RESUMO
The allylthio group of allicin and other organosulfur compounds, isolated from garlic, is considered a pharmacophore, and a key structure component of the molecule, which affords biological activities. In the foregoing studies, various 3-alkoxy-6-allylthiopyridazine derivatives (K-compounds) were synthesized, and their biological activities tested in animals. As expected, the various derivatives showed good hepatoprotective activities on carbon tetrachloride-treated mice and aflatoxin B1-treated rats, and chemopreventive activities on hepatocarcinoma cells in rats. Other new pyridazine derivatives, with the oxygen atom at the 3-position of the 3-alkoxy-6-allylthiopyridazine displaced by sulfur (S), were synthesized, and their activities tested in vitro. Thio-K6, one of the sulfur-substituted compounds, showed better chemopreventive activity toward hepatocarcinoma cells.
Assuntos
Antineoplásicos/síntese química , Piridazinas/síntese química , Ácidos Sulfínicos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dissulfetos , Relação Dose-Resposta a Droga , Humanos , Neoplasias Hepáticas/patologia , Piridazinas/química , Piridazinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Numerous studies have revealed the chemopreventive and hepatoprotective activities of dietary and synthetic organosulfur compounds. We previously showed that synthetic allylthiopyridazine derivatives, designated as K compounds, induced apoptosis in SK-Hep-1 hepatocarcinoma cells. In order to extend our program to pursue the chemopreventive potential of these compounds, we investigated the effects of the K compounds on invasive and migrative properties of the SK-Hep-1 cells in this study. Here, we show that 3-methoxy-6-allylthiopyridazine (K6) and 3-propoxy-6-allylthiopyridazine (K17) efficiently inhibit SK-Hep-1 cell invasion and migration. A prominent downregulation of matrix metalloproteinase (MMP)-2, but not MMP-9, was observed, presenting MMP-2 as a potential target molecule for the anti-invasive and anti-migrative activities of the compounds. Since hepatocarcinoma is characterized as a hypervascular tumor, we examined the effect of the compounds on angiogenesis of human umbilical vein endothelial cells (HUVECs). The K compounds exerted anti-angiogenic activity, supporting that the development of these compounds would be a promising approach for treatment of hepatocarcinoma. Taken in conjunction with the fact that hepatocellular carcinoma is one of the most lethal malignancies, our findings may be critical to the chemopreventive potential of these synthetic organosulfur compounds for hepatocarcinoma.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neovascularização Patológica , Piridazinas/farmacologia , Anticarcinógenos/farmacologia , Western Blotting , Linhagem Celular Tumoral , Movimento Celular , Células Cultivadas , Relação Dose-Resposta a Droga , Regulação para Baixo , Endotélio Vascular/citologia , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Modelos Químicos , Invasividade Neoplásica , Sais de Tetrazólio/farmacologia , Tiazóis/farmacologia , Fatores de Tempo , Veias Umbilicais/citologia , CicatrizaçãoRESUMO
Five kinds of allylthiopyridazine derivatives were synthesized and their chemoprotective activities examined in rats exposed to aflatoxin B1-toxicant. Rats were pretreated with five allylthiopyridazine derivatives at daily oral doses of 50 mg/kg for 10 consecutive days, and during this period with one or three repeated doses of the potent hepatotoxin, aflatoxin B1. The hepatoprotective effects of the allylthiopyridazine derivatives against aflatoxin B1 (1 mg/kg, three times at intervals of 3 days, i.p., or at 3 mg/kg, once at final days, i.p.) administration were showed the significantly normal as compared with control in body and liver weights. Aspartate aminotransferase and alanine aminotransferase levels were markedly elevated after aflatoxin B1 administration, and pretreatment with allylthiopyridazine derivatives, before aflatoxin B1 administration, resulted in decreased levels of these enzymes. In addition, the allylthiopyridazine derivatives, K6 (3-methoxy-), K8 (3-chloro-), K16 (3-ethoxy-) and K17 (3-n-propoxy), induced elevated hepatic GSH levels. Four kinds of allylthiopyridazine derivatives investigated were effective against aflatoxin B1-induced hepatotoxicity.