RESUMO
Multi-action cisplatin-based mono- (1) and di-clofibric acid (2) Pt(iv) "combo" derivatives were synthesized via both traditional and microwave assisted procedures. The two complexes offered very good performances (IC50 values in a nanomolar range) on a panel of human tumor cell lines, including the highly chemoresistant malignant pleural mesothelioma ones. Moreover, both 1 and 2 bypass the cisplatin resistance. Indeed, cisplatin and clofibric acid, the metabolites of the Pt(iv) â Pt(ii) intracellular reduction, proved to act synergistically. The adjuvant action of clofibric acid relies on the activation of peroxisome proliferator-activated receptor α (PPARα) that, in turn, decreases the level of Hypoxia-Inducible Factor-1α. Both compounds induced extensive apoptosis in tumor cells, also via oxidative stress. Finally, 2 exhibited excellent performances also under the hypoxic conditions typical of solid tumors, where cisplatin is less effective.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Cisplatino/análogos & derivados , Cisplatino/farmacologia , Ácido Clofíbrico/química , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Concentração Inibidora 50 , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/químicaRESUMO
The design, synthesis, characterization and biological properties of a Pt(iv) complex containing the very active inhibitor of histone deacetylase (2-propynyl)octanoic acid, POA, as an axial ligand are reported here. The title complex, namely (OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato)platinum(iv), 1, containing POA in racemic or in enantiomeric forms, was one/two orders of magnitude more active than cisplatin, depending on the chemo-sensitivity of the cancer cell lines. Moreover, 1 exhibited similar or even better antiproliferative activity than (OC-6-33)-diamminedichloridobis(2-propylpentanoato)platinum(iv), 2, containing two molecules of the well-known histone deacetylase inhibitor 2-propylpentanoic (valproic) acid. The high potency of 1 is likely due to its high cellular accumulation and to the synergism between the DNA-damaging cisplatin and the histone deacetylase inhibitor POA, both released upon the intracellular reduction of 1. Prodrug 1, after oral administration, caused an impressive reduction of the tumor mass (94%) in a model of solid tumor (murine Lewis lung carcinoma), compared to that of the control, whereas (intraperitoneal) cisplatin induced a tumor regression of 75% only. A good accumulation of 1 was observed in the tumor mass. The time course of the body weight attested that cisplatin induced elevated anorexia, whereas treatment with 1 did not induce significant body weight loss throughout the therapeutic experiment.
Assuntos
Antineoplásicos/química , Cisplatino/química , Complexos de Coordenação/química , Platina/química , Pró-Fármacos/química , Administração Oral , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Caprilatos/química , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/metabolismo , Complexos de Coordenação/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Isomerismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Distribuição Tecidual , Transplante HomólogoRESUMO
A small series of Pt(IV) prodrugs containing Gln-like (Gln=glutamine) axial ligands has been designed with the aim to take advantage of the increased demand of Gln showed by some cancer cells (glutamine addiction). In complex 4 the Gln, linked through the α-carboxylic group is recognized by the Gln transporters, in particular by the solute carrier transporter SLC1A5. All compounds showed cellular accumulation, as well as antiproliferative activity, related to their lipophilicity, as already demonstrated for the majority of Pt(IV) prodrugs, that enter cells mainly by passive diffusion. On the contrary, when the Gln concentration in cell medium is near or lower to the physiological value, complex 4 acts as a Trojan horse: it enters SLC1A5-overexpressing cells, where, upon reduction, it releases the active metabolite cisplatin and the Gln-containing ligand, thus preventing any possible extrusion by the L-type amino acid transporter LAT1. This selective mechanism could decrease off-target accumulation of 4 and, consequently, Pt-associated side-effects.
Assuntos
Antineoplásicos , Cisplatino , Glutamina , Neoplasias Pulmonares/tratamento farmacológico , Pró-Fármacos , Células A549 , Sistema ASC de Transporte de Aminoácidos/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Transporte Biológico Ativo/efeitos dos fármacos , Cisplatino/química , Cisplatino/farmacocinética , Cisplatino/farmacologia , Glutamina/química , Glutamina/farmacocinética , Glutamina/farmacologia , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Antígenos de Histocompatibilidade Menor/metabolismo , Proteínas de Neoplasias/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologiaRESUMO
Pt(IV) complexes are usually prepared by oxidation of the corresponding Pt(II) counterparts, typically using hydrogen peroxide or chlorine. A different way to synthesize asymmetrical Pt(IV) compounds is the oxidative chlorination of Pt(II) counterparts with N-chlorosuccinimide. The reaction between cisplatin cis-[PtCl2(NH3)2], carboplatin, cis-[PtCl2(dach)] and cis-[Pt(cbdc)(dach)] (cbdc = cyclobutane-1,1'-dicarboxylato; dach = cyclohexane-1R,2R-diamine) with N-chlorosuccinimide in ethane-1,2-diol was optimized to produce the asymmetric Pt(IV) octahedral complexes [PtA2Cl(glyc)X2] (A2 = 2 NH3 or dach; glyc = 2-hydroxyethanolato; X2 = 2 Cl or cbdc) in high yield and purity. The X-ray crystal structure of the [Pt(cbdc)Cl(dach)(glyc)] complex is also reported. Moreover, the oxidation method proved to be versatile enough to produce other mixed Pt(IV) derivatives varying the reaction medium. The two trichlorido complexes easily undergo a pH-dependent hydrolysis reaction, whereas the dicarboxylato compounds are stable enough to allow further coupling reactions for drug targeting and delivery via the glyc reactive pendant. Therefore, the coupling reaction between the [Pt(cbdc)Cl(dach)(glyc)] and a model carboxylic acid, a model amine, and selectively protected amino acids is reported.
Assuntos
Cloro/química , Compostos de Platina/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Oxirredução , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria UltravioletaRESUMO
The genus Ophioglossum consists of ferns with different therapeutic properties, including vulnerary virtues. The species Ophioglossum vulgatum L. is traditionally used on wounds and burns as an ointment, suggesting the occurrence of lipophilic compounds with tissue repair properties. We isolated and characterized a galactosyldiacylglycerol mixture (1), composed mainly of 1,2-di-O-linolenoyl-3-O-ß-D-galactopyranosyl-glycerol, from the frond dichloromethane extract. The wound healing properties of 1 were assessed in vitro on keratinocytes. Scratch wound assays showed increased wound closure rates in keratinocyte monolayers exposed to subtoxic doses, previously determined in cytotoxicity assays. The strongest effect, obtained at a dose of 5 µg/mL, approached that of a platelet lysate used in clinical settings. The use of inhibitors of the main cellular pathways involved in wound repair, revealed important roles for intracellular calcium and the ERK1/2 MAP kinase. Conversely, a PCR array of genes involved in wound healing showed an almost total absence of gene modulation. Taken together, the data suggest that 1 acts through a Ca(2+)-dependent, nongenomic mechanism involving the activation of ERK1/2 MAP kinase. Hence, 1 is a main candidate to explain the wound healing virtues of O. vulgatum ointment, and is proposed as a possible new drug in tissue repair and regenerative medicine.
Assuntos
Gleiquênias , Galactolipídeos/farmacologia , Queratinócitos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Cicatrização/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Gleiquênias/química , Galactolipídeos/isolamento & purificação , Humanos , Queratinócitos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/farmacologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/farmacologia , Fitoterapia , Extratos Vegetais/isolamento & purificação , Folhas de Planta , Plantas MedicinaisRESUMO
Two new glycosylated and acylated flavonols, viz. quercetin-3-O-[(6-caffeoyl)-ß-glucopyranosyl (1âââ3) α-rhamnopyranoside]-7-O-α-rhamnopyranoside (2), and kaempferol-3-O-[(6-caffeoyl)-ß-glucopyranosyl (1âââ3) α-rhamnopyranoside]-7-O-α-rhamnopyranoside (3), together with the known quercetin-3-O-methyl ether (1), were isolated from the aerial parts of the fern Ophioglossum vulgatum L. Their structures were established by means of 1D and 2D NMR spectra, as well as ESI-MS and ESI-HRMS spectra. Compounds 1-3 were all found to be active in scratch-wound healing assays on keratinocytes, with 3 being the most active one and showing maximum activity at 20 µM.