No abstract

Solid-phase chemistry, organic synthesis, and an apparatus for multiple, simultaneous synthesis have been combined to generate libraries of organic compounds ("diversomers"). Arrays of compounds were synthesized over two to three steps incorporating chemically diverse building blocks on a polystyrene-based solid support in a multiple, simultaneous manner. The generality of this approach is illustrated by the syntheses of dipeptides, hydantoins, and benzodiazepines.

No abstract

The exo-amino groups of 2'-deoxyadenosine and 2'-deoxycytidine have been blocked as the benzyi carbamates, and 2'-deoxyguanosine has been blocked as its 2-N-benzyloxycarbonyl carbamate and 6-0-benzyl ether. These blocked nucleos ides have been incorporated into an efficient oligodeoxyribonucleotide synthetic scheme and the resuit{ng oligomer successfully deblocked using transfer hydrogenation.The deblocking conditions result in no reduction of the pyriiidine bases.

A series of stereochemically pure 7-[3-(1-aminoethyl)-1-pyrrolidinyl]-1, 4-dihydro-4-oxoquinoline and 1,8-naphthyridine-3-carboxylic acids, with varied substituents at the 1-, 5-, and 8-positions, were synthesized to study the effects of the 7-[3-(1-aminoethyl)-1- pyrrolidinyl] moiety on potency and in vivo efficacy relative to the known 7-[3-(aminomethyl)-1- pyrrolidinyl] derivatives. The antibacterial efficacies of the target compounds and their relevant reference agents were determined in vitro using an assortment of Gram-negative and Gram-positive organisms and in vivo using Escherichia coli and Streptococcus pyogenes mouse infection models. The effects of the 7-[3-(1-aminoethyl)-1-pyrrolidinyl] moiety were also examined at the level of the target enzyme by employing a DNA-gyrase supercoiling inhibition assay. Selected compounds were further evaluated for potential phototoxic and clastogenic liabilities using a phototoxicity mouse model and an in vitro mammalian cell cytotoxicity assay. It was found that the differences in in vitro antibacterial activity between the stereoisomers were significantly greater than previously reported for other optically pure 3-substituted pyrrolidinyl side chains. Relative to their 7-[3-(aminomethyl)-1-pyrrolidinyl] analogs, the (3R,1S)-3-(1-aminoethyl)pyrrolidines generally conferred a 2-4-fold increase in Gram-positive in vitro activity and an average of 10-fold improvement in oral efficacy. The level of phototoxicity and cytotoxicity of the product quinolones was ultimately determined by the combined influence of the 7-[3-(1-aminoethyl)-1-pyrrolidinyl] side chains and the other quinolone substituents. From this study, several compounds were identified with outstanding antibacterial activity and low degrees of phototoxicity and mammalian cell cytotoxicity. One such agent, 34F-R,S (PD 140248), showed the best overall blend of safety and efficacy.