RESUMO
In this study, we have investigated the genotoxic, cytostatic, antineoplastic and apoptotic effects of three newly synthesized modified steroidal esters, having as alkylating agent p-N,N-bis(2-chloroethyl) aminophenyl butyrate (CHL) or p-N,N-bis(2-chloroethyl) aminophenyl acetate (PHE) esterified with the steroidal nucleus modified in the B- and D-ring. The genotoxic and cytotoxic effects of the compounds were investigated both in vitro, in lymphocyte cultures obtained from blood samples of healthy donors and in vivo, in ascites cells of P388 leukemia obtained from the peritoneal cavity of DBA/2 mice. Preparations were scored for sister-chromatid exchange (SCE) and proliferation-rate indices (PRI). The newly synthesized compounds were also studied for antineoplastic activity against lymphocytic P388 and lymphoid L1210 leukemias in mice, by calculating the mean of the median survival of the drug-treated animals (T) versus the untreated control (C) (T/C%). The activity of caspase-2 and caspase-3, indicators of apoptosis, was assessed biochemically in primary cultures of human lymphocytes. Our results show that the newly synthesized compounds caused severe genotoxic effects by significantly increasing the frequency of SCE and decreasing the PRI values in cultures of peripheral lymphocytes in vitro and in ascites cells of lymphocytic P388 leukemia in vivo. A significant correlation was also observed in both the in vitro and in vivo experiments: the higher the SCE frequency the lower the PRI value (r=-0.65, P<0.001 and r=-0.99, P<0.01, respectively). The measured antileukemic potency was statistically increased by all test compounds in both types of tumours, while the activity of caspase-2 and caspase-3 showed a statistically significant increase after two periods of exposure. The genotoxic (increase of SCE), cytostatic/cytotoxic (decrease of PRI) and antileukemic effects (increase of T/C%) in combination with the induction of apoptosis (activation of caspase-2 and caspase-3) caused by the newly synthesized compounds, lead us to propose them as agents with potentially antineoplastic properties.
Assuntos
Androsterona/análogos & derivados , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Azasteroides/farmacologia , Citostáticos/farmacologia , Compostos de Mostarda Nitrogenada/farmacologia , Esteroides/farmacologia , Androsterona/síntese química , Androsterona/química , Androsterona/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Ascite/genética , Ascite/metabolismo , Ascite/patologia , Azasteroides/síntese química , Azasteroides/química , Caspase 2/metabolismo , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citostáticos/síntese química , Citostáticos/química , Ensaios de Seleção de Medicamentos Antitumorais , Ésteres , Feminino , Humanos , Leucemia L1210/patologia , Leucemia L1210/prevenção & controle , Leucemia P388/patologia , Leucemia P388/prevenção & controle , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Estrutura Molecular , Testes de Mutagenicidade , Compostos de Mostarda Nitrogenada/síntese química , Compostos de Mostarda Nitrogenada/química , Troca de Cromátide Irmã/efeitos dos fármacos , Esteroides/síntese química , Esteroides/química , Análise de SobrevidaRESUMO
A series of new mixed-ligand neutral copper(II) complexes of the general type [Cu(amine)(i-MNT)] and [Cu(tz)(i-MNT)] was prepared and characterized by elemental, spectroscopic methods, mu(eff), Lambda(mu) measurements and molecular modeling studies. The acute toxicity, the cytogenetic and the in vivo antitumor activity of the new complexes, is related to their chemical and physicochemical properties. Among the Cu(II) compounds tested the complex with 2-amino-5-methyl thiazole increases significantly the life span of leukemia P388 bearing mice in vivo.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cobre/química , Compostos Organometálicos/síntese química , Compostos Organometálicos/farmacologia , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Animais , Antineoplásicos/síntese química , Feminino , Humanos , Leucemia P388/tratamento farmacológico , Ligantes , Linfócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Modelos Moleculares , Compostos Organometálicos/química , Troca de Cromátide Irmã/efeitos dos fármacos , Espectrofotometria Infravermelho , Relação Estrutura-Atividade , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologiaRESUMO
Quinones are of significant interest due to their important role in specific cellular functions. Quinoproteins are a big class of oxyreductive agents occurring in bacteria and other organisms. In this investigation derivatives of 2-amino-1,4-benzoquinone, 2-amino-1,4-naphthoquinone and 2-amino-5,8-dihydroxy-1,4-naphthoquinone with a di- and a tripeptide were prepared for first time. The effect of the synthesized compounds on sister chomatid exchange (SCE) rates and human lymphocyte proliferation kinetics on a molar basis was studied. Among these coupled products the most effective in inducing SCEs and depressing proliferation rate indices is the coupling product of 2-amino-1,4-naphthoquinone with the tripeptide GHK (10). Next in order of magnitude in inducing cytogenetic effects is 2-amino-1,4-naphthoquinone (2) and its coupling products with glycine and serine (4 and 5), while the rest displayed marginal activity.
Assuntos
Benzoquinonas/síntese química , Benzoquinonas/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/farmacologia , Oligopeptídeos/química , Troca de Cromátide Irmã/efeitos dos fármacos , Dano ao DNA , Reparo do DNA , Humanos , Linfócitos/ultraestrutura , Metáfase/efeitos dos fármacosRESUMO
The effect of six novel complexes of Pt(II) and Pd(II) with pyridine-2-carboxyaldehyde thiosemicarbazone (HPyTsc) on sister chromatid exchange rate and human lymphocyte proliferation kinetic was studied. Also, the effect of Pt(II) and Pd(II) complexes against leukemia P388 was investigated. Among these compounds, the most effective in inducing cytogenetic and antineoplastic effects are the complexes [Pd(PyTsc)2] and [Pt(PyTsc)2]. Next in order of magnitude in inducing antineoplastic and cytogenetic effects is the compound [Pt(HPyTsc)2]Cl2 while the rest, i.e. [Pd(PyTsc)Cl], HPyTsc, [Pd(HPyTsc)2]Cl2, and [Pt(PyTsc)Cl], show marginal cytogenetic and antineoplastic effects.
Assuntos
Antineoplásicos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Compostos Organoplatínicos/farmacologia , Paládio/farmacologia , Troca de Cromátide Irmã/efeitos dos fármacos , Tiossemicarbazonas/farmacologia , Animais , Feminino , Humanos , Leucemia P388/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Paládio/química , Tiossemicarbazonas/químicaRESUMO
The effect of novel Pd(II) complexes with derivatives of 2-acetyl-pyridinethisemicarbazone, N4-ethyl (HAc4Et) and 3-hexamethyleneiminylthiosemicarbazone (HAchexim), on Sister Chromatid Exchange (SCE) rates and human lymphocyte proliferation kinetics was studied. Also, the effect of Pd(II) complexes on DNA synthesis of P388 and L1210 cell cultures and against Leukemia P388 was investigated. Among these compounds, the compound Bis(3-hexamethyleneiminyl-2-acetylpyridine-thisemicarbazonato++ +) palladium (II) was found to be distinctly effective against Leukemia P388, in inhibiting incorporation of 3H-thymidine into DNA and in inducing SCEs and cell division delays.