RESUMO
A series of pyrimidoquinazoline analogues, possessing either 4,5-g or 5,4-g fusion, were studied with respect to cytotoxicity, topoisomerase II inhibitory activity, in vivo activity, and DNA cleavage and DNA-protein cross-linking properties. These analogues were designed as electron-deficient anthraquinones with dual alkylating centers to cross-link DNA with topoisomerase II. Our studies verified the presence of DNA-protein cross-linking in vitro as well as topoisomerase II poisoning by pyrimidoquinazoline analogues. In addition, COMPARE analysis revealed that the pyrimidoquinazolines possess inhibitory activity against both topoisomerase II and protein kinases, such as the paullones, a dual property observed in other antineoplastic agents influencing phosphoester transfer.
Assuntos
Antineoplásicos/síntese química , Reagentes de Ligações Cruzadas/síntese química , DNA/química , Inibidores Enzimáticos/síntese química , Inibidores de Proteínas Quinases , Quinazolinas/síntese química , Inibidores da Topoisomerase II , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Reagentes de Ligações Cruzadas/química , Reagentes de Ligações Cruzadas/farmacologia , DNA Topoisomerases Tipo II/química , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Quinazolinas/química , Quinazolinas/farmacologia , Solubilidade , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
AMP-activated protein kinase (AMPK) is a heterotrimeric kinase that regulates cellular energy metabolism by affecting energy-consuming pathways such as de novo lipid biosynthesis and glucose production as well as energy-producing pathways such as lipid oxidation and glucose uptake. Accordingly, compounds that activate AMPK represent potential drug candidates for the treatment of hyperlipidemia and type 2 diabetes. Screening of a proprietary library of AMP mimetics identified the phosphonic acid 2 that bears little structural resemblance to AMP but is capable of activating AMPK with high potency (EC50 = 6 nM vs AMP EC50 = 6 µM) and specificity. Phosphonate prodrugs of 2 inhibited de novo lipogenesis in cellular and animal models of hyperlipidemia.