Pyrazole derivatives. 5. Synthesis and antineoplastic activity of 3-(2-chloroethyl)-3,4-dihydro-4-oxopyrazolo[5,1-d]-1,2,3, 5-tetrazine-8-carboxamide and related compounds.

Two pyrazolotetrazine derivatives were synthesized as the analogous prodrugs of the light-sensitive antineoplastic agents dacarbazine and BIC. Both the pyrazole derivatives are stable under ordinary light illumination. Biological evaluation of these pyrazoles revealed that the compound containing a 2-chloroethyl function (6a) demonstrated good antineoplastic activity in experimental animals, but the one containing a methyl function (6b) was inactive. The inactivity of compound 6b may suggest that compound 6a and related imidazotetrazines may simply act as biological alkylating agents per se rather than as prodrugs. The information could also imply that the postulated dealkylation mechanism for the triazene derivatives should be reexamined.

Quinolone antibacterial agents. Synthesis and structure-activity relationships of a series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)quinolones. Highly soluble quinolone prodrugs with in vivo pseudomonas activity.

A series of amino acid prodrugs of racemic and chiral 7-(3-amino-1-pyrrolidinyl)-6-fluoro-1,8-naphthyridine-3-carboxylic acids, 1-cyclopropyl-6,8-difluoro-3-quinolinecarboxylic acids, 1-cyclopropyl-6-fluoro-3-quinolinecarboxylic acids, and 5-amino-1-cyclopropyl-6,8-difluoro-3-quinolinecarboxylic acids have been prepared and evaluated for comparative antibacterial activity. Compounds were prepared by acylation of the 3-amino group of the pyrrolidine with common amino acids using standard peptide chemistry. This series has been compared with the parent compounds for antibacterial activity in vitro and in vivo as well as for comparative solubility. The amino acid analogues were less active in vitro, but had equal or increased efficacy in vivo. Indeed, it was proven that these compounds, which were stable to acid and base under the reaction conditions for their preparation, were rapidly cleaved in serum to give the parent quinolones. The amino acid derivatives showed a 3-70 times improved solubility when compared to the parent compounds. The most active compound of the series was [S-(R*,R*)]-7-[3-[(2-amino-1-oxopropyl)-amino]-1-pyrrolidinyl]-1- cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (PD 131112).

Characterization of clinafloxacin photodegradation products by LC-MS/MS and NMR.

Exposure of clinafloxacin to light results in photochemical degradation. The polar and nonpolar photodegradation products were profiled by HPLC using two sets of conditions. Clinafloxacin was subjected to severe light exposure conditions to obtain elevated levels of the photodegradation products for characterization. The structures of eight new degradation products were elucidated based on information from LC-MS/MS fragmentation and NMR spectra following isolation by preparative HPLC. Two photodegradation routes were identified: (1) dechlorination, followed by further reactions involving the quinolone ring, to yield polar photodegradation products; and (2) degradation of the pyrrolidine side-chain, yielding the nonpolar photodegradation products.

Post-column reaction detection system for the determination of organophosphorus compounds by liquid chromatography.

The development and application of a post-column reaction detection system for organophosphorus compounds based upon their photodegradation to ortho-phosphate followed by the formation of reduced heteropolymolybdate is reported. Photodegradation occurs in a fused-silica tube coiled about a 450-W xenon lamp in the presence of ammonium peroxydisulfate. Photodegradation yields were practically quantitative for the organophosphates, -phosphonates, and -phosphorodithioates tested. Factors affecting the rate of the chromogenic reaction were optimized so that its contribution to the total band-broadening was negligible. The effect of interfering organic modifiers in the mobile phase was studied using the acetate ion as a model. Separations were developed using no organic solvents in the mobile phases. The determination of dialkylphosphates in urine and organophosphorus pesticides in tomatoes illustrate the potential of the methodology.