SOME STUDIES OF THE CHEMISTRY OF PYRIDINE-I-OXIDES

The generation of pyridyl-l-oxide carbanions and their subsequent condensation with electrophilic reagents is described. The intermediate carbanions react with bromine and chlorine to give 2,6-dihalopyridine-l-oxides, with sulfur to give biologically active 1-hydroxy-2- pyridinethiones, with oxygen to give 1-hydroxy-2- 4 r pyridones, with benzyl bromide to yield 1-benzyloxy- pyridinium bromide, with epoxides to form polymers, with acetaldehyde and cyclohexanone to give secondary and tertiary alcohols, respectively, and with Schiff bases, to yield secondary amines. A series of bases, other than n-butyllithium, were examined for their ability to generate the pyridyl-l-oxide carbanions. Dehydration and polymerization of some 2-pyridyl alkanol-l-oxides gave poly-(2-vinylpyridine-l-oxide). In vitro pharmacological testing results are given for some of the sulfur compounds prepared

SOME EXTRACTIVES FROM POPULUS BALSAMIFERA L. AND OPUNTIA FRAGILIS Nutt.

The purpose of this thesis is to give an account of a systematic investigation carried out on the extractives of Populus balsamifera and Opuntia fragilis. Salicaceae (the Willow family) consist of the Populus (Poplar) genus and the Salix (Willow) genus. Eight species of the Populus genus are known in North America (1) (Schematic I). Of these eight species, only P. balsamifera, P. tremuloides, and P. trichocarna have drawn the attention of research workers. However P. tremula (European Aspen) and P. grandid-entata found elsewhere have been studied quite extensively. The buds (Balm of Gilead) of P. balsamifera (or P. tacamahaca, other— wise known as Balsam poplar) have been studied in reasonable detail, where—as considerably less work has been reported on the bark and heartwood; virtually- nothing has been done on the leaves. A study by Farwell (2) showed that commercial Poplar buds are collected from P. balsamifera Linn, and P. tacamahaca Mill. Goris and Canal (3), working with the fresh buds 7 of P. balsamifera, isolated 2',6-dihydroxy-4-methoxyll-phenylpropiophenone (I) from the oil which was identical to the synthetic material they later synthetized (4). Further studies on P. balsamifera buds by Goris and Canal (5) established the presence of asparagine, saccharose, salicoside, cinnamic, propionic, butyric, E-hydroxybenzoic, 3,4-dihydroxycinnamic and 213-dihydrcxybenzoic acids; a sesquiterpene alcohol, the cinnamyl and phenylethyl esters of cinnamic and lignoceric acids, hydrocarbons C25H52, C27H56, and C29H60, as well as acetophenone, the 1 2,46- dihydrOXY- 4 V -methoxy—p—phenylpropiophenone which they reported earlier

Design, synthesis, biological evaluation, and nitric-oxide release studies of a novel series of celecoxib prodrugs possessing a nitric-oxide donor moiety

A new group of hybrid nitric oxide-releasing anti-inflammatory drugs (NONO-coxibs), in which an O2 ‑acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate NO-donor moiety is attached directly to the carboxylic acid group of 1-(4-aminosulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids (6a–c), were synthesized. A low amount of NO was released from the diazen-1-ium-1,2-diolate compounds 6a–c upon incubation with phosphate buffer saline (PBS) at pH 7.4 (range: pH 7.97–8.51), whereas, the percentage of NO released was significantly higher (84.5%–85.05% of the theoretical maximal release of two molecules of NO/molecule of the parent hybrid ester prodrug) when the diazen-1-ium-1,2-diolate ester prodrugs were incubated in the presence of rat serum. These incubation studies demonstrated that both NO and the anti-inflammatory 1-(4-aminosulfonylphenyl)-5-(4-H, 4-F or 4-Me-phenyl)-1H‑pyrazol-3-carboxylic acid (4a–c) would be released from the parent NONO-coxib upon in vivo cleavage by non-specific serum esterases. The parent compounds 4a-c displayed good antiinflammatory effects (ID50=81.4–112.4 mg/kg p.o.) between those exhibited by the reference drugs, aspirin (ID50=114.3 mg/kg p.o.) and celecoxib (ID50=12.6 mg/kg p.o.). Hybrid ester anti-inflammatory/NO-donor prodrugs (NONO‑coxibs) offer a potential drug-design concept directed toward the development of antiinflammatory drugs that are lacking adverse ulcerogenic and/or cardiovascular effects