Covalent modification of cyclooxygenase-2 (COX-2) by 2-acetoxyphenyl alkyl sulfides, a new class of selective COX-2 inactivators.

Abstract

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.

• Authors: A S Kalgutkar, K R Kozak, B C Crews, G P Hochgesang Jr, L J Marnett
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 41 Issue 24 Pg. 4800-18 (Nov 19 1998) ISSN: 0022-2623 [Print] United States
• PMID: 9822550 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Alkynes
• Anti-Inflammatory Agents, Non-Steroidal
• Antineoplastic Agents
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Isoenzymes
• Membrane Proteins
• Sulfides
• o-(acetoxyphenyl)hept-2-ynyl sulfide
• Thromboxane B2
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Dinoprostone
• Acetylene

Topics

• Acetylation
• Acetylene (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Alkynes
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Colonic Neoplasms (enzymology, pathology)
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Dinoprostone (antagonists & inhibitors)
• Exudates and Transudates (drug effects, metabolism)
• Humans
• In Vitro Techniques
• Inhibitory Concentration 50
• Isoenzymes (antagonists & inhibitors, metabolism)
• Kinetics
• Macrophages (drug effects, enzymology)
• Membrane Proteins
• Mice
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Rats
• Sheep
• Structure-Activity Relationship
• Sulfides (chemical synthesis, chemistry, pharmacology)
• Thromboxane B2 (blood)
• Tumor Cells, Cultured