Cyclooxygenase inhibitory

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).

Lee D, Cuendet M, Schunke Vigo J, Graham JG, Cabieses F, Fong HHS, Pezzuto JM, Kinghom AD (2001) A Novel Cyclooxygenase-Inhibitory Stilbenolignan from the Seeds of Aiphanes aculeata. Org Lett 3 2169... 

Kuboki A, Yamamoto T, Ohira S (2003) Total Synthesis of ( )-Aiphanol, a Novel Cyclooxygenase-Inhibitory Stilbenolignan. Chem Lett 32 420... 

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. 

A novel cyclooxygenase-inhibitory stilbenolignan from the Seeds of Aiphanes aculeata. Org Lett 3 2169... 

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>. 

Figure 3.6 Docking simulations. (Source Liu H, Huang X, Shen J, et al. Inhibitory mode of 1,5-diarylpyrazole derivatives against cyclooxygenase-2 and cyclooxygenase-1 molecular docking and 3D QSAR analyses, Journal of Medicinal Chemistry 45 4816-4827 (2002). Used with permission.)...

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... 

Crew TE, Elder DJE, Paraskeva C A. Cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drug enhances the growth inhibitory effect of butyrate in colorectal carcinoma cells expressing COX-2 protein regulation of COX-2 by butyrate. Carcinogenesis 2000 21 69-77. 

Piazza GA, Rahm AK, Finn T, et al. Apoptosis fully accounts for the growth inhibitory properties of sulindac metabolites by a mechanism independent of cyclooxygenase inhibition, cell cycle arrest or p53 mediation. Cancer Res 1997 57 2452-2459. 

All NSAIDs except aspirin inhibit cyclooxygenase reversibly. Inhibition by aspirin, caused by the covalent acetylation of the enzyme, is irreversible. In platelets most NSAIDs block thromboxane synthesis more than that of prostacyclin and the overall effect is therefore inhibition of platelet aggregation. This effect is already noticeable at low doses. Because of the irreversible nature of the enzyme inhibition by aspirin and the fact that in platelets the novo enzyme synthesis is not possible the aggregation inhibitory effects of aspirin last several days. 

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

Broussochalcone A (32) Antioxidant activity (inhibition of lipid peroxidation) Inhibition of cyclooxygenase Inhibition of nitric oxide production Inhibition of respiratory burst in neutrophils Platelet aggregation inhibitory activity1 [42] [431 [42] [44] [431... 

Kazinol B (37) Inhibition of cyclooxygenase Platelet aggregation inhibitory activity11 [43] [43]... 

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