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1.
Melanoma Res ; 28(1): 8-20, 2018 02.
Article in English | MEDLINE | ID: mdl-29135861

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cyclohexanes/pharmacology , Ethylenediamines/pharmacology , Melanoma, Experimental/pathology , Membrane Potential, Mitochondrial/drug effects , Oxidative Stress/drug effects , Propionates/pharmacology , Animals , Autophagy , In Vitro Techniques , Melanoma, Experimental/drug therapy , Mice , Mice, Inbred C57BL , Reactive Oxygen Species/metabolism , Tumor Cells, Cultured
2.
J Inorg Biochem ; 172: 55-66, 2017 07.
Article in English | MEDLINE | ID: mdl-28433833

ABSTRACT

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.


Subject(s)
Ascorbic Acid/metabolism , Esters/pharmacology , Ethylenediamines/chemistry , Gold/pharmacology , Serum Albumin, Bovine/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Ascorbic Acid/chemistry , Cell Cycle/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Dose-Response Relationship, Drug , Drug Stability , Esters/chemical synthesis , Esters/chemistry , Gold/chemistry , Gold/metabolism , HeLa Cells , Humans , K562 Cells , Ligands , Magnetic Resonance Spectroscopy , Molecular Structure , Quantum Theory , Serum Albumin, Bovine/chemistry , Time Factors
3.
Chem Biol Drug Des ; 90(2): 262-271, 2017 08.
Article in English | MEDLINE | ID: mdl-28102932

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Leukemia/drug therapy , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Ethylenediamines/chemical synthesis , Ethylenediamines/chemistry , Ethylenediamines/pharmacology , Halogenation , Humans , Leukemia/metabolism , Ligands , Organoplatinum Compounds/chemical synthesis , Oxidative Stress/drug effects
4.
Anticancer Agents Med Chem ; 17(8): 1136-1143, 2017.
Article in English | MEDLINE | ID: mdl-27928952

ABSTRACT

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.


Subject(s)
Alanine/analogs & derivatives , Antineoplastic Agents/pharmacology , Esters/pharmacology , Ethylenediamines/pharmacology , Organoplatinum Compounds/pharmacology , Alanine/chemistry , Alanine/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Death/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Esters/chemistry , Ethylenediamines/chemistry , Humans , Molecular Structure , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Quantum Theory , Structure-Activity Relationship , Tumor Cells, Cultured
5.
Biometals ; 28(2): 425-30, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25715906

ABSTRACT

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.


Subject(s)
Coordination Complexes/chemistry , Dimethyl Sulfoxide/chemistry , Muramidase/chemistry , Gold/chemistry , Platinum/chemistry , Ruthenium/chemistry , Solutions , Solvents/chemistry , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Ultraviolet
6.
Eur J Med Chem ; 90: 766-74, 2015 Jan 27.
Article in English | MEDLINE | ID: mdl-25528331

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Esters/pharmacology , Ethylenediamines/pharmacology , Organogold Compounds/pharmacology , Propionates/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Esters/chemical synthesis , Esters/chemistry , Ethylenediamines/chemistry , HeLa Cells , Humans , K562 Cells , Models, Molecular , Molecular Structure , Organogold Compounds/chemical synthesis , Organogold Compounds/chemistry , Propionates/chemistry , Structure-Activity Relationship
7.
Eur J Med Chem ; 82: 372-84, 2014 Jul 23.
Article in English | MEDLINE | ID: mdl-24927057

ABSTRACT

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).


Subject(s)
Antineoplastic Agents/pharmacology , Organoplatinum Compounds/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Death/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Models, Molecular , Molecular Structure , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
8.
Bioorg Chem ; 54: 73-80, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24836201

ABSTRACT

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.


Subject(s)
Alanine/analogs & derivatives , Antineoplastic Agents/pharmacology , Esters/pharmacology , Reactive Oxygen Species/metabolism , Alanine/chemical synthesis , Alanine/chemistry , Alanine/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Astrocytes/drug effects , Cell Cycle/drug effects , Cell Death/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Esters/chemical synthesis , Esters/chemistry , Humans , Mice , Molecular Structure , Oxidative Stress/drug effects , Rats , Rats, Wistar , Structure-Activity Relationship
9.
J Inorg Biochem ; 128: 146-53, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23988849

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/chemistry , Esters/chemistry , Gold/chemistry , Organoplatinum Compounds/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Cycle/drug effects , Cell Survival/drug effects , Cells, Cultured , HeLa Cells , Humans , Inhibitory Concentration 50 , K562 Cells , Models, Chemical , Molecular Structure , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/pharmacology , Oxidation-Reduction
10.
Metallomics ; 4(11): 1155-9, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23014886

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Melanoma, Experimental/drug therapy , Organoplatinum Compounds/pharmacology , Analysis of Variance , Animals , Cell Cycle/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Cisplatin/pharmacology , Drug Screening Assays, Antitumor , Mice , Mice, Inbred C57BL , Organoplatinum Compounds/therapeutic use
11.
Metallomics ; 4(9): 979-87, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22820831

ABSTRACT

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.


Subject(s)
Apoptosis/drug effects , Caspases/metabolism , Colonic Neoplasms/enzymology , Colonic Neoplasms/pathology , Drug Resistance, Neoplasm/drug effects , Organoplatinum Compounds/pharmacology , Animals , Cell Line, Tumor , Cell Survival/drug effects , Cisplatin/chemistry , Cisplatin/pharmacology , Cisplatin/toxicity , Humans , Ligands , Mice , Molecular Conformation , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/toxicity , Oxidative Stress/drug effects , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism
12.
J Inorg Biochem ; 109: 40-8, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22369771

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/chemical synthesis , Coordination Complexes/chemical synthesis , Cyclohexanes/chemical synthesis , Ethylenediamines/chemical synthesis , Organoplatinum Compounds/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Edetic Acid/chemistry , Ethylenediamines/chemistry , Ethylenediamines/pharmacology , Flow Cytometry , Humans , Magnetic Resonance Spectroscopy , Mice , Molecular Structure , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Spectrometry, Mass, Electrospray Ionization , Spectroscopy, Fourier Transform Infrared
13.
Eur J Med Chem ; 47(1): 194-201, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22071257

ABSTRACT

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.


Subject(s)
Diamines/chemistry , Immunologic Factors/chemistry , Immunologic Factors/pharmacology , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Platinum/chemistry , Animals , Cell Survival/drug effects , Interferon-gamma/metabolism , Interleukin-17/metabolism , Ligands , Lymph Nodes/cytology , Lymph Nodes/immunology , Mice , Nitric Oxide/biosynthesis , Peritoneum/drug effects , Peritoneum/metabolism , Rats , Spleen/cytology , Spleen/immunology
14.
ChemMedChem ; 6(10): 1884-91, 2011 Oct 04.
Article in English | MEDLINE | ID: mdl-21805645

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/pharmacology , Ethylenediamines/chemistry , Ruthenium/chemistry , Cell Line, Tumor , Humans , Ligands , Neoplasms/drug therapy , Stereoisomerism , Structure-Activity Relationship
15.
Eur J Med Chem ; 45(9): 3601-6, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20570025

ABSTRACT

Four novel bidentate N,N'-ligand precursors, including O,O'-dialkyl esters (alkyl = ethyl, n-propyl, n-butyl and n-pentyl), L1 x 2 HCl-L4 x 2 HCl, of (S,S)-ethylenediamine-N,N'-di-2-(4-methyl)-pentanoic acid dihydrochloride [(S,S)-H(4)eddl]Cl(2) and the corresponding palladium(II) complexes 1-4, were prepared and characterized by IR, (1)H NMR and (13)C NMR spectroscopy and elemental analysis. In vitro cytotoxicity of all compounds was determined against chronic lymphocytic leukemia cells (CLL). The compounds were found to exhibit higher antitumoral activity than cisplatin. The most active compound 2, [PdCl(2){(S,S)-nPr(2)eddl}], was found to be 13.6 times more active than cisplatin on CLL cells.


Subject(s)
Edetic Acid/analogs & derivatives , Ethylenediamines/chemistry , Leucine/analogs & derivatives , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Organometallic Compounds/chemical synthesis , Organometallic Compounds/pharmacology , Palladium/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Edetic Acid/chemistry , Esters , Humans , Inhibitory Concentration 50 , Leucine/chemistry , Ligands , Organometallic Compounds/chemistry , Spectrum Analysis
16.
ChemMedChem ; 5(6): 881-9, 2010 Jun 07.
Article in English | MEDLINE | ID: mdl-20408161

ABSTRACT

The present study describes the synthesis and anticancer activity of novel octahedral Pt(IV) complexes with cyclohexyl functionalized ethylenediamine-N,N'-diacetate-type ligands. Molecular mechanics calculations and density functional theory analysis revealed that s-cis is the preferred geometry of these Pt(IV) complexes with tetradentate-coordinated (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate. The viability of cancer cell lines (U251 human glioma, C6 rat glioma, L929 mouse fibrosarcoma, and B16 human melanoma) was assessed by measuring mitochondrial dehydrogenase activity and lactate dehydrogenase release. Cell-cycle distribution, oxidative stress, caspase activation, and induction of autophagy were analyzed by flow cytometry using appropriate fluorescent reporter dyes. The cytotoxic activity of novel Pt(IV) complexes against various cancer cell lines (IC(50) range: 1.9-8.7 microM) was higher than that of cisplatin (IC(50) range: 10.9-67.0 microM) and proceeded through completely different mechanisms. Cisplatin induced caspase-dependent apoptosis associated with the cytoprotective autophagic response. In contrast, the new Pt(IV) complexes caused rapid, caspase-independent, oxidative stress-mediated non-apoptotic cell death characterized by massive cytoplasmic vacuolization, cell membrane damage, and the absence of protective autophagy.


Subject(s)
Antineoplastic Agents/chemical synthesis , Coordination Complexes/chemical synthesis , Ethylenediamines/chemistry , Platinum/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Apoptosis , Cell Line, Tumor , Cisplatin/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/toxicity , Humans , Ligands , Mice , Rats
17.
Eur J Med Chem ; 44(9): 3452-8, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19272676

ABSTRACT

New R(2)eddip-type esters (R = cyclopentyl, L3 x 2 HCl 1.5 H(2)O; cyclohexyl, L4 x 2 HCl x H(2)O) and corresponding palladium(II) complexes, [PdCl(2)L3] (3) and [PdCl(2)L4] x H(2)O (4), as well as [PdCl(2)L2] (2; L2 diisobutyl ester of eddip) were synthesized and characterized by IR, (1)H and (13)C NMR spectroscopies and elemental analysis. The crystal structure of L3 x 2 HCl x 2 CHCl(3) was resolved and is given herein. The NMR spectroscopy confirmed the presence of two isomers (from three possible) for each palladium(II) complex. DFT calculations support the formation of two diastereoisomers. In addition, antitumoral investigations were performed and these investigations also included the diisopropyl ester of eddip (L1) and corresponding palladium(II) complex, [PdCl(2)L1] (1). In vitro antiproliferative activity was determined against several tumor cell lines HeLa, Fem-x, K562 and rested and stimulated normal immunocompetent cells (human peripheral blood mononuclear cells--PBMCs) using MTT test.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Palladium/chemistry , Palladium/pharmacology , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Humans , Isomerism , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Ligands , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Quantum Theory
18.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 3): o656-7, 2009 Feb 28.
Article in English | MEDLINE | ID: mdl-21582304

ABSTRACT

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.

19.
J Inorg Biochem ; 102(8): 1558-70, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18353439

ABSTRACT

A variety of substituted titanocene and ansa-titanocene complexes have been synthesized and characterized using traditional methods. The cytotoxic activity of the different titanocene complexes was tested against tumour cell lines human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x and normal immunocompetent cells, peripheral blood mononuclear cells PBMC. Alkenyl substitution, either on the cyclopentadienyl ring or on the silicon-atom ansa-bridge of the titanocene compounds [Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(3){CMe(2)CH(2)CH(2)CHCH(2)})}Cl(2)] (8), [Ti{Me(CH(2)CH)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (9) and [Ti(eta(5)-C(5)H(4){CMe(2)CH(2)CH(2)CHCH(2)})(2)Cl(2)] (12) showed higher cytotoxic activities (IC(50) values from 24+/-3 to 151+/-10 microM) relative to complexes bearing an additional alkenyl-substituted silyl substituent on the silicon bridge [Ti{Me{(CH(2)CH)Me(2)SiCH(2)CH(2)}Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (10) and [Ti{Me{(CH(2)CH)(3)SiCH(2)CH(2)}Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (11) which causes a dramatic decrease of the cytotoxicity (IC(50) values from 155+/-9 to >200 microM). In addition, the synthesis of the analogous niobocene complex [Nb(eta(5)-C(5)H(4){CMe(2)CH(2)CH(2)CH=CH(2)})(2)Cl(2)] (13), is described. Structural studies based on DFT calculations of the most active complexes 8, 9 and 12 and the X-ray crystal structure of 13 are reported.


Subject(s)
Antineoplastic Agents/chemistry , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Leukocytes, Mononuclear/drug effects , Molecular Structure , Structure-Activity Relationship
20.
J Inorg Biochem ; 102(4): 892-900, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18226835

ABSTRACT

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.


Subject(s)
Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/pharmacology , Propionates/chemical synthesis , Propionates/pharmacology , Crystallography, X-Ray , HeLa Cells , Humans , Ligands , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Spectrophotometry, Infrared
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