56490-42-7Relevant articles and documents
Covalent modification of cyclooxygenase-2 (COX-2) by 2-acetoxyphenyl alkyl sulfides, a new class of selective COX-2 inactivators
Kalgutkar, Amit S.,Kozak, Kevin R.,Crews, Brenda C.,Hochgesang Jr., G. Phillip,Marnett, Lawrence J.
, p. 4800 - 4818 (2007/10/03)
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.
Adrenergic agents. III. Synthesis and adrenergic activity of some catecholamine analogs bearing a substituted sulfonyl or sulfonylalkyl group in the meta position
Kaiser,Schwartz,Colella,Wardell Jr.
, p. 674 - 683 (2007/10/06)
The m phenolic group of catecholamine β adrenergic agonists may be replaced by various functionalities capable of undergoing H bonding. Considerable latitude in the nature of the OH simulating group is permissible with retention of activity; however, the most extensively studied analogs are ones in which a mobile proton is attached to an O or N atom. In a search for new selective bronchodilators a series of catecholamine analogs bearing a substituted sulfonyl or sulfonylalkyl group in the meta position (i.e., groups in which the mobile H is attached to a C atom) was examined. These compounds were studied for β adrenergic agonist activity in vitro by measuring their ability to relax tracheal smooth muscle and to increase the rate of spontaneously beating right atria of guinea pigs. Adrenergic activity was influenced by the nature of the aklylene bridge between the sulfonyl and aromatic groups, branching of the ethanolamine side chain, stereochemistry, and substitution of the sulfonyl and amino groups. β Adrenergic blockade was noted for some compounds having the sulfonyl attached directly to the ring. Greatest β adrenergic agonist potency and tissue selectivity was observed with a m MeSO2CH2 substituent. One of these compounds, α [[(1,1 dimethylethyl)amino]methyl] 4 hydroxy 3 [(methylsulfonyl)methyl]benzenemethanol hydrochloride (sulfonterol hydrochloride, USAN), was studied more extensively in animals and is presently being examined for bronchodilator activity in man.
