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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism*
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Alkynes / chemistry
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Alkynes / pharmacology*
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Animals
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacology*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Carboxylic Ester Hydrolases / metabolism*
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Carcinoma, Hepatocellular / drug therapy
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Cell Proliferation / drug effects*
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Cells, Cultured
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Cyclohexanones / chemistry
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Cyclohexanones / pharmacology*
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Cytoskeletal Proteins / metabolism*
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Inflammation / drug therapy
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Inflammation / metabolism
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Inflammation / pathology
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Kelch-Like ECH-Associated Protein 1
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Lipopolysaccharides / pharmacology
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Liver Neoplasms / drug therapy
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Liver Neoplasms / metabolism
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Liver Neoplasms / pathology
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism
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Mice
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Models, Molecular
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Molecular Structure
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NF-E2-Related Factor 2 / metabolism*
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Nitric Oxide Synthase Type II / antagonists & inhibitors*
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Nitric Oxide Synthase Type II / metabolism
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Signal Transduction / drug effects*
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Structure-Activity Relationship
Substances
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Adaptor Proteins, Signal Transducing
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Alkynes
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Anti-Inflammatory Agents
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Antineoplastic Agents
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Cyclohexanones
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Cytoskeletal Proteins
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Keap1 protein, mouse
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Kelch-Like ECH-Associated Protein 1
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Lipopolysaccharides
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NF-E2-Related Factor 2
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Nfe2l2 protein, mouse
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Nitric Oxide Synthase Type II
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Carboxylic Ester Hydrolases
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arylesterase