Aspirin-like molecules that covalently inactivate cyclooxygenase-2
AS Kalgutkar, BC Crews, SW Rowlinson, C Garner… - Science, 1998 - science.org
AS Kalgutkar, BC Crews, SW Rowlinson, C Garner, K Seibert, LJ Marnett
Science, 1998•science.orgMany 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 …
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 …
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 waso-(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.
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