Cyclooxygenase inhibitory activity

An (E)-selective CM reaction with an acrylate (Scheme 61) was applied by Smith and O Doherty in the enantioselective synthesis of three natural products with cyclooxygenase inhibitory activity (cryptocarya triacetate (312), cryptocaryolone (313), and cryptocaryolone diacetate (314)) [142]. CM reaction of homoallylic alcohol 309 with ethyl acrylate mediated by catalyst C led (E)-selectively to d-hydroxy enoate 310 in near quantitative yield. Subsequent Evans acetal-forming reaction of 310, which required the trans double bond in 310 to prevent lactonization, led to key intermediate 311 that was converted to 312-314. 

Table 1. Cyclooxygenase inhibitory activities of celecoxib (1), rofecoxib (2) and indomethacin (4), IC50 (pM).

In addition, dichotomin D showed moderate cyclooxygenase inhibitory activity (72.6% inhibition at 100 (jlM), whereas dichotomin A did not show any activity. This may also be due to differences in sequencing and/or conformation. 

Su, B.-N. et al.. Constituents of the bark and twigs ofArtocarpus dadah with cyclooxygenase inhibitory activity, J. Nat Prod., 65,163,2002. 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

The stems of the plant Perilla frutescens var. acuta have yielded two new prenyl 3-benzoxepine derivatives, perilloxin 53 and dehydroperilloxin 54, whose structures were established by spectroscopic means. An in vitro cyclooxygenase-1 bioassay was used to guide the separation of these natural products, which possessed moderate inhibitory activities against this enzyme (IC50 values for 53 and 54 were 23.2M and 30.4M respectively) <00JNP403>... 

Ketorolac 132, a nonstereoidal anti-inflammatory drug with cyclooxygenase (COX) inhibitory activity, was marketed as a racemic mixture. It is now well established that (V)-ketorolac is the active enantiomer <1999MI382>. Therefore, efforts were devoted to the selective synthesis of this active stereomer, either by enzymatic kinetic resolution <2001TA1865> or by enantioselective synthesis <2005AGE609>. 

Several interesting findings dealing with 2-quinolinylmethyl esters related to Rev 5901A (139) have been reported. Workers at Wyeth-Ayerst found that attachment of this moeity to a number of classical NSAIDs endowed these cyclooxygenase inhibitors with 5-LO inhibitory activity in cell assays... 

Jang, D.S. et al., Prenylated flavonoids of the leaves of Macaranga conifera with inhibitory activity against cyclooxygenase-2, Phytochemistry, 61, 867, 2002. 

Kawai, S., Nishida, S., Kato, M., Furumaya, Y., Okamoto, R., Koshino, T, Mizushima, Y. Comparison of cyclooxygenase-1 and -2 inhibitory activities of various nonsteroidal anti-inflammatory drugs using human platelets and synovial cells, Eur. J. Pharmacol. 1998, 347, 87-94. 

Fig. 4 Structures of SC-58125, NS-398, thiazolones and oxazolones associated with cyclooxygenase-2 (COX-2) inhibitory activity...

There is good evidence to suggest that cyclooxygenase-2 (COX-2) inhibitors will have important advantages over conventional non-steroidal anti-inflammatory drugs in arthritic disorders, and may be of value in Alzheimer s disease. The numerous compounds that exhibit COX-2 inhibitory activity are reviewed systematically in Chapter 5. 

Cyclovalone (25), which differs from curcumin in the linker between the two phenyl rings, and three analogs showed anti-inflammatory activity based on inhibition of the enzyme cyclooxygenase [14], Fig. (5). Curcumin was used as a reference, and compounds 26, 27, and 28 were more potent than curcumin. Compounds 26 and 28 showed greater inhibition than compounds 25 and 27, respectively. Therefore, in this series, di-methyl substitution enhanced the ability to inhibit cyclooxygenase more than mono-methoxy substitution. Compound 25 showed greater inhibitory activity than compound 27 however compounds 26 and 28 had similar activity. Hence, the authors concluded that modification of the cyclic ketone from cyclohexanone to... 

These anthors concluded that addition of a NO-donating moiety to aspirin resnlts in a new chemical entity that maintains cyclooxygenase-1 and platelet inhibitory activity while nearly avoiding gastrointestinal damage. ... 

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