RESUMO
2-Acetyl-(6-picolyl)-4N-substituted thiosemicarbazones and their copper(II) complexes were shown to be potent antineoplastic and cytotoxic agents against murine and human cultured cells. Numerous derivatives were as active against solid tumor growth as clinically useful agents. The agents inhibited L1210 DNA and RNA syntheses with inhibition of key regulatory enzyme activities of the purine pathway as well as nucleoside kinase activities. d[NTP] pools were reduced and DNA strand scission occurred. These agents were DNA topoisomerase II inhibitors with lower IC50 values than that of VP-16. However, they did not cause L1210 DNA protein linked breaks and actually protected against those breaks afforded by VP-16. The agents were not synergistic with VP-16 in reducing cell growth or DNA synthesis although they did reduce growth of L1210 cells in agar suspended media.
Assuntos
Cobre/química , Tiossemicarbazonas/toxicidade , Animais , Antineoplásicos/toxicidade , Divisão Celular/efeitos dos fármacos , Dano ao DNA/genética , Replicação do DNA/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Etoposídeo/farmacologia , Humanos , Camundongos , Estrutura Molecular , Fosfotransferases/antagonistas & inibidores , Inibidores da Topoisomerase II , Células Tumorais CultivadasRESUMO
A series of 2-acetyl-pyridyl-4N-substituted thiosemicarbazones copper(II) complexes was evaluated for their cytotoxic mode of action in a variety of human and rodent tumor cell cultures. It was determined that these compounds may induce cytotoxicity by affecting several metabolic pathways including a reduction in de novo purine synthesis, and inhibition of IMP dehydrogenase, and DNA polymerase alpha activities. Selected compounds also demonstrated the ability to inhibit L1210 DNA topoisomerase II activity at micromolar concentrations. These agents were able to antagonize etoposide-induced formation of cleavable complexes as measured by K+/SDS precipitation and in vitro cleavage reactions.
