ABSTRACT
During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.
Subject(s)
Antineoplastic Agents/chemical synthesis , Oxazoles/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Chromatography, High Pressure Liquid , Colchicine/chemistry , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Female , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Oxazoles/chemistry , Oxazoles/pharmacology , Structure-Activity Relationship , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
ABT-773 is a novel ketolide effective against antibacterial-resistant respiratory tract pathogens. The pharmacokinetic profile of ABT-773 was studied in rats and consisted of a mean peak concentration in plasma of 1.07 microg/ml and an area under the concentration-time curve (AUC) of 12.03 microg. h/ml when the compound was delivered at a dose of 25 mg/kg of body weight. It concentrated in rat lung tissue, with a lung tissue-to-plasma ratio of 29 based on the AUC. In acute systemic infections in mice, ABT-773 showed efficacy against macrolide-susceptible strains of Staphylococcus aureus, Streptococcus pneumoniae, S. pyogenes, and Listeria monocytogenes. Additionally, ABT-773 improved the survival of mice infected with resistant S. pneumoniae containing either the ermB gene, the mefE gene, or altered penicillin binding protein genes. In a rat lung model of infection, ABT-773 demonstrated 50% effective doses lower than those of comparator macrolides when evaluated against the following strains of S. pneumoniae: a macrolide-lincosamide-streptogramin B-susceptible strain, an ermB strain, and an mefE strain. ABT-773 was also effective against Haemophilus influenzae lung infections in rats. Thus, ABT-773 may prove to be a useful new antibacterial agent for the treatment of respiratory tract infections.
Subject(s)
Bacterial Infections/drug therapy , Erythromycin/analogs & derivatives , Erythromycin/therapeutic use , Ketolides , Animals , Bacterial Infections/metabolism , Disease Models, Animal , Drug Resistance, Microbial , Erythromycin/pharmacokinetics , Female , Haemophilus Infections/drug therapy , Haemophilus Infections/metabolism , Haemophilus influenzae/drug effects , Listeriosis/drug therapy , Listeriosis/metabolism , Lung Diseases/drug therapy , Lung Diseases/metabolism , Lung Diseases/microbiology , Male , Mice , Rats , Rats, Sprague-Dawley , Respiratory Tract Diseases/drug therapy , Respiratory Tract Diseases/metabolism , Staphylococcal Infections/drug therapy , Staphylococcal Infections/metabolism , Streptococcal Infections/drug therapy , Streptococcal Infections/metabolism , Streptococcus pneumoniae/drug effects , Treatment OutcomeABSTRACT
Sulfonate analogues of combretastatin A-4 have been prepared. These compounds compete with colchicine and combretastatin A-4 for the colchicine binding site on tubulin and are potent inhibitors of tubulin polymerization and cell proliferation. Importantly, these compounds also inhibit the proliferation of P-glycoprotein positive (+) cancer cells, which are resistant to many other antitumor agents.
