently, reversible covalent drugs, which bind with protein targets but not permanently, have been gaining attention because of their unique features. To explore such reversible covalent drugs, we have synthesized monocyclic, bicyclic, and tricyclic compounds containing 3 as an electrophilic fragment and evaluated them as activators of the Keap1/Nrf2/ARE pathway and inhibitors of iNOS. Notably, these compounds maintain the unique features of the chemical reactivity and biological potency of 3. Among them, a monocyclic compound 5 is the most potent in these assays while a tricyclic compound 14 displays a more robust and specific activation profile compared to 5. In conclusion, we demonstrate that 3 is a useful electrophilic fragment for exploring reversible covalent drugs.

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