RESUMO
New platinum(II) complexes of cyclopentanecarboxylic acid hydrazide (cpcah) were prepared, characterized by elemental analysis, IR and 1H NMR spectra, and evaluated for in vitro cytotoxicity in Friend leukemia (FL) and A2780 ovarian tumor cells, induction of apoptosis in FL cells, as well as for in vivo antitumor activity toward murine L1210 leukemia and Lewis lung carcinoma. The spectral analyses indicated a cis-square planar structure of the complexes with hydrazide ligand coordinated via the NH2 group. The compounds exerted significantly lower in vitro and in vivo toxicities as compared with those of cisplatin (cis-diamminedichloroplatinum(II), DDP). On the other hand, the complex [Pt(NH3)(cpcah)Cl2] exhibited antitumor activity against L1210 leukemia in mice comparable to that of cisplatin, resulting at a dose of 42 mg/kg (administered 3 times) in a T/C (mean survival time) of 280%. This compound displayed an in vitro macromolecular synthesis inhibition pattern similar to that of DDP. At concentrations close to the cytostatic ones (10-20 microM) this complex, as well as DDP, was able to induce apoptosis in FL cells as shown by neutral comet assay and morphological analysis. We concluded that there is a correlation between the ability of platinum complexes to induce apoptosis and their antitumor activity.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ácidos Carboxílicos/química , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Cisplatino/química , Cisplatino/farmacologia , DNA de Neoplasias/biossíntese , DNA de Neoplasias/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração Inibidora 50 , Leucemia L1210/tratamento farmacológico , Leucemia Eritroblástica Aguda/tratamento farmacológico , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos , Compostos Organoplatínicos/química , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Biossíntese de Proteínas , Proteínas/efeitos dos fármacos , Espectrofotometria Infravermelho , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
New platinum (II) complexes of cyclohexanecarboxylic acid hydrazide (chcah) were synthesized and characterized by elemental analysis, IR, and 1H NMR spectra. Their inhibitory effects on cell growth and macromolecular synthesis of Friend leukemia cells in culture as well as the in vivo antitumor activity towards L1210 leukemia in mice were compared with those of complexes containing differently substituted aromatic acid hydrazides. Some of the complexes exhibited antineoplastic activity. No correlation between the in vivo cytotoxicity and the in vivo antitumor activity was found. However, there was a relationship between the in vitro macromolecular synthesis inhibition profile and the in vivo antineoplastic effect, similar to that of cisplatin. On the other hand, only agents containing one amine ligand were active in vivo. The substitution of the aromatic ring by a cycloalkane residue increased significantly the antitumor effect, with [Pt(NH3)(chcah)Cl2] being the most active compound in this study.
Assuntos
Antineoplásicos/toxicidade , Hidrazinas/farmacologia , Leucemia L1210/patologia , Leucemia Experimental/patologia , Compostos Organoplatínicos/toxicidade , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Divisão Celular/efeitos dos fármacos , DNA de Neoplasias/biossíntese , Hidrazinas/síntese química , Hidrazinas/química , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , Proteínas de Neoplasias/biossíntese , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , RNA Neoplásico/biossíntese , Relação Estrutura-Atividade , Células Tumorais CultivadasAssuntos
Antibacterianos/síntese química , Antineoplásicos/síntese química , Bactérias/efeitos dos fármacos , Ácido Orótico/síntese química , Animais , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Cromatografia em Camada Fina , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Leucemia L1210/tratamento farmacológico , Camundongos , Camundongos Endogâmicos , Ácido Orótico/farmacologia , Espectrofotometria Infravermelho , Espectrofotometria UltravioletaRESUMO
Antibacterial and antitumor activity of 10 platinum complexes of N3-phenylsubstituted amidrazones and hydrazinopyrimidines has been studied. It has been found that the platinum complexes of amidrazones, containing substituents in the benzene nuclear or in the NH2-group, exhibit a better antibacterial activity while those without substituents in their benzene nuclears have a pronounced antibacterial activity mostly on bacterial test-systems used in the prescreening of antitumor agents (S. lutea and UV-2). Most of the studid platinum complexes of hydrazinopyrimidines show inhibitory effect on the bacterial strains used in the prescreening of antitumor agents. The antitumor activity of platinum complexes has been tested on L1210 leukemia, adenocarcinoma 755 and Lewis carcinoma. An inhibitory effect is observed in the case of adenocarcinoma 755 with the cis-isomer of the platinum complex of N3-p-tolylbenzamidrazone (the tumor growth was 60% suppressed).
