RESUMO
It is generally accepted that adjacent guanine residues in DNA are the primary target for platinum antitumor drugs and that differences in the conformations of the Pt-DNA adducts can play a role in their antitumor activity. In this study, we investigated the effect of the carrier ligand cis-1,3-diaminocyclohexane (cis-1,3-DACH) upon formation, stability, and stereochemistry of the (cis-1,3-DACH)PtG2 and (cis-1,3-DACH)Pt(d(GpG)) adducts (G = 9-EthlyGuanine, guanosine, 5'- and 3'-guanosine monophosphate; d(GpG) = deoxyguanosil(3'-5')deoxyguanosine). A peculiar feature of the cis-1,3-DACH carrier ligand is the steric bulk of the diamine, which is asymmetric with respect to the Pt-coordination plane. The (cis-1,3-DACH)Pt(5'GMP)2 and (cis-1,3-DACH)Pt(3'GMP)2 adducts show preference for the ΛHT and ∆HT conformations, respectively (HT stands for Head-to-Tail). Moreover, the increased intensity of the circular dichroism signals in the cis-1,3-DACH derivatives with respect to the analogous cis-(NH3)2 species could be a consequence of the greater bite angle of the cis-1,3-DACH carrier ligand with respect to cis-(NH3)2. Finally, the (cis-1,3-DACH)Pt(d(GpG)) adduct is present in two isomeric forms, each one giving a pair of H8 resonances linked by a NOE cross peak. The two isomers were formed in comparable amounts and had a dominance of the HH conformer but with some contribution of the ΔHT conformer which is related to the HH conformer by having the 3'-G base flipped with respect to the 5'-G residue.
Assuntos
Adutos de DNA , DNA , Oxaliplatina , DNA/química , DNA/metabolismo , Adutos de DNA/química , Oxaliplatina/química , Oxaliplatina/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Ligantes , Modelos Moleculares , Conformação de Ácido NucleicoRESUMO
The year 2023 marks the 45th year since FDA approval of cisplatin as an anticancer drug, and, at present, it is widely used against a spectrum of human tumors, including early-stage ovarian cancer, non-small cell lung cancer (typically developed by smokers), head and neck, and advanced bladder cancer [...].
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias de Cabeça e Pescoço , Neoplasias Pulmonares , Neoplasias da Bexiga Urinária , Humanos , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Kiteplatin, [PtCl2(cis-1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxaliplatin diamine ligand trans-1R,2R-DACH and has been proposed as a valuable drug candidate against cisplatin- and oxaliplatin-resistant tumors, in particular, colorectal cancer. To further improve the activity of kiteplatin, it has been transformed into a Pt(IV) prodrug by the addition of two benzoato groups in the axial positions. The new compound, cis,trans,cis-[PtCl2(OBz)2(cis-1,4-DACH)] (1; OBz = benzoate), showed cytotoxic activity at nanomolar concentration against a wide panel of human cancer cell lines. Based on these very promising results, the investigation has been extended to the in vivo activity of compound 1 in a Lewis Lung Carcinoma (LLC) model and its suitability for oral administration. Compound 1 resulted to be remarkably stable in acidic conditions (pH 1.5 to mimic the stomach environment) undergoing a drop of the initial concentration to ~60% of the initial one only after 72 h incubation at 37 °C; thus resulting amenable for oral administration. Interestingly, in a murine model (2·106 LLC cells implanted i.m. into the right hind leg of 8-week old male and female C57BL mice), a comparable reduction of tumor mass (~75%) was observed by administering compound 1 by oral gavage and the standard drug cisplatin by intraperitoneal injection, thus indicating that, indeed, there is the possibility of oral administration for this dibenzoato prodrug of kiteplatin. Moreover, since the mechanism of action of Pt(IV) prodrugs involves an initial activation by chemical reduction to cytotoxic Pt(II) species, the reduction of 1 by two bioreductants (ascorbic acid/sodium ascorbate and glutathione) was investigated resulting to be rather slow (not complete after 120 h incubation at 37 °C). Finally, the neurotoxicity of 1 was evaluated using an in vitro assay.
Assuntos
Antineoplásicos , Neoplasias , Pró-Fármacos , Administração Oral , Animais , Antineoplásicos/uso terapêutico , Cisplatino/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos , Oxaliplatina/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologiaRESUMO
Two new Pt(II)-pyrophosphato complexes containing the carrier ligands cis-1,3-diaminocyclohexane (cis-1,3-DACH) and trans-1,2-diamine-4-cyclohexene (1,2-DACHEX), variants of the 1R,2R-diaminocyclohexane ligand present in the clinically used Pt-drug oxaliplatin, have been synthesized with the aim of developing new potential antitumor drugs with high bone tropism. The complexes are more stable at physiological pH than in acid conditions, with Na2[Pt(pyrophosphato)(cis-1,3-DACH)] (1) slightly more stable than [Pt(dihydrogenpyrophosphato)(1,2-DACHEX)] (2). The greater reactivity at acidic pH ensures a greater efficacy at the tumor site. Preliminary NMR studies indicate that 1 and 2 react slowly with 5'-GMP (used as a model of nucleic acids), releasing the pyrophosphate ligand and affording the bis 5'-GMP adduct. In vitro cytotoxicity assays performed against a panel of four human cancer cell lines have shown that both compounds are more active than oxaliplatin. Flow cytometry studies on HCT116 cells showed that the pyrophosphato compounds with the non-classical 1,3- and 1,4-diaminocyclohexane ligands (1 and 4) are the most capable to induce cells' death by apoptosis and necrosis.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Compostos Organoplatínicos/farmacologia , Oxaliplatina/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células HCT116 , Humanos , Concentração de Íons de Hidrogênio , Masculino , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Células PC-3RESUMO
The search for more effective platinum anticancer drugs has led to the design, synthesis, and preclinical testing of hundreds of new platinum complexes. This search resulted in the recognition and subsequent FDA approval of the third-generation Pt(II) anticancer drug, [Pt(1,2-diaminocyclohexane)(oxalate)], oxaliplatin, as an effective agent in treating colorectal and gastrointestinal cancers. Another promising example of the class of anticancer platinum(II) complexes incorporating the Pt(1,n-diaminocycloalkane) moiety is kiteplatin ([Pt(cis-1,4-DACH)Cl2], DACH = diaminocyclohexane). We report here our progress in evaluating the role of the cycloalkyl moiety in these complexes focusing on the synthesis, characterization, evaluation of the antiproliferative activity in tumor cells and studies of the mechanism of action of new [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes wherein the cis-1,3-diaminocycloalkane group contains the cyclobutyl, cyclopentyl, and cyclohexyl moieties. We demonstrate that [Pt(cis-1,3-DACH)Cl2] destroys cancer cells with greater efficacy than the other two investigated 1,3-diamminocycloalkane derivatives, or cisplatin. Moreover, the investigated [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes show selectivity toward tumor cells relative to non-tumorigenic normal cells. We also performed several mechanistic studies in cell-free media focused on understanding some early steps in the mechanism of antitumor activity of bifunctional platinum(II) complexes. Our data indicate that reactivities of the investigated [Pt(cis-1,3-diaminocycloalkane)Cl2] complexes and cisplatin with glutathione and DNA binding do not correlate with antiproliferative activity of these platinum(II) complexes in cancer cells. In contrast, we show that the higher antiproliferative activity in cancer cells of [Pt(cis-1,3-DACH)Cl2] originates from its highest hydrophobicity and most efficient cellular uptake.
Assuntos
Antineoplásicos/síntese química , Hidrocarbonetos Cíclicos/síntese química , Compostos Organometálicos/síntese química , Platina/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Cisplatino/normas , DNA/química , Ensaios de Seleção de Medicamentos Antitumorais , Glutationa/química , Humanos , Compostos Organometálicos/farmacologiaRESUMO
Six platinum(IV) compounds derived from an oxaliplatin analogue containing the unsaturated cyclic diamine trans-1,2-diamino-4-cyclohexene (DACHEX), in place of the 1,2-diaminocyclohexane, and a range of axial ligands, were synthesized and characterized. The derivatives with at least one axial chlorido ligand demonstrated solvent-assisted photoreduction. The electrochemical redox behavior was investigated by cyclic voltammetry; all compounds showed reduction potentials suitable for activation in vivo. X-ray photoelectron spectroscopy (XPS) data indicated an X-ray-induced surface reduction of the Pt(IV) substrates, which correlates with the reduction potentials measured by cyclic voltammetry. The cytotoxic activity was assessed in vitro on a panel of human cancer cell lines, also including oxaliplatin-resistant cancer cells, and compared with that of the reference compounds cisplatin and oxaliplatin; all IC50 values were remarkably lower than those elicited by cisplatin and somewhat lower than those of oxaliplatin. Compared to the other Pt(IV) compounds of the series, the bis-benzoate derivative was by far (5-8 times) the most cytotoxic showing that low reduction potential and high lipophilicity are essential for good cytotoxicity. Interestingly, all the complexes proved to be more active than cisplatin and oxaliplatin even in three-dimensional spheroids of A431 human cervical cancer cells.
Assuntos
Antineoplásicos/química , Cicloexenos/química , Compostos Organoplatínicos/química , Oxaliplatina/análogos & derivados , Pró-Fármacos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/química , Cisplatino/farmacologia , Cicloexenos/síntese química , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/farmacologia , Oxaliplatina/química , Oxaliplatina/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologiaRESUMO
Platinum(II) drugs are activated intracellularly by aquation of the leaving groups and then bind to DNA, forming DNA adducts capable to activate various signal-transduction pathways. Mostly explored in recent years are Pt(IV) complexes which allow the presence of two additional ligands in the axial positions suitable for the attachment of other cancer-targeting ligands. Here we have extended this strategy by coordinating in the axial positions of kiteplatin ([PtCl2(cis-1,4-DACH)], DACH = Diaminocyclohexane) and its CBDCA (1,1-cyclobutanedicarboxylate) analogue the antioxidant α-Lipoic acid (ALA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK). The new compounds (cis,trans,cis-[Pt(CBDCA)(ALA)2(cis-1,4-DACH)], 2, and cis,trans,cis-[PtCl2(ALA)2(cis-1,4-DACH)], 3), after intracellular reduction, release the precursor Pt(II) species and two molecules of ALA. The Pt residue is able to target DNA, while ALA could act on mitochondria as activator of the pyruvate dehydrogenase complex, thus suppressing anaerobic glycolysis. Compounds 2 and 3 were tested in vitro on a panel of five human cancer cell lines and compared to cisplatin, oxaliplatin, and kiteplatin. They proved to be much more effective than the reference compounds, with complex 3 most effective in 3D spheroid tumor cultures. Notably, treatment of human A431 carcinoma cells with 2 and 3 did not determine increase of cellular ROS (usually correlated to inhibition of mitochondrial PDK) and did not induce a significant depolarization of the mitochondrial membrane or alteration of other morphological mitochondrial parameters.
Assuntos
Mitocôndrias/metabolismo , Compostos Organoplatínicos/metabolismo , Platina/metabolismo , Pró-Fármacos/metabolismo , Ácido Tióctico/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/química , Cisplatino/metabolismo , Cisplatino/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Mitocôndrias/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Estrutura Molecular , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Platina/química , Platina/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ácido Tióctico/química , Ácido Tióctico/farmacologiaRESUMO
Two new Pt(II) derivatives of kiteplatin ([PtCl2(cis-1,4-DACH)]) with pyrophosphate as carrier ligand, one mononuclear (1) and one dinuclear (2), were synthesized with the aim of potentiating the efficacy of kiteplatin. Complex 1 resulted to be remarkably stable at physiological pH, but it undergoes a fast hydrolysis reaction at acidic pH releasing free pyrophosphate and (aquated) kiteplatin. The dinuclear compound 2 resulted to be less stable than 1 at both neutral and acidic pH forming 1 and (aquated) kiteplatin as first step. Both compounds (1 and 2) do not react as such with 5'-GMP, whereas their hydrolysis products readily form adducts with the nucleotide. The in vitro cytotoxicity assays against a panel of six human cancer cell lines showed that complex 2 affects cancer cell viability even at nanomolar concentrations. The cytotoxic activity of 2 is greater (up to 2 orders of magnitude) than that of cisplatin, oxaliplatin, and kiteplatin, whereas the mononuclear complex 1 has shown a cytotoxic activity comparable to that of oxaliplatin and kiteplatin, but higher than cisplatin. The latter result is not surprising, since the presence of two negative charges reduces the uptake of 1 into the tumor cells as compared to the neutral compound 2. The remarkable activity of 2 against the pancreatic cell line BxPC3 (average IC50 = 0.07 µM) deserves further investigation.
Assuntos
Antineoplásicos/farmacologia , Difosfatos/farmacologia , Compostos Organoplatínicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Difosfatos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Relação Estrutura-AtividadeRESUMO
The immediate visual comparison of platinum chemotherapeutics' effects in eukaryotic cells using accessible plant models of transgenic Arabidopsis thaliana is reported. The leading anticancer drug cisplatin, a third generation drug used for colon cancer, oxaliplatin and kiteplatin, promising Pt-based anticancer drugs effective against resistant lines, were administered to transgenic A. thaliana plants monitoring their effects on cells from different tissues. The transgenic plants' cell cytoskeletons were labelled by the green fluorescent protein (GFP)-tagged microtubule-protein TUA6 (TUA6-GFP), while the vacuolar organization was evidenced by two soluble chimerical GFPs (GFPChi and AleuGFP) and one transmembrane GFP-tagged tonoplast intrinsic protein 1-1 (TIP1.1-GFP). The three drugs showed easily recognizable effects on plant subcellular organization, thereby providing evidence for a differentiated drug targeting. Genetically modified A. thaliana are confirmed as a possible rapid and low-cost screening tool for better understanding the mechanism of action of human anticancer drugs.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Compostos Organoplatínicos/farmacologia , Células Vegetais/efeitos dos fármacos , Células Vegetais/metabolismo , Arabidopsis , Transporte Biológico/efeitos dos fármacos , Citoesqueleto/metabolismo , Expressão Gênica , Genes Reporter , Complexo de Golgi/efeitos dos fármacos , Complexo de Golgi/metabolismo , Oxaliplatina , Plantas Geneticamente Modificadas , Vacúolos/metabolismoRESUMO
Signal transducer and activator of transcription 3 (STAT3) has been implicated as a hub for multiple oncogenic pathways. The constitutive activation of STAT3 is present in several cancers, including gliomas (GBMs), and is associated with poor therapeutic responses. Phosphorylation of STAT3 triggers its dimerization and nuclear transport, where it promotes the transcription of genes that stimulate tumor growth. In light of this role, inhibitors of the STAT3 pathway are attractive therapeutic targets for cancer. To this end, we evaluated the STAT3-inhibitory activities of three compounds (CPA-7 [trichloronitritodiammineplatinum(IV)], WP1066 [(S,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-phenylethyl)acrylamide, C17H14BrN3O], and ML116 [4-benzyl-1-{thieno[2,3-d]pyrimidin-4-yl}piperidine, C18H19N3S]) in cultured rodent and human glioma cells, including GBM cancer stem cells. Our results demonstrate a potent induction of growth arrest in GBM cells after drug treatment with a concomitant induction of cell death. Although these compounds were effective at inhibiting STAT3 phosphorylation, they also displayed variable dose-dependent inhibition of STAT1, STAT5, and nuclear factor κ light-chain enhancer of activated B cells. The therapeutic efficacy of these compounds was further evaluated in peripheral and intracranial mouse tumor models. Whereas CPA-7 elicited regression of peripheral tumors, both melanoma and GBM, its efficacy was not evident when the tumors were implanted within the brain. Our data suggest poor permeability of this compound to tumors located within the central nervous system. WP1066 and ML116 exhibited poor in vivo efficacy. In summary, CPA-7 constitutes a powerful anticancer agent in models of peripheral solid cancers. Our data strongly support further development of CPA-7-derived compounds with increased permeability to enhance their efficacy in primary and metastatic brain tumors.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/secundário , Fator de Transcrição STAT3/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Compostos Clorados/farmacocinética , Compostos Clorados/farmacologia , Compostos Clorados/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Glioma/metabolismo , Glioma/patologia , Células HEK293 , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Humanos , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Compostos de Platina/farmacocinética , Compostos de Platina/farmacologia , Compostos de Platina/uso terapêutico , Piridinas/farmacocinética , Piridinas/farmacologia , Piridinas/uso terapêutico , Fator de Transcrição STAT3/genética , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Distribuição Tecidual , Tirfostinas/farmacocinética , Tirfostinas/farmacologia , Tirfostinas/uso terapêuticoRESUMO
Six enantiomerically pure, oxaliplatin-like, platinum compounds (two platinum(II) and four platinum(IV)), all containing unsaturated cyclic diamine trans-1,2-diamino-4-cyclohexene (DACHEX) as a substitute for the trans-1,2-diaminocyclohexane used in oxaliplatin, were investigated. The complexes were characterized by elemental analyses, ESI-MS, and 1H-NMR spectroscopy. For the four Pt(IV) complexes the electrochemical redox behaviour, investigated by cyclic voltammetry, showed that all complexes possess reduction potentials suitable for activation in vivo. The antiproliferative activity was assessed in vitro on human cancer cell lines, also selected for resistance to platinum-based drugs or belonging to the MultiDrug-Resistant (MDR) phenotype. All complexes exhibited antiproliferative activity superior to that of cisplatin and almost equivalent to or better than that of oxaliplatin; moreover, most complexes were also capable of overcoming both the cisplatin- and the oxaliplatin-resistance. By comparing the effectiveness of the enantiomerically pure compounds with the racemic one, the R,R enantiomer emerged as the most effective in the case of Pt(II) complexes whereas the S,S enantiomer was the most effective in the case of the Pt(IV) derivatives. From the results obtained also against 3D spheroid tumor models, cis,trans,cis-[Pt(OXA)(OBz)2(1S,2S-DACHEX)] (OBz = benzoate) emerged as the most promising candidate for further preclinical investigation.
Assuntos
OxaliplatinaRESUMO
A new family of anticancer compounds has been derived from oxaliplatin by inserting a double-bond between carbons 4 and 5 of the 1,2-diaminocyclohexane ring. Testing against a panel of human tumour cell lines including cervical (A431), ovarian (2008), and colon carcinomas (HCT-15 and LoVo), and two oxaliplatin-resistant clones (LoVo OXP and LoVo MDR) has shown that the new compounds have, in general, equal if not better cytotoxic activity and are able to overcome the oxaliplatin-resistance. Moreover, the oxalato derivative induced lipid droplets increase in LoVo OXP cells thus suggesting the involvement of metabolism stress in its mechanism of action.
RESUMO
The use of Pt(iv) complexes as potential anticancer drugs is attractive, because they have higher stability and less side effects than Pt(ii) compounds. Moreover, some Pt(iv) complexes can also be activated with light, opening an avenue to photochemotherapy. Our purpose is to widen the library of photoactivatable Pt(iv)-based prodrugs and here we report on the oxidation of the Pt(ii) compound [PtCl(4'-phenyl-2,2':6',2''-terpyridine)][CF3SO3] (1) with PhICl2 or H2O2. The synthetic procedure avoids the formation of multiple species: the treatment with PhICl2 produces the Pt(iv) complex with axial chlorides, [PtCl3(4'-phenyl-2,2':6',2''-terpyridine)][CF3SO3] (2), while H2O2 oxidation and post-synthesis carboxylation produce [Pt(OCOCH3)2Cl(4'-phenyl-2,2':6',2''-terpyridine)][CF3SO3] (3), bearing acetates in the axial positions. 2 and 3 are stable in physiological-like buffers and in DMSO in the dark, but undergo photoreduction to 1 upon irradiation at 365 nm. Their stability toward reduction is a fundamental parameter to consider: cyclic voltammetry experiments show that the 2 electron reduction Pt(iv) â Pt(ii) occurs at a more negative potential for 3, because of the greater stabilization provided by the acetate axial groups; noteworthily, 3 is stable for hours also in the presence of mM concentration of glutathione. The cytotoxicity of 2 and 3 toward A2780 and A2780cis cell lines reveals that 3 is the least toxic in the dark, but is able to produce cytotoxic effects far higher than cisplatin when irradiated. To shed light on the mechanistic aspects, the interaction with protein and DNA models has been explored through high-resolution mass spectrometry revealing that 2 and 3 behave as prodrugs, but are able to bind to biological targets only after irradiation.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Luz , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Animais , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , DNA/metabolismo , Humanos , Compostos Organoplatínicos/metabolismoRESUMO
With the aim to obtain dual acting drugs able to target both nuclear DNA and mitochondria, Pt(iv) kiteplatin derivatives having dichloroacetate (DCA) ligands in axial positions have been synthesized. The rather fast hydrolysis (t1/2 of ca. 1 h) and reduction (by ascorbic acid) of these Pt(iv) derivatives did not impede a potent pharmacological effect on tumor cells. Moreover, similarly to kiteplatin, also the Pt(iv)-DCA compounds proved to be capable of overcoming oxaliplatin-resistance, which is particularly important in view of the fact that metastatic colorectal cancer is the third most common cancer in males and the second in females. The possible role of DCA released by the Pt(iv) compounds in eliciting the antiproliferative activity has also been investigated. Pt(iv)-DCA compounds determine a substantial increase of ROS production, blockage of oxidative phosphorylation, hypopolarization of the mitochondrial membrane, and caspase-3/7 mediated apoptotic cell death.
Assuntos
Antineoplásicos/farmacologia , Ácido Dicloroacético/farmacologia , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ácido Dicloroacético/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligantes , Estrutura Molecular , Compostos Organoplatínicos/síntese química , Compostos Organoplatínicos/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
Platinum complexes of the type [Pt(PL)(AL)]2+ where PL is a derivative of 1,10-phenanthroline and AL is cis-1,4-diaminocyclohexane (1,4-dach), have been synthesised and characterised by ultraviolet spectroscopy, elemental microanalysis, nuclear magnetic resonance and X-ray crystallography. The calf-thymus DNA binding affinity of these complexes was determined by isothermal titration calorimetry, revealing higher DNA affinity than their 1S,2S-diaminocyclohexane analogues. In vitro cytotoxicity was assessed in eleven human cell lines, revealing unexpectedly low activity for the 1,4-dach complexes.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Fenantrolinas/química , Animais , Antineoplásicos/metabolismo , Bovinos , Linhagem Celular Tumoral , DNA/metabolismo , Humanos , Compostos Organoplatínicos/metabolismoRESUMO
Kiteplatin, the neglected drug analogous of cisplatin but containing cis-1,4-DACH in place of the two ammines, has been recently reevaluated for its activity against cisplatin- and oxaliplatin-resistant tumors, in particular colo-rectal cancer. With the aim of further improving the pharmacological activity of this drug, Pt(IV) prodrugs were derived by addition of two, differently substituted, benzoate groups in axial positions (X-ray structure). The cytotoxic activity of both compounds resulted markedly potentiated reaching nanomolar concentration against a wide panel of human cancer cells. The ability of benzoate ligands to enhance the activity of kiteplatin most likely originates from their lipophilicity promoting a higher drug accumulation in cancer cells; however, it is to be noted that the increase in pharmacological effect is far greater than the increase in cellular uptake. Overcoming cisplatin- and oxaliplatin-resistance by kiteplatin derivatives appears to relate to the inability of membrane extrusion pumps to remove active Pt species from tumor cells.
Assuntos
Antineoplásicos/síntese química , Benzoatos/química , Compostos Organoplatínicos/síntese química , Platina/química , Pró-Fármacos/síntese química , Células A549 , Antineoplásicos/farmacologia , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Cristalografia por Raios X , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Ligantes , Células MCF-7 , Modelos Moleculares , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Pró-Fármacos/farmacologiaRESUMO
Hydroxyapatite (HA) nanocrystals are important inorganic constituents of biological hard tissues in vertebrates and have been proposed as a bone substitute or a coating material for prostheses in biomedicine. Hydroxyapatite is also amenable for its capacity to bind to a great variety of biomolecules and therapeutic agents. As drug carriers, apatite nanoparticles also have the advantage of pH dependent solubility and low toxicity. Thus HA nanoparticles are negligibly soluble at physiological pH but their dissolution is accelerated at lower pH such as that typically found in the vicinity of tumors. In the present study we have investigated the adsorption on and the release from biomimetic HA nanoparticles of two platinum derivatives of cis-1,4-diaminocyclohexane ([PtX2(cis-1,4-DACH)], X2 = Cl2 (1) and 1,1-cyclobutanedicarboxylate (CBDCA, 2)). The first of the two compounds proved to be active against colon cancer cells also resistant to oxaliplatin. The release has been investigated as a function of pH to mimic the different physiological environments of healthy tissues and tumors, and the in vitro cytotoxicity of the releasates from the HA matrices has been assessed against various human cancer cell lines. The results fully confirmed the potential of 1-loaded HA nanoparticles as bone-specific drug delivery devices.
Assuntos
Antineoplásicos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Durapatita/administração & dosagem , Nanopartículas/administração & dosagem , Compostos Organoplatínicos/administração & dosagem , Adsorção , Antineoplásicos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Durapatita/química , Humanos , Concentração de Íons de Hidrogênio , Nanopartículas/química , Compostos Organoplatínicos/químicaRESUMO
Biodegradable, PEG-coated, nanoparticles (NPs) have gained therapeutic application as injectable colloidal systems for the controlled and site-specific release of drugs. In this paper, encapsulation in PLGA-PEG polymer NPs has been exploited to lower the toxicity and to increase the antitumor activity of kiteplatin ([PtCl2(cis-1,4-DACH)]). Kiteplatin contains an isomeric form of the diamine ligand present in oxaliplatin and proved to be particularly active against ovarian and colon cancers. To favor encapsulation of the platinum drug in the hydrophobic core of the polymeric micelles, Pt(iv) prodrugs having hydrophobic carboxylic ligands at the axial positions were used in place of hydrophilic Pt(ii) complexes (compounds 1-4). The size, size distribution, and zeta potential (ZP) were measured by dynamic light scattering (DLS) and laser Doppler velocimetry (LDV), and drug encapsulation efficiency (EE) correlated to the alkyl chain length of the different Pt(iv) prodrugs. The number of the Pt atoms per NP (in the range of 1.3-2.4 × 10(6)) is comparable to that of polysilsesquioxane-based NPs and higher than that found for other nanoparticle platforms. The platinum-loaded PLGA-PEG NPs, tested in vivo in a syngeneic murine solid tumor (LLC), had a higher antitumor effect and, most importantly, were markedly less toxic than kiteplatin.
Assuntos
Portadores de Fármacos/administração & dosagem , Compostos Organoplatínicos/administração & dosagem , Poliésteres/administração & dosagem , Polietilenoglicóis/administração & dosagem , Pró-Fármacos/administração & dosagem , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/química , Feminino , Masculino , Camundongos Endogâmicos C57BL , Micelas , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/química , Poliésteres/química , Polietilenoglicóis/química , Pró-Fármacos/químicaRESUMO
A microwave-assisted synthesis of cisplatin, cis-[Pt(NH3)2Cl2], has been developed and optimized on both a 0.2 and 0.05 millimolar scale. The optimized synthetic procedure was modeled after the Lebedinskii-Golovnya method and is suitable for incorporating the radionuclide, (195m)Pt, into cisplatin for biological studies. Highest yields (47%) and purity are obtained using a K2PtCl4 : NH4OAc : KCl molar ratio of 1 : 4 : 2 at a temperature of 100 °C. The entire synthesis and purification procedure requires approximately 80 min. At a reaction temperature of 150 °C, the trans isomer is the exclusive product, suggesting that complexes of the general form, trans-[Pt(RNH2)2Cl2], can be synthesized directly from K2PtCl4 using [RNH3]OAc (R = alkyl or aryl moieties) via a microwave process. Two novel separation procedures have been developed which efficiently remove the major impurity (1 : 1 Magnus-type salt) from the crude reaction product, yielding a product of purity comparable to that obtained by the Dhara method and suitable for biological studies. These procedures are applicable to both the micro- and macro-scale of synthesis. The question of whether this microwave-assisted synthesis of cisplatin will be a preferred method for incorporating (195m)Pt into cisplatin is yet to be determined.
Assuntos
Antineoplásicos/síntese química , Cisplatino/síntese química , Micro-Ondas , Compostos Organoplatínicos/síntese químicaRESUMO
The anticancer activity of cisplatin is triggered by its formation of intrastrand adducts involving adjacent G residues of DNA. To obtain information on the different conformers that can be formed, carrier ligands such as 2,2'-bipiperidine, which provide large steric bulk near the platinum coordination plane and decrease the dynamic motion about the Pt-N7 bonds, were introduced ("retro-modelling" approach). In the present study we investigate the effect of cis-1,4-diaminocyclohexane (cis-1,4-DACH) on the formation, stability, and stereochemistry of (cis-1,4-DACH)Pt(ss-oligo) adducts (ss-oligo = d(GpG) with 3'- and/or 5'-substituents). Interesting features of this ligand, absent in previous retro-modelling studies, include the large bite angle (expected to impede the ease of interconversion between possible conformers), the presence of two protons on each nitrogen (a characteristic associated with antitumor activity), and the absence of chiral centres. The use of cis-1,4-DACH has made it possible to detect different conformers in a system containing a primary diamine carrier ligand associated with anticancer activity and to confirm the previous hypothesis that the coexistence of different conformers established in studies of retro models having relatively bulky ligands is not an artefact resulting from carrier-ligand bulk. Moreover, the data for the (cis-1,4-DACH)Pt(d(GpG)) and (cis-1,4-DACH)Pt(d(GGTTT)) adducts indicate that at a temperature close to the physiological one (40 °C) HH1 and ΔHT1 conformers are present in comparable amounts. In contrast, at low temperature (close to 0 °C) the equilibrium shifts dramatically toward the more stable HH1 conformer (for the (cis-1,4-DACH)Pt(d(TGGT)) adduct the HH1 conformer is always dominant, even at high temperature). Notably, (cis-1,4-DACH)PtCl2 (Kiteplatin) has been recently reinvestigated and found to be particularly active against colorectal cancer (including oxaliplatin-resistant phenotypes).