title: Inhibition of prostaglandin 15-hydroxydehydrogenase by sulphasalazine and a novel series of potent analogues.
abstract: The ability of sulphasalazine, its colonic metabolites and various analogues to inhibit prostaglandin inactivation by two purified preparations of type INAD+-dependent prostaglandin 15-hydroxydehydrogenase or in various 100,000 g cytosolic supernatants was investigated using PGF2 alpha as substrate and radio-TLC. Bovine lung and human placental PGDH were inhibited in a dose-dependent and apparently non-competitive manner by sulphasalazine and most of the 26 salazine/sulphasalazine analogues tested, but the potencies of the analogues varied considerably. In a survey of structure-activity effects testing 30 drugs at a fixed dose (50 microM) in six test systems, it was established that only two aromatic rings are needed and that optimal PGDH inhibition requires -CH2COOH and -OH at positions 1 and 2 in the salicyl C ring system. Homosalazine was thus established as the type compound of a novel series of powerful PGDH inhibitors. Electronegative substituents meta or para in ring B produce compounds with greater than 150 X inhibitory potency of sulphasalazine, and a significant linear correlation (r = 0.82, P less than 0.002) was found between the inhibitory activity and the Hammett sigma substituent constant in this series of ten homosalazine analogues.
mesh_terms: D000818:Animals; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008168:Lung / Q000201:enzymology; D013329:Structure-Activity Relationship; D012460:Sulfasalazine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D012460:Sulfasalazine; D007521:Isocitrate Dehydrogenase