RESUMEN
The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.
Asunto(s)
Acridonas/química , Antimaláricos/química , Acridonas/farmacocinética , Acridonas/farmacología , Acridonas/uso terapéutico , Administración Oral , Animales , Antimaláricos/farmacocinética , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Semivida , Células Hep G2 , Humanos , Estadios del Ciclo de Vida/efectos de los fármacos , Malaria/tratamiento farmacológico , Malaria/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/aislamiento & purificación , Relación Estructura-ActividadRESUMEN
Unsymmetrical bifunctional antitumor agent WMC79 was further optimized to generate compound 7b that not only inhibited the growth of many tumor cell lines, but caused rapid apoptosis. Unlike the parent compound, 7b is toxic to both p53 positive and negative cancer cells. It has potent in vivo activity against xenografts of human colon and pancreatic tumors in athymic mice.
Asunto(s)
Acridonas/síntesis química , Antineoplásicos/síntesis química , Naftalimidas/síntesis química , Acridonas/química , Acridonas/farmacocinética , Acridonas/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Desnudos , Naftalimidas/química , Naftalimidas/farmacocinética , Naftalimidas/farmacología , Trasplante de Neoplasias , Ratas , Relación Estructura-Actividad , Distribución Tisular , Trasplante Heterólogo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Triazoloacridinones (TA) are a new group of potent antitumor compounds, from which the most active derivative, C-1305, has been selected for extended preclinical trials. This study investigated the mechanism of TA binding to DNA. Initially, for selected six TA derivatives differing in chemical structures as well as cytotoxicity and antitumor activity, the capability of noncovalent DNA binding was analyzed. We showed that all triazoloacridinones studied stabilized the DNA duplex at a low-concentration buffer but not at a salt concentration corresponding to that in cells. DNA viscometric studies suggested that intercalation to DNA did not play a major role in the mechanism of the cytotoxic action of TA. Studies involving cultured cells revealed that triazoloacridinone C-1305 after previous metabolic activation induced the formation of interstrand crosslinks in DNA of some tumor and fibroblast cells in a dose dependent manner. However, the detection of crosslink formation was possible only when the activity of topoisomerase II in cells was lowered. Furthermore, it was impossible to validate the relevance of the ability to crosslink DNA to biological activity of TA derivatives.
