RESUMO
We have examined the biological activity of 12 platinum(II)-based DNA intercalators of the type [Pt(I(L))(A(L))](2+), where I(L) is an intercalating ligand (1,10-phenanthroline or a methylated derivative) and A(L) is an ancillary ligand (diaminocyclohexane, diphenylethylenediamine or 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine). The chiral compounds (1-9) and the racemic compounds (10-12) were tested against a panel of human cancer cell lines, with a number of complexes displaying activity significantly greater than that of cisplatin (up to 100-fold increase in activity in the A-427 cell line). The activity of the complexes containing diphenylethylenediamine (8 and 9) and 1,2-bis(4-fluorophenyl)-1,2-ethylenediamine (10-12) was significantly lower compared to the complexes containing diaminocyclohexane (1-7). Further in vitro testing, such as DNA unwinding, competition assays, and DNase 1 footprinting, was conducted on the most active compound (5) and its enantiomer (6) to provide information about the mechanism of action. These complexes display activity in cisplatin resistant cell lines, have higher cellular uptake than cisplatin, and do not activate caspase-3 as cisplatin does, indicating that these complexes exhibit a different mechanism of action.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Platina/química , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Sequência de Bases , Transporte Biológico , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Cristalografia por Raios X , DNA Super-Helicoidal/química , DNA Super-Helicoidal/genética , Desoxirribonuclease I/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Humanos , Ligantes , Dados de Sequência Molecular , Desnaturação de Ácido Nucleico/efeitos dos fármacos , Compostos Organometálicos/síntese química , Compostos Organometálicos/metabolismo , Relação Estrutura-Atividade , TemperaturaRESUMO
An in vivo study for determining the toxicity and efficacy of [Pt(S,S-dach)(phen)Cl(2).1.5H(2)O.0.5HCl (PHENSS) in female Specific Pathogen Free (SPF) Swiss nude mice bearing PC3 tumour xenografts revealed PHENSS to be non-toxic and effective in decreasing tumour growth.
Assuntos
Antineoplásicos/uso terapêutico , Compostos Organoplatínicos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intraperitoneais , Masculino , Dose Máxima Tolerável , Camundongos , Camundongos Nus , Estrutura Molecular , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/química , Organismos Livres de Patógenos Específicos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Four platinum(II) metallointercalating complexes of 1,10-phenanthroline (phen) with the chiral ancillary ligands trans-R,R- and trans-S,S-1,2-diaminocyclohexane (R,R- and S,S-dach, respectively), and N,N'-dimethyl-R,R- and N,N'-dimethyl-S,S-1,2-diaminocyclohexane (Me(2)-R,R-dach and Me(2)-S,S-dach, respectively) have been synthesised and characterised. The crystal structure of [Pt(Me(2)-S,S-dach)(phen)](ClO(4))(2)1.5 H(2)O (C(20)H(26)Cl(2)N(4)O(9.5)Pt) has been determined; orthorhombic, space group P2(1)2(1)2(1)(No. 19), a=23.194(8), b=25.131(9), c=8.522(3) A. In vitro cytotoxic assays (IC(50)) in the human bladder cancer cell line 5637 and in the murine leukemia L1210 cell line revealed that [Pt(S,S-dach)(phen)](ClO(4))(2) (0.091 and 0.13 microM, respectively) and [Pt(R,R-dach)(phen)](ClO(4))(2) (0.54 and 1.50 microM, respectively) were more cytotoxic than cisplatin (0.31 and 0.50 microM, respectively) and considerably more cytotoxic than their methylated counterparts, [Pt(Me(2)-R,R-dach)(phen)](ClO(4))(2) and [Pt(Me(2)-S,S-dach)(phen)](ClO(4))(2) (both>23 microM). Chiral discrimination for [Pt(S,S-dach)(phen)](ClO(4))(2) over its R,R-enantiomer was observed in all 13 cancer cell lines investigated. Moreover, [Pt(S,S-dach)(phen)](ClO(4))(2) was more active than cisplatin in all cell lines tested and shows only partial cross-resistance to cisplatin in two cisplatin resistant cell lines.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Substâncias Intercalantes/síntese química , Compostos de Platina/síntese química , Compostos de Platina/farmacologia , Linhagem Celular Tumoral , Humanos , Substâncias Intercalantes/farmacologia , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A platinum metal complex in which terpyridine joins estradiol (via an ethynyl link) to a platinum with a labile ligand (chloride) has been designed, synthesised and its X-ray crystal structure determined. The aim of this work was to link a targeting motif (in this case estrogen) to a metal-based biomolecule recognition unit (the platinum moiety). The target molecule: 17alpha-[4'-ethynyl-2,2':6',2'-terpyridine]-17beta-estradiol platinum(II) chloride (PtEEtpy) has been shown to bind to both human and bovine serum albumin (SA) and to DNA. FTICR mass spectrometry shows that the bimolecular units are in each case linked through coordination to the platinum with displacement of the chloride ligand. Circular dichroism indicates that a termolecular entity involving PtEEtpy, SA and DNA is formed. A range of electrospray mass spectrometry experiments showed that the PtEEtpy complex breaks and forms coordination bonds relatively easily. A whole cell estrogen receptor assay in an estrogen receptor positive cell (MCF-7) confirms binding of both EEtpy and PtEEtpy to the estrogen receptor in cells. The work demonstrates the concept of linking a targeting moiety (in this case estrogen) to a DNA binding agent.