RESUMO
We studied the effects of some aniline and dioxaborininopyridine derivatives on the rate of oxidative deamination of putrescine and polyamines in a tissue with high mitotic index. These effects were evaluated quantitatively by measuring diamine oxidase and polyamine oxidase activities in a model cell-free test system of regenerating rat liver tissue. Aniline derivatives exhibited mainly antiproliferative effects and promoted oxidative degradation of putrescine, spermidine, and spermine. Dioxaborininopyridine derivatives inhibited this process, thus exhibiting carcinogenic properties.
Assuntos
Amina Oxidase (contendo Cobre)/química , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Carcinógenos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/química , Piridinas/farmacologia , Compostos de Anilina/síntese química , Animais , Antineoplásicos/síntese química , Compostos de Boro/síntese química , Carcinógenos/síntese química , Sistema Livre de Células/química , Sistema Livre de Células/efeitos dos fármacos , Sistema Livre de Células/metabolismo , Ensaios Enzimáticos , Cinética , Fígado/química , Fígado/metabolismo , Regeneração Hepática , Masculino , Oxirredução , Putrescina/química , Piridinas/síntese química , Ratos , Espermidina/química , Espermina/química , Relação Estrutura-Atividade , Poliamina OxidaseRESUMO
In vitro immunohistochemical investigations on the human hepatoma cell line (Huh7) infected with hepatitis C virus (HCV) strain JFH-1 showed that AV0012 compound blocks the early stages of viral infection. AV0012 also blocked viral infection spread in tissue culture through the secreted virus and through tight cell-to-cell contact. AV0012 is a specific inhibitor of HCV but not of related pestivirus, flaviviruses and other RNA-containing viruses such as bovine diarrhea (BVDV), Venezuelan equine encephalitis (strain TC-83), dengue type 2 (New Guinea), yellow fever (strain 17D), west Nile fever, parainfluenza (type 3) virus, RSV (strain A2), and Rhinovirus (type 2 strain HGP). It is established that human serum does not significantly affect the antiviral activity of AV0012 in vitro. The drug combination studies with AV0012 and interferon alpha 2a in vitro showed that the two inhibitors act additively, which makes possible the use of this combination in clinical tests. AV0012 is highly soluble and stable in aqueous solutions and murine blood plasma, has limited metabolic stability, low binding to human plasma proteins, high permeability through biological membranes, and only interacts with isoenzymes 2D6 and 3A4 of human cytochrome P450. In animal pharmacokinetic studies, AV0012 was rapidly absorbed into the blood stream upon oral administration, showed sufficiently long half-elimination times, and had high oral bioavailability that reached 92% in monkeys. Further preclinical development of AV0012 is in progress.