title: NO-donors (VII [1]): synthesis and cyclooxygenase inhibitory properties of N-and S-nitrooxypivaloyl-cysteine derivatives of naproxen -- a novel type of NO-NSAID.
abstract: Nitric oxide (NO)has been reported to subserve many of the same mucosal protection mechanisms as prostaglandins and is sufficient for acute gastroprotection and ulcer healing. In fact, NO-donating NSAID hybrid compounds such as the nitrooxybutyl ester of naproxen show reduced ulcerogenic activity while maintaining anti-inflammatory activity. We introduce two prototypes of novel triple-hybrid compounds consisting of cysteine which is known to enhance the activity of organic nitrates and to reduce nitrate tolerance, an NSAID (naproxen), and an organic nitrate (nitrooxypivaloic acid). L-Cysteine ethyl ester first was N-acylated in a CH(2)Cl(2)/H(2)O twophase system using the acid chlorides of naproxen or nitrooxypivaloic acid, respectively, and sodium acetate, or alternatively using the DCC-activated nitrooxy acid in absolute CH(2)Cl(2). The N-acylated intermediates were subsequently S-acylated using the acid chlorides or alternatively the carbonyldiimidazole (CDI)-activated acids again. The two naproxen-cysteine-nitrate hybrid prodrugs were screened in vitro for their cyclooxygenase inhibitory properties relative to naproxen. In this screening the N-nitrooxyacylcysteine derivative was found to be inactive in the concentration range of 0.1-10 micromol/L against both COX-1 and COX-2, while the S-nitrooxyacylcysteine derivative had only weak activity against COX-1.
authors.affiliation: Institute of Pharmacy, University of Bonn, Bonn, Germany.
authors.forename: Rahmana E
authors.initials: RE
authors.lastname: Kartasasmita
authors.forename: Stefan
authors.initials: S
authors.lastname: Laufer
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins; D009288:Naproxen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D007527:Isoenzymes; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D011355:Prodrugs; D009288:Naproxen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat