Abstract
Many of aspirin's therapeutic effects arise from its acetylation of cyclooxygenase-2 (COX-2), whereas its antithrombotic and ulcerogenic effects result from its acetylation of COX-1. Here, aspirin-like molecules were designed that preferentially acetylate and irreversibly inactivate COX-2. The most potent of these compounds was o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS). Relative to aspirin, APHS was 60 times as reactive against COX-2 and 100 times as selective for its inhibition; it also inhibited COX-2 in cultured macrophages and colon cancer cells and in the rat air pouch in vivo. Such compounds may lead to the development of aspirin-like drugs for the treatment or prevention of immunological and proliferative diseases without gastrointestinal or hematologic side effects.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylation
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Acetylene / analogs & derivatives*
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Acetylene / chemical synthesis
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Acetylene / chemistry
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Acetylene / pharmacology
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Alkynes
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Aspirin / chemistry
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Aspirin / pharmacology
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Binding Sites
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Cell Division / drug effects
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Cell Line
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Colonic Neoplasms / enzymology
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Colonic Neoplasms / pathology
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / chemical synthesis*
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Cyclooxygenase Inhibitors / chemistry
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Cyclooxygenase Inhibitors / pharmacology
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Dinoprostone / biosynthesis
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Drug Design
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Humans
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Indomethacin / pharmacology
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Isoenzymes / chemistry
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Isoenzymes / genetics
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Isoenzymes / metabolism*
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Macrophages / enzymology
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Membrane Proteins
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Mutagenesis, Site-Directed
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Prostaglandin D2 / biosynthesis
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Prostaglandin-Endoperoxide Synthases / chemistry
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Prostaglandin-Endoperoxide Synthases / genetics
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Prostaglandin-Endoperoxide Synthases / metabolism*
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Rats
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Rats, Inbred Lew
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Sulfides / chemical synthesis*
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Sulfides / chemistry
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Sulfides / pharmacology
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Thromboxane B2 / biosynthesis
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Tumor Cells, Cultured
Substances
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Alkynes
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Isoenzymes
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Membrane Proteins
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Sulfides
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o-(acetoxyphenyl)hept-2-ynyl sulfide
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Thromboxane B2
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Dinoprostone
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Acetylene
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Aspirin
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Prostaglandin D2
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Indomethacin