Aspirin-like molecules that covalently inactivate cyclooxygenase-2.
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.
Kalgutkar
A S
AS
A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Crews
B C
BC
Rowlinson
S W
SW
Garner
C
C
Seibert
K
K
Marnett
L J
LJ
D000107:Acetylation; D000114:Acetylene / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000480:Alkynes; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001241:Aspirin / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D015195:Drug Design; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology; D008565:Membrane Proteins; D016297:Mutagenesis, Site-Directed; D015230:Prostaglandin D2 / Q000096:biosynthesis; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D000480:Alkynes; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D013440:Sulfides; C112390:o-(acetoxyphenyl)hept-2-ynyl sulfide; D013929:Thromboxane B2; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D000114:Acetylene; D001241:Aspirin; D015230:Prostaglandin D2; D007213:Indomethacin