Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
24
|
| pubmed:dateCreated |
1998-12-17
|
| pubmed:abstractText |
All of the selective COX-2 inhibitors described to date inhibit the isoform by binding tightly but noncovalently at the substrate binding site. Recently, we reported the first account of selective covalent modification of COX-2 by a novel inactivator, 2-acetoxyphenyl hept-2-ynyl sulfide (70) (Science 1998, 280, 1268-1270). Compound 70 selectively inactivates COX-2 by acetylating the same serine residue that aspirin acetylates. This paper describes the extensive structure-activity relationship (SAR) studies on the initial lead compound 2-acetoxyphenyl methyl sulfide (36) that led to the discovery of 70. Extension of the S-alkyl chain in 36 with higher alkyl homologues led to significant increases in inhibitory potency. The heptyl chain in 2-acetoxyphenyl heptyl sulfide (46) was optimum for COX-2 inhibitory potency, and introduction of a triple bond in the heptyl chain (compound 70) led to further increments in potency and selectivity. The alkynyl analogues were more potent and selective COX-2 inhibitors than the corresponding alkyl homologues. Sulfides were more potent and selective COX-2 inhibitors than the corresponding sulfoxides or sulfones or other heteroatom-containing compounds. In addition to inhibiting purified COX-2, 36, 46, and 70 also inhibited COX-2 activity in murine macrophages. Analogue 36 which displayed moderate potency and selectivity against purified human COX-2 was a potent inhibitor of COX-2 activity in the mouse macrophages. Tryptic digestion and peptide mapping of COX-2 reacted with [1-14C-acetyl]-36 indicated that selective COX-2 inhibition by 36 also resulted in the acetylation of Ser516. That COX-2 inhibition by aspirin resulted from the acetylation of Ser516 was confirmed by tryptic digestion and peptide mapping of COX-2 labeled with [1-14C-acetyl]salicyclic acid. The efficacy of the sulfides in inhibiting COX-2 activity in inflammatory cells, our recent results on the selectivity of 70 in attenuating growth of COX-2-expressing colon cancer cells, and its selectivity for inhibition of COX-2 over COX-1 in vivo indicate that this novel class of covalent modifiers may serve as potential therapeutic agents in inflammatory and proliferative disorders.
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| pubmed:grant | |
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Acetylene,
http://linkedlifedata.com/resource/pubmed/chemical/Alkynes,
http://linkedlifedata.com/resource/pubmed/chemical/Anti-Inflammatory Agents...,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase 2 Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Dinoprostone,
http://linkedlifedata.com/resource/pubmed/chemical/Isoenzymes,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/PTGS2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Prostaglandin-Endoperoxide Synthases,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfides,
http://linkedlifedata.com/resource/pubmed/chemical/Thromboxane B2,
http://linkedlifedata.com/resource/pubmed/chemical/o-(acetoxyphenyl)hept-2-ynyl sulfide
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Nov
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
19
|
| pubmed:volume |
41
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
4800-18
|
| pubmed:dateRevised |
2007-11-14
|
| pubmed:meshHeading |
pubmed-meshheading:9822550-Acetylation,
pubmed-meshheading:9822550-Acetylene,
pubmed-meshheading:9822550-Alkynes,
pubmed-meshheading:9822550-Animals,
pubmed-meshheading:9822550-Anti-Inflammatory Agents, Non-Steroidal,
pubmed-meshheading:9822550-Antineoplastic Agents,
pubmed-meshheading:9822550-Colonic Neoplasms,
pubmed-meshheading:9822550-Cyclooxygenase 2,
pubmed-meshheading:9822550-Cyclooxygenase 2 Inhibitors,
pubmed-meshheading:9822550-Cyclooxygenase Inhibitors,
pubmed-meshheading:9822550-Dinoprostone,
pubmed-meshheading:9822550-Exudates and Transudates,
pubmed-meshheading:9822550-Humans,
pubmed-meshheading:9822550-Inhibitory Concentration 50,
pubmed-meshheading:9822550-Isoenzymes,
pubmed-meshheading:9822550-Kinetics,
pubmed-meshheading:9822550-Macrophages,
pubmed-meshheading:9822550-Membrane Proteins,
pubmed-meshheading:9822550-Mice,
pubmed-meshheading:9822550-Prostaglandin-Endoperoxide Synthases,
pubmed-meshheading:9822550-Rats,
pubmed-meshheading:9822550-Sheep,
pubmed-meshheading:9822550-Structure-Activity Relationship,
pubmed-meshheading:9822550-Sulfides,
pubmed-meshheading:9822550-Thromboxane B2,
pubmed-meshheading:9822550-Tumor Cells, Cultured
|
| pubmed:year |
1998
|
| pubmed:articleTitle |
Covalent modification of cyclooxygenase-2 (COX-2) by 2-acetoxyphenyl alkyl sulfides, a new class of selective COX-2 inactivators.
|
| pubmed:affiliation |
A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Departments of Biochemistry and Chemistry, Center in Molecular Toxicology and The Vanderbilt Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
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| pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, U.S. Gov't, P.H.S.
|