RESUMO
Two new series of antitumor agents, 4-aminomethylthioxanthenones (6-50) and 5-aminomethylbenzothiopyranoindazoles (51-61), are described and compared. Nearly all members of both series display excellent in vivo activity versus murine pancreatic adenocarcinoma 03 (Panc03) although there is little to distinguish the two series from each other. In both series there is no discernible relationship between structure and in vivo efficacy. Selected analogues were evaluated in vitro; all were observed to have moderate to strong DNA binding via intercalation. However, varying degrees of in vitro P388 cytotoxicity and topoisomerase II inhibition were seen. In general, those molecules which exhibited strong topoisomerase II inhibition were significantly more cytotoxic than those which did not. In both series, those derivatives (48-50, 60, and 61) having a phenolic hydroxy substitution exhibited the most potent P388 cytotoxicity and topoisomerase II inhibition.
Assuntos
Antineoplásicos , Inibidores Enzimáticos , Indazóis , Piranos , Tioxantenos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , DNA de Neoplasias/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Indazóis/síntese química , Indazóis/química , Indazóis/farmacologia , Substâncias Intercalantes/síntese química , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Leucemia P388/patologia , Camundongos , Transplante de Neoplasias , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Piranos/síntese química , Piranos/química , Piranos/farmacologia , Relação Estrutura-Atividade , Tioxantenos/síntese química , Tioxantenos/química , Tioxantenos/farmacologia , Inibidores da Topoisomerase II , Células Tumorais CultivadasRESUMO
A series of novel N-[1-alkyl-4(1H)-pyridinylidene]alkylamine hydrohalides has been prepared and evaluated as inhibitors of dental plaque formation, in vitro. Several members of the series exhibited potency ca. 9-fold greater than that of chlorhexidine vs Streptococcus sobrinus 6715-13. The di-n-octyl analogue, 11 (pirtenidine), was found to be highly efficacious against several other oral plaque-forming microorganisms and is presently undergoing preclinical evaluation.
Assuntos
Actinomyces/efeitos dos fármacos , Aminopiridinas/farmacologia , Antibacterianos , Placa Dentária/microbiologia , Streptococcus/efeitos dos fármacos , Placa Dentária/prevenção & controle , Humanos , Testes de Sensibilidade MicrobianaRESUMO
The syntheses of 4-(2-phenyl-1H-indol-3-yl)cyclohexane-1-carboxylic acids are described. These compounds express potent in vitro inhibition of the human classical complement pathway, and qualitative SAR have been determined. Several of the in vitro active compounds also suppressed the complement dependent reverse passive Arthus reaction (RPAR) in guinea pigs.
Assuntos
Proteínas Inativadoras do Complemento/síntese química , Ácidos Cicloexanocarboxílicos/síntese química , Animais , Reação de Arthus , Via Clássica do Complemento/efeitos dos fármacos , Ácidos Cicloexanocarboxílicos/farmacologia , Cobaias , Hemólise , Humanos , Masculino , EstereoisomerismoRESUMO
A series of novel 3-quinolinecarboxylic acid derivatives have been prepared and their antibacterial activity evaluated. These derivatives are characterized by fluorine attached to the 6-position and substituted amino groups appended to the 1- and 7-positions. Structure-activity relationship studies indicate that antibacterial potency is greatest when the 1-substituent is methylamino and the 7-substituent is either 4-methyl-1-piperazinyl, 16, or 1-piperazinyl, 21. Derivatives 16 and 21, the 1-methylamino analogues of pefloxacin and norfloxacin, respectively, show comparable in vitro and in vivo antibacterial potency to these two known agents. The activity (vs. Escherichia coli Vogel) of 16 (amifloxacin) is the following: in vitro MIC (microgram/mL) = 0.25; in vivo (mice) PD50 (mg/kg) = 1.0 (po), 0.6 (sc).
