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1.
Biometals ; 28(2): 425-30, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25715906

RESUMEN

The reactions of four representative metallodrugs with the model protein HEWL were investigated within a non-aqueous environment-i.e. in pure DMSO- through UV-Vis absorption spectroscopy and ESI MS analysis. Notably, formation of a variety of metallodrug-protein adducts was clearly documented. This is the first example for this kind of protein metalation reactions carried out within a pure organic solvent. It is shown that the applied solution conditions greatly affect the nature of the formed adducts, this being well accounted for by the fact that the overall protein conformation is greatly perturbed within pure DMSO; in addition, the activation profiles of the studied metallodrugs are also highly dependent on the nature of the solvent. The implications of these results are discussed.


Asunto(s)
Complejos de Coordinación/química , Dimetilsulfóxido/química , Muramidasa/química , Oro/química , Platino (Metal)/química , Rutenio/química , Soluciones , Solventes/química , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Ultravioleta
2.
Bioorg Chem ; 54: 73-80, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24836201

RESUMEN

This study involves the synthesis and characterization of novel cyclohexyl 1,3-propanediamine-N,N'-diacetate molecules as well as investigation of their cytotoxic action. New acid 1a was synthesized by reaction between (S)-2-amino-3-cyclohexylpropanoic acid and 1,3-dibromopropane, while the esters (1b-1e) derived from this acid were obtained by reaction of the corresponding absolute alcohol, thionyl chloride and synthesized acid. All compounds were characterized by IR, ESI-MS, ((1)H, (13)C and HSQC) NMR spectroscopy and elemental analysis. The cytotoxic activity of all compounds was tested on several tumour cell lines: human (U251) and rat (C6) glioma, human promyelocytic leukaemia (HL-60), human neuroblastoma (SHSY-5Y) and mouse fibrosarcoma (L929) as well as primary rat astrocytes. The present study reveals potent antitumour activity of novel purely organic compounds (1a-1e), which was most pronounced in human glioma (U251) cells. The esterification is required for the novel compounds' cytotoxic action since the n-butyl ester 1e was the most efficient compound. Importantly, n-butyl ester 1e was more toxic to glioma cells in comparison to rat astrocytes, with 24-h IC50 values lower than those for cisplatin. n-Butyl ester 1e induced production of reactive oxygen species (ROS) and caused an oxidative-stress-derived accumulation of glioma cells in the G0/G1 phase of the cell cycle, as well as caspase activation and DNA fragmentation, suggesting that apoptosis induction plays an important role in the novel compounds' antiglioma action.


Asunto(s)
Alanina/análogos & derivados , Antineoplásicos/farmacología , Ésteres/farmacología , Especies Reactivas de Oxígeno/metabolismo , Alanina/síntesis química , Alanina/química , Alanina/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Astrocitos/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ésteres/síntesis química , Ésteres/química , Humanos , Ratones , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Relación Estructura-Actividad
3.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 3): o656-7, 2009 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-21582304

RESUMEN

In the crystal structure of the title compound, C(12)H(26)N(2)O(4) (2+)·2(Br(0.085)Cl(0.915))(-)·4C(5)H(9)OH, the complete cation is generated by crystallographic twofold symmetry. Contamination of the chloride counter-anion with bromide occured during the preparation, due to the use of 1,2-dibromo-ethane. One of the solvent mol-ecules is disordered, with occupancies 0.53 (3):0.47 (3). The crystal packing is stabilized by an infinite two dimensional ⋯X⋯H-N-H⋯X⋯ hydrogen-bonding network (X: Br(-)/Cl(-) ≃ 1:12). In addition, O-H⋯X and O-H⋯O hydrogen bonds involving solvent mol-ecules are observed.

4.
J Inorg Biochem ; 102(4): 892-900, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18226835

RESUMEN

Syntheses of two novel ligand precursors O,O'-diisopropyl- (1a) and O,O'-diisobutyl-(S,S)-ethylenediamine-N,N'-di-2-propanoate dihydrochloride monohydrate (1b) and the corresponding dichloroplatinum(II) (2a and 2b) and tetrachloroplatinum(IV) complexes (3a and 3b) are described here. The substances were characterized by IR, (1)H and (13)C spectroscopy and elemental analysis. Crystal structures were determined for 1a and the corresponding platinum(IV) complex, 3a. In vitro antiproliferative activity was determined against tumor cell lines: human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x, rested and stimulated normal immunocompetent cells (human peripheral blood mononuclear PBMC cells) using KBR test (Kenacid Blue Dye binding test). The IC(50)(microM) values for the most active compound 3a were: 30.48+/-2.54; 12.26+/-2.60; 13.68+/-3.22; 80.18+/-24.07 and 71.30+/-21.70, respectively.


Asunto(s)
Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/farmacología , Propionatos/síntesis química , Propionatos/farmacología , Cristalografía por Rayos X , Células HeLa , Humanos , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Espectrofotometría Infrarroja
5.
Acta Crystallogr Sect E Struct Rep Online ; 64(Pt 7): o1232, 2008 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-21202869

RESUMEN

In the crystal structure of the title compound, C(10)H(22)N(2)O(4) (2+)·2Cl(-) or (H(2)Me(2)eddp)Cl(2) (H(2)Me(2)eddp(2+) is the dimethyl N,N'-di-3-propane-carboxylato-ethane-1,2-diyldiimin-ium cation), the packing is stabilized by an infinite two-dimensional ⋯Cl⋯H-N-H⋯Cl⋯ hydrogen-bonding network. In addition, short C-H⋯Cl contacts are observed.

6.
Melanoma Res ; 28(1): 8-20, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29135861

RESUMEN

Melanoma, an aggressive skin tumor with high metastatic potential, is associated with high mortality and increasing morbidity. Multiple available chemotherapeutic and immunotherapeutic modalities failed to improve survival in advanced disease, and the search for new agents is ongoing. The aim of this study was to investigate antimelanoma effects of O,O-diethyl-(S,S)-ethylenediamine-N,N'di-2-(3-cyclohexyl) propanoate dihydrochloride (EE), a previously synthesized and characterized organic compound. Mouse melanoma B16 cell viability was assessed using acid phosphatase, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, sulforhodamine B, and lactate dehydrogenase assays. Apoptosis and autophagy were investigated using flow cytometry, fluorescence and electron microscopy, and western blotting. In vivo antitumor potential was assessed in subcutaneous mouse melanoma model after 14 days of treatment with EE. Tumor mass and volume were measured, and RT-PCR was used for investigating the expression of autophagy-related, proapoptotic, and antiapoptotic molecules in tumor tissue. Investigated organic compound exerts significant cytotoxic effect against B16 cells. EE induced apoptosis, as confirmed by phosphatidyl serine externalisation, caspase activation, and ultrastructural features typical for apoptosis seen on fluorescence and electron microscopes. The apoptotic mechanism included prompt disruption of mitochondrial membrane potential and oxidative stress. No autophagy was observed. Antimelanoma action and apoptosis induction were confirmed in vivo, as EE decreased mass and volume of tumors, and increased expression of several proapoptotic genes. EE possesses significant antimelanoma action and causes caspase-dependent apoptosis mediated by mitochondrial damage and reactive oxygen species production. Decrease in tumor growth and increase in expression of proapoptotic genes in tumor tissue suggest that EE warrants further investigation as a candidate agent in treating melanoma.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ciclohexanos/farmacología , Etilenodiaminas/farmacología , Melanoma Experimental/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Propionatos/farmacología , Animales , Autofagia , Técnicas In Vitro , Melanoma Experimental/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Células Tumorales Cultivadas
7.
Chem Biol Drug Des ; 90(2): 262-271, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28102932

RESUMEN

This study presents the synthesis, characterization, and antitumor action of five new Pt(II) halogenido, chlorido, and iodido complexes with edda type of ligands. (S,S)-Ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid dihydrochloride and its methyl, ethyl, and n-propyl esters were prepared according to the previously reported procedure. All investigated complexes were characterized by IR, ESI-MS (1 H, 13 C, and HMBC) NMR spectroscopy, and elemental analysis. Their cytotoxic action was investigated in four human tumor cell lines: promyelocytic (HL-60) and lymphocytic (REH) leukemia, glioma (U251), and lung carcinoma (H460). Cell viability was assessed by acid phosphatase and LDH assay, while oxidative stress and cell death parameters were analyzed by flow cytometry. The results showed that novel Pt(II) complexes exhibited antitumor action superior to precursor ligands, with iodido complexes being more efficient than corresponding chlorido complexes. Human promyelocytic cell line (HL-60) was the most sensitive to antitumor action of all investigated substances and was used for investigation of the underlying mode of antileukemic action. The investigated Pt(II) complexes showed more potent antileukemic action than corresponding Pt(IV) complex, through induction of oxidative stress and apoptosis, evidenced by caspase (8, 9, and 3) activation and phosphatidylserine externalization.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Leucemia/tratamiento farmacológico , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacología , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Etilenodiaminas/síntesis química , Etilenodiaminas/química , Etilenodiaminas/farmacología , Halogenación , Humanos , Leucemia/metabolismo , Ligandos , Compuestos Organoplatinos/síntesis química , Estrés Oxidativo/efectos de los fármacos
8.
Anticancer Agents Med Chem ; 17(8): 1136-1143, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-27928952

RESUMEN

AIMS: Platinum(II) and platinum(IV) complexes [PtCln{(S,S)-(i-Am)2eddip}] (n = 2, 4: 1, 2, respectively; (S,S)-(i-Am)2eddip = O,O'-diisoamyl-(S,S)-ethylenediamine-N,N'-di-2-propanoate) were synthesized and characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy and mass spectrometry. METHOD: Quantum chemical calculations were used to predict formed isomers of 1 and 2. Furthermore, reduction of 2 with ascorbic acid was followed by time-dependant 13C NMR spectroscopy in order to enable assignation of the formed isomers for complex 1. In vitro cytotoxic activity was determined for 1 and 2 on a panel of five human tumor cell lines derived from cervix adenocarcinoma (HeLa), alveolar basal adenocarcinoma (A549), breast adenocarcinoma (MDA-453), colorectal cancer (LS 174), erythromyeloblastoid leukemia (K562), as well as one non-malignant human lung fibroblast cell line (MRC-5), using MTT assay. RESULT: Both complexes exhibited high (2 against K562: IC50 = 5.4 µM), more active than cisplatin, to moderate activity (1). Both complexes caused considerable decrease of cell number in K562 cells in G1, S and G2 phases, concordantly increasing subpopulation in sub-G1 fraction. Morphological analysis of K562 cell death induced by platinum(II/IV) complexes indicate apoptosis.


Asunto(s)
Alanina/análogos & derivados , Antineoplásicos/farmacología , Ésteres/farmacología , Etilenodiaminas/farmacología , Compuestos Organoplatinos/farmacología , Alanina/química , Alanina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Ésteres/química , Etilenodiaminas/química , Humanos , Estructura Molecular , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Teoría Cuántica , Relación Estructura-Actividad , Células Tumorales Cultivadas
9.
J Inorg Biochem ; 172: 55-66, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28433833

RESUMEN

Four novel gold(III) complexes of general formulae [AuCl2{(S,S)-R2eddl}]PF6 (R2eddl=O,O'-dialkyl-(S,S)-ethylenediamine-N,N'-di-2-(4-methyl)pentanoate, R=n-Pr, n-Bu, n-Pe, i-Bu; 1-4, respectively), were synthesized and characterized by elemental analysis, UV/Vis, IR, and NMR spectroscopy, as well as high resolution mass spectrometry. Density functional theory calculations pointed out that (R,R)-N,N'-configuration diastereoisomers were energetically the most favorable. Duo to high cytotoxic activity complex 3 was chosen for stability study in DMSO, no decomposition occurs within 24h, and for the reaction with ascorbic acid in which was reduced immediately. Additionally, 3 interacts with bovine serum albumin (BSA) as proven by UV/Vis spectroscopy. In vitro antitumor activity was determined against human cervix adenocarcinoma (HeLa), human myelogenous leukemia (K562), and human melanoma (Fem-x) cancer cell lines, as well as against non-cancerous human embryonic lung fibroblast cells MRC-5. The highest activity was observed against K562 cells (IC50: 5.04-6.51µM). Selectivity indices showed that these complexes are less toxic than cisplatin. 3 had a similar viability kinetics on HeLa cells as cisplatin. Drug accumulation studies in HeLa cells showed that the total gold uptake increased much faster than that of cisplatin pointing out that 3 more efficiently enters the cells than cisplatin. Furthermore, morphological and cell cycle analysis reveal that gold(III) complexes induced apoptosis in time- and dose-dependent manner.


Asunto(s)
Ácido Ascórbico/metabolismo , Ésteres/farmacología , Etilenodiaminas/química , Oro/farmacología , Albúmina Sérica Bovina/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Ácido Ascórbico/química , Ciclo Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Ésteres/síntesis química , Ésteres/química , Oro/química , Oro/metabolismo , Células HeLa , Humanos , Células K562 , Ligandos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Teoría Cuántica , Albúmina Sérica Bovina/química , Factores de Tiempo
10.
J Inorg Biochem ; 99(2): 488-96, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15621281

RESUMEN

This paper reports on syntheses and characterization of chlorotribromo(O,O-n-butyl-ethylenediamine-N,N'-di-3-propanoate)platinum(IV) [II], dichlorodiiodo(O,O-n-butyl-ethylenediamine-N,N'-di-3-propanoate)platinum(IV) [III], and dichloro(O,O-n-butyl-ethylenediamine-N,N'-di-3-propanoate)platinum(II) [V] complexes, with the formulae [Pt(dbeddp)Br(3)Cl], [Pt(dbeddp)Cl(2)I(2)] and [Pt(dbeddp)Cl(2)], respectively. The complexes were characterized by elemental analysis, infrared, (1)H and (13)C NMR spectroscopy and electrospray mass spectrometry. In the aim to assess the selectivity in the antitumor action of these complexes, as well, as tetrachloro(O,O-n-butyl-ethylenediamine-N,N'-di-3-propanoate)platinum(IV) [I] and tetrachloro(O,O-n-pentyl-ethylenediamine-N,N'-di-3-propanoate)platinum(IV) [IV], the antiproliferative action of these compounds was determined to human adenocarcinoma HeLa cells, to human myelogenous leukemia K562 cells and to normal immunocompetent cells, i.e., on human peripheral blood mononuclear PBMC cells.


Asunto(s)
Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/farmacología , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células HeLa , Humanos , Técnicas In Vitro , Células K562 , Leucocitos Mononucleares/efectos de los fármacos , Ligandos , Estructura Molecular , Compuestos Organoplatinos/química
11.
Eur J Med Chem ; 90: 766-74, 2015 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-25528331

RESUMEN

Five novel gold(III) complexes of general formulas [AuCl2{(S,S)-R2eddip}]PF6, ((S,S)-eddip = (S,S)-ethylenediamine-N,N'-di-2-propanoate, R = n-Bu, n-Pe, i-Bu, i-Am, cPe; 1-5, respectively) were synthesized and characterized by UV/Vis, IR and NMR spectroscopy and mass spectrometry. DFT calculations indicated that (R,R)-N,N'-configuration diastereoisomers were the most stable for 1-5. 3 is stable in DMSO for at least 24 h, but immediate hydrolysis in PBS occurs. 3 is readily reduced with ascorbic acid and forms adducts with bovine serum albumin (BSA). In vitro anticancer activity of the gold(III) complexes against human cervix adenocarcinoma HeLa, human myelogenous leukemia K562, human melanoma Fem-x tumor cell lines, as well as against non-cancerous human embryonic lung fibroblast cell line MRC-5 was determined using MTT assay. Complex 4 showed highest activity and selectivity (IC50(Fem-x) = 1.3 ± 0.2; IC50(MRC-5)/IC50(Fem-x) = 72.5 ± 12.4), 4 times more active and 28 times more selective than cisplatin. Complexes induced apoptotic mode of death in a time-dependent manner in HeLa cells.


Asunto(s)
Antineoplásicos/farmacología , Ésteres/farmacología , Etilenodiaminas/farmacología , Compuestos Orgánicos de Oro/farmacología , Propionatos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Ésteres/síntesis química , Ésteres/química , Etilenodiaminas/química , Células HeLa , Humanos , Células K562 , Modelos Moleculares , Estructura Molecular , Compuestos Orgánicos de Oro/síntesis química , Compuestos Orgánicos de Oro/química , Propionatos/química , Relación Estructura-Actividad
12.
J Inorg Biochem ; 98(8): 1378-84, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15271514

RESUMEN

The cytotoxicities of two platinum(IV) complexes of formula [PtX2(eddp)].nH2O (eddp=ethylenediamine-N,N'-di-3-propionate, X=chloro [I] or bromo [II], n=1 or 1.24) are reported. The complexes have been obtained by direct reaction of potassium hexahaloplatinate(IV) with H2eddp.2HCl followed by addition of a base (LiOH). The crystal and molecular structure has confirmed that the complex with bromo ligands, similarly to the complex with chloro ligands previously reported, has trans configuration of the halogens. In both the chloro and bromo complexes there appear to be intramolecular N-H...X interactions which account for a narrowing of the corresponding X-Pt-N angles below 90degrees. The trans isomer (configuration index OC-6-13, two nitrogens and two oxygens of eddp bound in the equatorial plane) is the only one obtained in the reaction of hexahaloplatinate(IV) with the eddp ligand while a similar reaction performed with ethylenediamine-N,N'-diacetate (edda) affords exclusively the symmetrical cis-isomer (configuration index OC-6-33, equatorial nitrogen and axial oxygen atoms of edda). The longer chain of the propionato groups (as compared to the acetato ones) is responsible for such a change in preferred configuration. NMR data have revealed a very large diastereotopic splitting of the propionato methylene protons to the nitrogens (0.88 ppm). The trans disposition of the halogen ligands in the compounds with eddp leads to deactivation of platinum(IV) complexes in comparison to those with edda having cis disposition of the leaving chlorides (human ovarian cancer cell line A2780, IC50 [muM] of 92.6 +/- 12 and 30.3 +/- 7.5 for [I] and [II], respectively).

13.
J Inorg Biochem ; 97(2): 215-20, 2003 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-14512200

RESUMEN

The new potential antitumour soluble drug K[Ru(eddp)Cl(2)].3H(2)O, (eddp=ethylenediamine-N,N'-di-3-propionate) has been isolated and characterized. The analysis of the interaction of this complex with pBR322 plasmid DNA by circular dichroism spectroscopy shows that the ruthenium complex initially induces alteration of both CD positive and negative features resembling those previously observed for monofunctional platinum complexes. Further addition of drug at r(i) higher than 0.50 suggests appreciable conformational alterations of typical secondary structure of B-type DNA, implying loss of DNA helicity and unwinding of the double helix. The results reported herein about the binding of K[Ru(eddp)Cl(2)] to the named plasmid performed by electrophoresis indicate that the Ru(III) center preferentially forms initial monofunctional adducts with this plasmid. In addition, the DNA binding data suggest that the plasmid is cleaved by K[Ru(eddp)Cl(2)] in the presence of physiological concentrations of ascorbate. These results support the hypothesis that reactive Ru(II) species may be formed from Ru(III) upon incubation with a reductant agent such as ascorbate. The testing of the cytotoxic activity of this complex against several human cancer cell lines evidenced that K[Ru(eddp)Cl(2)] complex had a remarkable and selective antiproliferative effect against the cervix carcinoma HeLa and colon adenocarcinoma HT-29, behaving in these two cases as an antineoplastic drug.


Asunto(s)
Antineoplásicos/química , ADN/química , Compuestos Organometálicos/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Ácido Ascórbico/química , División Celular/efectos de los fármacos , Línea Celular Tumoral , Cromatografía en Agarosa , Dicroismo Circular , Relación Dosis-Respuesta a Droga , Células HT29 , Células HeLa , Humanos , Hidrólisis , Sustancias Intercalantes/síntesis química , Sustancias Intercalantes/química , Sustancias Intercalantes/farmacología , Conformación de Ácido Nucleico/efectos de los fármacos , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Oxidación-Reducción , Plásmidos/química , Rutenio/química , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta
14.
Eur J Med Chem ; 82: 372-84, 2014 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-24927057

RESUMEN

Novel Pt(II) complexes of general formula [PtI2(L(1-3))], (C1-C3): where L(1-3) are isobutyl, n-pentyl and isopentyl esters of (S,S)-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid has been synthesized and characterized by elemental analysis, UV/Vis, IR, ((1)H, (13)C and HSQC, Pt) NMR spectroscopy and ESI mass spectrometry. Spectroscopic data and computational studies have shown the usual square planar coordination geometry of synthesized complexes, with coordination of ligands via nitrogen donor atoms. The cytotoxic activity of novel ligands and corresponding complexes were investigated on a palette of different cells line. Complexes C1-C3 exhibited activity comparable to cisplatin, with IC50 values (µM) ranging from 4.6 ± 0.6 to 17.2 ± 2, and showed the highest potential in HeLa, LS-174 and EA.hy.926 cells. Ligands L1-L3 exhibited two- to four-times less activity than corresponding complexes. Analysis of the mode of action in HeLa cells, by ICP-MS study, showed markedly higher intracellular accumulation and DNA binding affinity of C1-C3 versus cisplatin, after 4 h and 20 h post-treatment. Annexin-V-FITC assay, flow cytometry and fluorescence microscopy study demonstrated occurrence of cell death through both apoptotic and necrotic changes. Tested complexes, at corresponding IC50 concentrations, caused considerable "sub-G1" peak, without other substantial alterations of cell cycle, while only C1 induced higher level of phosphatidylserine externalization (11.7%), comparing to ligand L1 (4.9%) and cisplatin (8.4%). Structure-activity comparison indicated variations of C1-C3 cytotoxicity, related to the drug/ligand lipophilicity (C log P value), while intracellular platinum content and DNA platination increased on increase of length and branching of ester chain, in sequence: C1 (isobutyl) < C2 (n-pentyl) < C3 (isopentyl).


Asunto(s)
Antineoplásicos/farmacología , Compuestos Organoplatinos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Modelos Moleculares , Estructura Molecular , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/química , Relación Estructura-Actividad , Células Tumorales Cultivadas
15.
J Inorg Biochem ; 128: 146-53, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23988849

RESUMEN

Six novel gold(III) complexes containing O,O'-dialkyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate ([AuCl2{(S,S)-R2eddch}]PF6, R=Me, Et, n-Pr, n-Bu, i-Bu, i-Am; 1-6, respectively) were synthesized and characterized by elemental analysis, UV/Visible, IR and NMR spectroscopy, mass spectrometry and differential pulse voltammetry. Density functional theory (DFT) calculations confirmed that diastereoisomer with the N,N' atoms configured (S,S) was the most stable. In vitro antiproliferative activity was determined against human cervix adenocarcinoma HeLa and human myelogenous leukemia K562 tumor cell lines, as well as against rested and stimulated normal immunocompetent human peripheral blood mononuclear cells (PBMC) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Complex 6 expressed the highest activity against K562 cells (IC50 = 3.8 ± 0.5 µM). Apoptosis, seen as condensation of HeLa cell nuclei was the mode of cell death induced by complexes 2-6. Complexes 3-6 induced death of K562 cells inhibiting cell entry in mitosis.


Asunto(s)
Antineoplásicos/química , Ésteres/química , Oro/química , Compuestos Organoplatinos/química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Células HeLa , Humanos , Concentración 50 Inhibidora , Células K562 , Modelos Químicos , Estructura Molecular , Compuestos Organoplatinos/síntesis química , Compuestos Organoplatinos/farmacología , Oxidación-Reducción
16.
Metallomics ; 4(11): 1155-9, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23014886

RESUMEN

Tetrachlorido(O,O'-dibutyl-ethylenediamine-N,N'-di-3-propionate)platinum(iv) complex, [PtCl(4)(n-Bu(2)eddp)], was previously found to be effective against fibrosarcoma and glioma cell lines. Here we presented that [PtCl(4)(n-Bu(2)eddp)] strongly reduced the growth of B16 melanoma cells in vitro. Inhibition of cell viability was accompanied with induction of both necrotic and apoptotic cell death. In addition, [PtCl(4)(n-Bu(2)eddp)] concealed the expansion of tumors induced in syngeneic C57Bl/6 mice without visible signs of nephrotoxicity.


Asunto(s)
Antineoplásicos/farmacología , Melanoma Experimental/tratamiento farmacológico , Compuestos Organoplatinos/farmacología , Análisis de Varianza , Animales , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Ratones , Ratones Endogámicos C57BL , Compuestos Organoplatinos/uso terapéutico
17.
Eur J Med Chem ; 47(1): 194-201, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22071257

RESUMEN

We have recently reported that a novel octahedral Pt(IV) complex with di-n-propyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoato ligand has a potent cytotoxic effect on glioma, melanoma and fibrosarcoma cell lines. In this work, we investigated the influence of the Pt(IV) compound on immune cells. We determined its effect on the viability of spleen cells and lymph node cells and on their capability to produce interferon (IFN)-γ and interleukin (IL)-17. Also, we researched the compound's impact on peritoneal macrophages and generation of NO in these cells. Our results show that the complex has limited influence on cell viability of immune cells, but profound inhibitory effect on the production of examined immune mediators. These results are valuable as they show that the novel Pt(IV) complex applied in concentrations which are effective against tumor cells do not affect immune cell viability. Moreover, they also imply that the complex has immunomodulatory properties.


Asunto(s)
Diaminas/química , Factores Inmunológicos/química , Factores Inmunológicos/farmacología , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Platino (Metal)/química , Animales , Supervivencia Celular/efectos de los fármacos , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Ligandos , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ratones , Óxido Nítrico/biosíntesis , Peritoneo/efectos de los fármacos , Peritoneo/metabolismo , Ratas , Bazo/citología , Bazo/inmunología
18.
J Inorg Biochem ; 109: 40-8, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22369771

RESUMEN

This paper focuses on the synthesis, characterization and biological activity of new N,N'-methylene modified cyclohexyl ethylenediamine-N,N'-diacetate (edda)-type ligands and their Pt(IV) complexes. Both the ligands and complexes were characterized by infrared, UV-vis, ESI-MS, 1D ((1)H, (13)C, (195)Pt) and 2D (COSY, HSQC, HMBC) NMR spectroscopy and elemental analysis. The possible correlation between the reduction potentials and the cytotoxicity of the complexes was examined. The potential antitumoral activity of all compounds was tested in vitro on human melanoma A375, human glioblastoma U251, human prostate cancer PC3, human colon cancer HCT116, mouse melanoma B16 and mouse colon cancer CT26CL25 cells, as well as primary fibroblasts and keratinocytes. The results obtained revealed strong antitumor potential of the newly synthesized drugs with preserved efficacy against cisplatin resistant lines and less toxicity towards nonmalignant counterparts. The mechanism found to be responsible for the observed tumoricidal action of each synthesized compound was induction of apoptosis generally accompanied with caspase activation. Taken together, the effective response to the treatment of a wide range of different cell lines, including cisplatin resistant subclones, as well as induction of apoptosis, as the mechanism suggested to be the most desirable way of eliminating malignant cells, represents a great advantage of this novel group of drugs in comparison to other members in this metallo-drug family.


Asunto(s)
Antineoplásicos/síntesis química , Complejos de Coordinación/síntesis química , Ciclohexanos/síntesis química , Etilenodiaminas/síntesis química , Compuestos Organoplatinos/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Ciclohexanos/química , Ciclohexanos/farmacología , Ácido Edético/química , Etilenodiaminas/química , Etilenodiaminas/farmacología , Citometría de Flujo , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacología , Espectrometría de Masa por Ionización de Electrospray , Espectroscopía Infrarroja por Transformada de Fourier
19.
Metallomics ; 4(9): 979-87, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22820831

RESUMEN

Several new R(2)eddp (R = i-Pr, i-Bu; eddp = ethylenediamine-N,N'-di-3-propionate) esters and corresponding platinum(ii) and platinum(iv) complexes of the general formula [PtCl(n)(R(2)edda-type)] (n = 2, 4) were synthesized and characterized by spectroscopic methods (IR, (1)H and (13)C NMR) and elemental analysis. The crystal structure of platinum(iv) complex [PtCl(4){(c-Pe)(2)eddip}] (3a) was resolved and is given herein. Ligand precursors, platinum(ii), and platinum(iv) complexes were tested against eight tumor cell lines (CT26CL25, HTC116, SW620, PC3, LNCaP, U251, A375, and B16). Selectivity in the action of those compounds between tumor and two normal primary cells (fibroblasts and keratinocytes) are discussed. A structure-activity relationship of these compounds is discussed. Furthermore, cell cycle distribution, induction of necrosis, apoptosis, autophagy, anoikis, caspase activation, ROS, and RNS are presented on the cisplatin-resistant colon carcinoma HCT116 cell line.


Asunto(s)
Apoptosis/efectos de los fármacos , Caspasas/metabolismo , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Compuestos Organoplatinos/farmacología , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cisplatino/química , Cisplatino/farmacología , Cisplatino/toxicidad , Humanos , Ligandos , Ratones , Conformación Molecular , Compuestos Organoplatinos/química , Compuestos Organoplatinos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo
20.
ChemMedChem ; 6(10): 1884-91, 2011 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-21805645

RESUMEN

Herein we describe the synthesis, characterization, and anticancer activity of novel p-cymeneruthenium(II) complexes containing methyl, ethyl, n-propyl, and n-butyl esters of (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid. The results of IR, UV/Vis, ESIMS, (1)H, and (13)C NMR characterization reveal that ligand coordination occurs through nitrogen donor atoms of the ester ligands, with the organoruthenium moiety being kept in complex. These ruthenium(II) complexes are cytotoxic toward various cancer cell lines including leukemic HL-60, K562, and REH cells (IC(50): 1.0-20.2 µM), with the n-butyl ester complex being the most effective. It causes apoptotic cell death associated with mitochondrial depolarization, caspase activation, phosphatidylserine exposure, and DNA fragmentation. Importantly, the n-butyl ester complex is more effective against leukemic patients' blood mononuclear cells relative to those from healthy control subjects, thus indicating a fairly selective antileukemic action of Ru(II)-based compounds.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Etilenodiaminas/química , Rutenio/química , Línea Celular Tumoral , Humanos , Ligandos , Neoplasias/tratamiento farmacológico , Estereoisomerismo , Relación Estructura-Actividad
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