RESUMO
Distamycin, a natural polyamide containing three heterocycle rings with a polar end, has inspired several groups to prepare synthetic analogues, which proved to have anti-trypanosomal and anti-tumoral activity. We describe the synthesis of bi and tri thiazoles amides that harbor different substitutions at their ends and the evaluation of their anti-Trypanosoma brucei activity. The most active compound 10b showed better biological activity (EC50 310 nM and selectivity index 16) than the control drug nifurtimox (EC50 15 µM and selectivity index 10). Studies on the mode of action show that the parasiticidal activity of 10b originates from disruption of lysosomal homeostasis, which is followed by release of redox active iron, an increase in oxidizing species and collapse of cell membrane integrity. In this respect, our study suggests that non-charged lipophylic distamycins destabilize cell membranes.
Assuntos
Distamicinas/farmacologia , Tripanossomicidas/química , Trypanosoma/efeitos dos fármacos , África , Antineoplásicos/química , Antineoplásicos/farmacologia , Membrana Celular/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Tiazóis/síntese química , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacosRESUMO
We have studied the protonation equilibria of a dicopper(II) complex [Cu(2)(micro-OH)(C(21)H(33)ON(6))](ClO(4))(2).H(2)O, (1), in aqueous solution, its interactions with DNA, its cytotoxic activity, and its uptake in tumoral cells. C(21)H(33)ON(6) corresponds to the ligand 4-methyl-2,6-bis[(6-methyl-1,4-diazepan-6-yl)iminomethyl]phenol. From spectrophotometric data the following pKa values were calculated 3.27, 4.80 and 6.10. Complex 1 effectively promotes the hydrolytic cleavage of double-strand plasmid DNA under anaerobic and aerobic conditions. The following kinetic parameters were calculated k(cat) of 2.73 x 10(-4)s(-1), K(M) of 1.36 x 10(-4)M and catalytic efficiency of 2.01 s(-1)M(-1), a 2.73 x 10(7) fold increase in the rate of the reaction compared to the uncatalyzed hydrolysis rate of DNA. Competition assays with distamycin reveal minor groove binding. Complex 1 inhibited the growth of two tumoral cell lines, GLC4 and K562, with the IC(50) values of 14.83 microM and 34.21 microM, respectively. There is a good correlation between cell growth inhibition and intracellular copper content. When treated with 1, cells accumulate approximately twice as much copper as with CuCl(2). Copper-DNA adducts are formed inside cells when they are exposed to the complex. In addition, at concentrations that compound 1 inhibits tumoral cell growth it does not affect macrophage viability. These results show that complex 1 has a good therapeutic prospect.
Assuntos
Antineoplásicos/farmacologia , Cobre , Clivagem do DNA/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Compostos Organometálicos/farmacologia , Animais , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Adutos de DNA/química , Adutos de DNA/metabolismo , Distamicinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Feminino , Humanos , Células K562 , Cinética , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Neoplasias/metabolismo , Compostos Organometálicos/químicaRESUMO
Hydrolysis of DNA is of increasing importance in biotechnology and medicine. In this Letter, we present the DNA-cleavage potential of metal-free hydroxylamines and oximes as new members of nucleic acid cleavage agents.