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1.
Photochem Photobiol Sci ; 23(9): 1757-1769, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39242437

RESUMEN

Porphyrazines (Pzs) are porphyrin derivatives that show potential application as photosensitizers for photodynamic therapy (PDT), but are still far less explored in the literature. In this work, we evaluate how the photophysics and phototoxicity of the octakis(trifluoromethylphenyl)porphyrazine (H2Pz) against tumor cells can be modulated by coordination with Mg(II), Zn(II), Cu(II) and Co(II) ions. Fluorescence and singlet oxygen quantum yields for the Pzs were measured in organic solvents and in soy phosphatidylcholine (PC) liposomes suspended in water. While H2Pz and the respective complexes with Cu(II) and Co(II) showed very low efficiency to fluoresce and to produce 1O2, the Mg(II) and Zn(II) complexes showed significantly higher quantum yields in organic solvents. The fluorescence of these two Pzs in the liposomes was sensitive to the fluidity of the membrane, showing potential use as viscosity markers. The cytotoxicity of the compounds was tested in HaCaT (normal) and A431 (tumor) cells using soy PC liposomes as drug carriers. Despite the low 1O2 quantum yields in water, the Mg(II) and Zn(II) complexes showed IC50 values against A431 cells in the nanomolar range when activated with low doses of red LED light. Their phototoxicity was ca. three times higher for the tumor cells compared to the normal ones, showing promising application as photosensitizers for PDT protocols. Considering that H2Pz and the respective Co(II) and Cu(II) complexes were practically non-phototoxic to the cells, we demonstrate the importance of the central metal ion in the modulation of the photodynamic activity of porphyrazines.


Asunto(s)
Liposomas , Fármacos Fotosensibilizantes , Porfirinas , Humanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Porfirinas/química , Porfirinas/farmacología , Liposomas/química , Fotoquimioterapia , Oxígeno Singlete/metabolismo , Oxígeno Singlete/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Zinc/química , Zinc/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Iones/química
2.
J Inorg Biochem ; 246: 112303, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37413946

RESUMEN

Cancer is one of the main public health problems globally, there is a public demand for better drugs. Rational strategies or approaches are used to improve the success of drug discovery. Our strategy was to the repurposing of well-known antifungal agents as potential anticancer drugs, such as Clotrimazole (CTZ) and Ketoconazole (KTZ). We prepared the respective iodide imidazolium salt L1: (CTZ-Me)I and L2: (KTZ-Me)I to be the intermediates toward the synthesis of its respective NHC ligand and achieve the respective silver(I)-monoNHC and silver(I)-bisNHC derivatives: [Ag(L1)I] (1), [AgI(L2)] (2) [Ag(L1)2]I. (3), [Ag(L2)2]I. (4), as well as their corresponding coordination compounds [Ag(CTZ)2]NO3 (5) and [Ag(KTZ)2]NO3 (6) where these ligands (CTZ and KTZ) coordinate to silver through the N-imidazole atom. These compounds (L1, L2 and complexes 1-6) exhibited significant activity against the tested cancer cell lines (B16-F1, murine melanoma strains and CT26WT, murine colon carcinoma). The silver(I) complexes were more active than the free ligands, complexes 2 and 4 being the most selective in B16-F1 cancer cell line. Two possibles biological targets such as DNA and albumin were examined for the observed anticancer activity. Results show that DNA is not the main target, however, the interactions with albumin suggest it can transport/delivery the metal complexes.


Asunto(s)
Antineoplásicos , Complejos de Coordinación , Neoplasias , Humanos , Animales , Ratones , Preparaciones Farmacéuticas , Azoles/farmacología , Plata/farmacología , Ligandos , Antineoplásicos/farmacología , Cetoconazol , Complejos de Coordinación/farmacología , Clotrimazol
3.
Dalton Trans ; 50(41): 14908-14919, 2021 Oct 26.
Artículo en Inglés | MEDLINE | ID: mdl-34609400

RESUMEN

Although there are various treatment options for cancer, this disease still has caused an increasing number of deaths, demanding more efficient, selective and less harmful drugs. Several classes of ruthenium compounds have been investigated as metallodrugs for cancer, mainly after the entry of imidazolH [trans-RuCl4-(DMSO-S)(imidazole)] (NAMI-A) and indazolH [trans-RuCl4-(Indazol)2] (KP1019) in clinical trials. In this sense, RuII complexes with general formula [Ru(L1-3)(bipy)2]PF6 (1-3) (L1 = ethyl 3-(6-methyl-2-oxo-2H-chromen-3-yl)-3-oxopropanoate, L2 = ethyl 3-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-3-oxopropanoate, L3 = ethyl 3-(8-methoxy-2-oxo-2H-chromen-3-yl)-3-oxopropanoate and bipy = bipyridine) have been synthesized. The crystal structure of 2 revealed that the RuII atom lies on a distorted octahedral geometry with the deprotonated ligand (L2-) coordinated through ß-ketoester group oxygen atoms. In vitro cytotoxic activity of the compounds was evaluated against 4T1 (murine mammary carcinoma) and B16-F10 (murine metastatic melanoma) tumor cells, and the non-tumor cell line BHK-21 (baby hamster kidney). Coordination with RuII resulted in expressive enhancement of cytotoxic activity. The precursors were inactive below 100 µM and the final RuII complexes (1-3) showed IC50 ranging from 2.0 to 12.8 µM; 2 being the most potent compound. DNA interaction studies revealed a greater capacity of the complexes to interact with DNA than the ligands, where, 2 exhibited the highest Kb constant of 2.2 × 104 M-1. Fluorescence investigation demonstrated that 1-3 are capable of quenching the fluorescence emission of the EtdBr-DNA complex up to 40%. Molecular docking showed that the interaction of 1-3 between the DNA base pairs from the coumarin portion was with scores of 67.28, 68.62 and 64.88, respectively, and 75.45 for ellipticine, suggesting an intercalative mode of binding. Our findings show that the RuII complexes are eligible for continuing to be investigated as potential antitumor compounds.


Asunto(s)
Simulación del Acoplamiento Molecular
4.
Chem Biol Drug Des ; 97(1): 41-50, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32657521

RESUMEN

Four gold(I) complexes conceived as anticancer agents were synthesized by reacting [Au(PEt3 )Cl] and [Au(PPh3 )Cl] with ligands derived from δ-d-gluconolactone. The ligands' structure was designed to combine desired biological properties previously reported for each group. Ligands were synthesized from δ-d-gluconolactone via ketal protection and hydrazide formation followed by cyclization with CS2 to produce the novel oxadiazolidine-2-thione 7 and 8. Increasing of the ligands' lipophilicity via ketal protection proved useful since all four gold(I) complexes showed anticancer and antileishmanial properties. The IC50 values are at low micromolar range, varying from 2 to 3 µm for the most active compounds. The free D-gluconate 1,3,4 oxadiazole-derived ligands were neither toxic nor presented anticancer or antileishmanial properties. Triethylphosphine-derived compounds 9 and 10 were more selective against B16-F10 melanoma cell line. Although similar in vitro antileishmanial activity was observed for the gold(I) precursors themselves and their derived complexes, the latter were three times less toxic for human THP-1 macrophage cell line; this result is attributed to an isomeric variation of the D-gluconate ligand and the oxadiazole portion, which was one of the key concepts behind this work. These findings should encourage further research on gold(I) complexes to develop novel compounds with potential application in cancer and leishmaniasis chemotherapy.


Asunto(s)
Antineoplásicos/química , Antiprotozoarios/química , Complejos de Coordinación/química , Gluconatos/química , Oro/química , Lactonas/química , Tionas/química , Animales , Antineoplásicos/farmacología , Antiprotozoarios/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Ciclización , Humanos , Leishmania/efectos de los fármacos , Ligandos , Ratones , Oxadiazoles/química , Relación Estructura-Actividad
5.
Chem Biol Interact ; 331: 109218, 2020 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-32916141

RESUMEN

Flavonoids are natural products widely recognized for their plurality of applications such as antiviral, antiproliferative, antitumor activities and, antioxidant properties. The flavanone naringenin is presented in citrus fruits and has been studied to combat recurrent diseases that still lack effective treatment. Research groups have been investing efforts to the development of new, safe and active candidates to combat these agents or conditions and despite good results recently reported against the Zika virus (ZIKV) and tumor cells, the use of citrus naringenin is limited due to its low bioavailability. Structural exchanges through functionalization, for example, attaching lipophilic groups instead of hydroxyl groups, can further enhance biological properties. Here, the synthesis and characterization of regioselective naringenin mono-7-O-ethers and both mono and di-fatty acid esters, structurally lipophilic ones were demonstrated. Finally, in vitro studies of anti-ZIKV action and antiproliferative activities against melanoma (B16-F10) and breast carcinoma (4T1) cells showed the ether derivatives were actives, with IC50 ranging from 6.76, 18.5 and 22.6 µM to 28.53, 45.1 and 32.3 µM referring to ZIKV, B16-F10 and 4T1 cell lines, respectively. The lipophilic ethers present the ability to inhibit selectively ZIKV-replication in human cells and inhibitions. This class of modifications in flavonoid molecules could be further explore in the future development of specific anti-ZIKV compounds.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Antivirales/farmacología , Citrus/química , Flavanonas/química , Virus Zika/efectos de los fármacos , Animales , Antineoplásicos Fitogénicos/química , Antivirales/química , Productos Biológicos/química , Productos Biológicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citrus/metabolismo , Flavanonas/farmacología , Humanos , Ratones , Replicación Viral/efectos de los fármacos , Virus Zika/fisiología
6.
Bioorg Chem ; 100: 103936, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32438131

RESUMEN

The synthesis and structural characterization of novel platinum complexes ([PtII(Pz)2Cl2] - C1, C2 and C3) featuring diphenyl-pyrazole derived ligands: para-fluorophenyl and para-substituted phenyl (CH3, F and Cl for L1, L2 and L3, respectively) were reported and it was also evaluated their potential antitumor activity. The elemental, molar conductivity and thermogravimetric analysis combined with FTIR, UV-vis, NMR and mass spectrometry are in agreement with the chemical structure indicated by single-crystal X-ray diffraction. The antiproliferative activities were assessed against tumor (B16F10 and 4T1) and non-tumor (BHK21) cell lines, and the cytotoxicity of the compounds was strongly increased after metal complexation displaying promising activity. It was also assessed the ability of extracellular bovine serum albumin (BSA) and glutathione (GSH) to decrease the cytotoxicity of the complexes against B16F10. It was highlighted that only the C3 activity was not disturbed in those conditions, being confirmed by flow cytometry using Anexin-V/PI to evaluate interferences in the apoptosis process, even it was not predicted by molecular docking simulations. The interaction of the synthesized compounds with calf-thymus DNA (ctDNA) and bovine serum albumin (BSA) was also investigated through spectrophotometric assays and molecular docking simulations, indicating that C1 and C2 presented better interaction with the biomacromolecules than the corresponding ligands. In addition, agarose gel electrophoresis with plasmid DNA revealed that C1-C3 are capable of interaction with DNA and modify its electrophoretic mobility.


Asunto(s)
Complejos de Coordinación/síntesis química , Glutatión/química , Platino (Metal)/química , Pirazoles/química , Albúmina Sérica Bovina/química , Animales , Apoptosis/efectos de los fármacos , Sitios de Unión , Bovinos , Línea Celular , Complejos de Coordinación/química , Complejos de Coordinación/metabolismo , Complejos de Coordinación/farmacología , ADN/química , ADN/metabolismo , Glutatión/metabolismo , Ratones , Conformación Molecular , Simulación del Acoplamiento Molecular , Unión Proteica , Albúmina Sérica Bovina/metabolismo
7.
ACS Infect Dis ; 6(5): 1121-1139, 2020 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-32283915

RESUMEN

The drugs currently used to treat leishmaniases have limitations concerning cost, efficacy, and safety, making the search for new therapeutic approaches urgent. We found that the gold(I)-derived complexes were active against L. infantum and L. braziliensis intracellular amastigotes with IC50 values ranging from 0.5 to 5.5 µM. All gold(I) complexes were potent inhibitors of trypanothione reductase (TR), with enzyme IC50 values ranging from 1 to 7.8 µM. Triethylphosphine-derived complexes enhanced reactive oxygen species (ROS) production and decreased mitochondrial respiration after 2 h of exposure, indicating that gold(I) complexes cause oxidative stress by direct ROS production, by causing mitochondrial damage or by impairing TR activity and thus accumulating ROS. There was no cross-resistance to antimony; in fact, SbR (antimony-resistant mutants) strains were hypersensitive to some of the complexes. BALB/c mice infected with luciferase-expressing L. braziliensis or L. amazonensis and treated orally with 12.5 mg/kg/day of AdT Et (3) or AdO Et (4) presented reduced lesion size and parasite burden, as revealed by bioimaging. The combination of (3) and miltefosine allowed for a 50% reduction in miltefosine treatment time. Complexes 3 and 4 presented favorable pharmacokinetic and toxicity profiles that encourage further drug development studies. Gold(I) complexes are promising antileishmanial agents, with a potential for therapeutic use, including in leishmaniasis caused by antimony-resistant parasites.


Asunto(s)
Antiprotozoarios/farmacología , Oro/farmacología , Leishmaniasis , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , Animales , Leishmaniasis/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Estrés Oxidativo
8.
J Biol Inorg Chem ; 24(7): 1087-1103, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31620894

RESUMEN

Synthesis of dinuclear oxadiazole-adamantane platinum(II) and palladium(II) complexes (PtO, PdO) and mononuclear thiazolidine derivative complexes (PtT, PdT) was described. Characterization was performed by elemental analysis, infrared, UV-visible, 1H, 13C, 195Pt NMR spectra, MS spectroscopy and single crystal X-ray diffraction. The cytotoxicity by MTT assay against tumor and normal cell lines with or without extracellular GSH was also investigated. In general, mononuclear complexes containing thiazolidine-adamantane ligands were more cytotoxic than oxadiazole-adamantane derivatives. PtT complex proved to be as active as cisplatin. Dinuclear compounds were considered inactive to cells in evaluated conditions, due to their high stability with ligands in a chelated and bridged way. Results suggest that GSH cannot be considered a target. DNA- and BSA-binding interactions were evaluated using UV-visible and fluorescence spectroscopy, intercalating dyes and molecular docking. Upon coordination to platinum(II), the cytotoxic effect was appreciably improved against tested cell lines, in comparison to free thiazolidine ligand. Comparing thiazolidine derivatives, it is noticeable that the less active compound (PdT) presents stronger interaction with BSA, while PtT has the weaker interaction with BSA and relatively strong binding to isolated DNA, resulting in the most cytotoxic complex. This work shows that the presence of metal is significant but it should be available for interaction. The high lability of palladium complex made this stay retainable in BSA and two metal atoms do not increase activity if it is not able to do any interaction.


Asunto(s)
Adamantano/química , Azoles/química , ADN/metabolismo , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacología , Paladio/química , Animales , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Cricetinae , ADN/química , Humanos , Lignanos , Ratones , Simulación del Acoplamiento Molecular , Conformación de Ácido Nucleico , Compuestos Organoplatinos/metabolismo
9.
Eur J Med Chem ; 165: 18-30, 2019 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-30654237

RESUMEN

A series of1,2,4- and 1,3,4-oxadiazole derivatives were synthesized and evaluated for their anticancer activity. Halogenated 1,2,4-oxadiazoles were obtained from benzonitrile and coupled either lipophilic amines or with aminoalcohols. Lipophilic 1,3,4-oxadiazole derivatives were obtained through the Mannich reactions between 5-(aryl)-1,3,4-oxadiazole-2-thiol and alkylated or acylated amines. The in vitro cytotoxic effects were evaluated against 4T1- mammary carcinoma and CT26 - colon cancer cells. The best results were obtained for the 1,3,4-oxadiazole coupled to alkylated piperazine with 10-14 carbon chain moiety, with IC50 values ranging from 1.6 to 3.55µΜ for the 4T1 cell line, and from 1.6 to 3.9 µM for the CT26.WT cell line, and selectivity index up to 19. The most potent compounds were investigated with AnnexinV and PI staining as indicative of apoptosis induction.


Asunto(s)
Antineoplásicos/química , Oxadiazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Oxadiazoles/síntesis química , Oxadiazoles/química , Relación Estructura-Actividad
10.
Biometals ; 30(6): 859, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29022284

RESUMEN

This article has been corrected. One of the author names was given incorrect. Please find in this erratum the correct author name: "Heloiza Diniz Nicolella" that should be regarded as final by the reader.

11.
Biometals ; 30(6): 841-857, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-28840394

RESUMEN

Novel lipophilic gold(I) complexes containing 1,3,4-oxadiazol-2-thione or 1,3-thiazolidine-2-thione derivatives were synthesized and characterized by IR, high resolution mass spectrometry, and 1H, 13C 31P NMR. The cytotoxicity of the compounds was evaluated considering cisplatin and/or auranofin as reference in different tumor cell lines: colon cancer (CT26WT), metastatic skin melanoma (B16F10), breast adenocarcinoma (MCF-7), cervical carcinoma (HeLa), glioblastoma (M059 J). Normal human lung fibroblasts (GM07492-A) and kidney normal cell (BHK-21) were also evaluated. The gold(I) complexes were more active than their respective free ligands and cisplatin. Furthermore, antibacterial activity was evaluated against Gram-positive bacteria Staphylococcus aureus ATCC 25213, Staphylococcus epidermidis ATCC 12228 and Gram-negative bacteria Escherichia coli ATCC 11229 and Pseudomonas aeruginosa ATCC 27853 and expressed as the minimum inhibitory concentration (MIC). The complexes exhibited lower MIC values when compared to the ligands and chloramphenicol against Gram-positive bacteria and Gram-negative bacteria. Escherichia coli was sensitive one to the action of gold(I) complexes.


Asunto(s)
Antibacterianos/farmacología , Antineoplásicos/farmacología , Compuestos Orgánicos de Oro/química , Compuestos Orgánicos de Oro/farmacología , Animales , Antibacterianos/síntesis química , Antibacterianos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Técnicas de Química Sintética , Cricetinae , Evaluación Preclínica de Medicamentos , Escherichia coli/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Pruebas de Sensibilidad Microbiana , Compuestos Orgánicos de Oro/síntesis química , Pseudomonas aeruginosa/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Tionas/química
12.
Eur J Med Chem ; 127: 727-739, 2017 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-27823888

RESUMEN

The current anticancer and antileishmanial drug arsenal presents several limitations concerning their specificity, efficacy, costs and the emergence of drug-resistant cells lines, which encourages the urgent need to search for new alternatives. Inspired by the fact that gold(I)-based compounds are promising antitumoral and antileishmanial drug candidates, we synthesized novel gold(I) complexes containing phosphine and 5-phenyl-1,3,4-oxadiazole-2-thione and evaluated their anticancer and antileishmanial activities. Synthesis was performed by reacting 5-phenyl-1,3,4-oxadiazole-2-thione derivatives with chloro(triphenylphosphine)gold(I) and chloro(triethylphosphine)gold(I). The novel compounds were characterized by infrared, Raman, 1H, 13C nuclear magnetic resonance, high-resolution mass spectra, and x-ray crystallography. The coordination of the ligands to gold(I) occurred through the exocyclic sulfur atom. All gold(I) complexes were active at low micromolar or nanomolar range with IC50 values ranging from <0.10 to 1.66 µM against cancer cell lines and from 0.9 to 4.2 µM for Leishmania infantum intracellular amastigotes. Compound (6-A) was very selective against murine melanoma B16F10, colon cancer CT26.WT cell lines and L. infantum intracellular amastigotes. Compound (7-B) presented the highest anticancer activity against both cancer cell lines while the promising antileishmanial lead was compound (6-A). Tiethylphosphine gold(I) complexes were more active than the conterparts triphenylphosphine derivatives for both anticancer and antileishmanial activities. Triethylphosphine gold(I) derivatives presented antimony cross-resistance in L. guyanensis demonstrating their potential to be used as chemical tools to better understand mechanisms of drug resistance and action. These findings revealed the anticancer and antileishmanial potential of gold(I) oxadiazole phosphine derivatives.


Asunto(s)
Diseño de Fármacos , Oro/química , Leishmania infantum/efectos de los fármacos , Compuestos Orgánicos de Oro/química , Compuestos Orgánicos de Oro/farmacología , Oxadiazoles/química , Fosfinas/química , Antimonio/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Antiprotozoarios/química , Antiprotozoarios/farmacología , Línea Celular Tumoral , Resistencia a Medicamentos/efectos de los fármacos , Humanos
13.
J Biol Inorg Chem ; 21(2): 275-92, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26841791

RESUMEN

Gold complexes that could act as antitumor agents have attracted great attention. Heterocyclic compounds and their metal complexes display a broad spectrum of pharmacological properties. The present study reports the preparation and characterization of four novel gold(I) complexes containing tertiary phosphine and new ligands 5-adamantyl-1,3-thiazolidine-2-thione, 3-methyladamantane-1,3,4-oxadiazole-2-thione. Spectroscopic data suggest that gold is coordinated to the exocyclic sulfur atom in all cases, as confirmed by X-ray crystallographic data obtained for complex (1) and supported by quantum-mechanical calculations. The cytotoxicity of the compounds has been evaluated in comparison to cisplatin and auranofin in three different tumor cell lines, colon cancer (CT26WT), metastatic skin melanoma (B16F10), mammary adenocarcinoma (4T1) and kidney normal cell (BHK-21). The gold complexes were more active than their respective free ligands and able to inhibit the thioredoxin reductase (TrxR) enzyme, even in the presence of albumin. Molecular modeling studies were carried out to understand the interaction between the compounds and the TrxR enzyme, considered as a potential target for new compounds in cancer treatment. The docking results show that the adamantane ring is essential to stabilize the ligand-enzyme complex prior the formation of covalent bond with gold center. The structure of the new gold compounds was established on the basis of spectroscopic data, DFT calculations and X-ray diffraction. TrxR inhibition was evaluated and the results correlated with the assays in tumor cells, suggesting the TrxR as possible target for these compounds.


Asunto(s)
Adamantano/farmacología , Antineoplásicos/farmacología , Azoles/química , Oro/química , Reductasa de Tiorredoxina-Disulfuro/antagonistas & inhibidores , Adamantano/química , Animales , Línea Celular Tumoral , Cricetinae , Humanos , Ratones , Análisis Espectral/métodos
14.
Biometals ; 28(5): 845-60, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26091950

RESUMEN

Novel gold(I) and gold(III) complexes containing derivatives of D-galactose, D-ribose and D-glucono-1,5-lactone as ligands were synthesized and characterized by IR, (1)H, and (13)C NMR, high resolution mass spectra and cyclic voltammetry. The compounds were evaluated in vitro for their cytotoxicity against three types of tumor cells: cervical carcinoma (HeLa) breast adenocarcinoma (MCF-7) and glioblastoma (MO59J) and one non-tumor cell line: human lung fibroblasts (GM07492A). Their antitubercular activity was evaluated as well expressed as the minimum inhibitory concentration (MIC90) in µg/mL. In general, the gold(I) complexes were more active than gold(III) complexes, for example, the gold(I) complex (1) was about 8.8 times and 7.6 times more cytotoxic than gold(III) complex (8) in MO59J and MCF-7 cells, respectively. Ribose and alkyl phosphine derivative complexes were more active than galactose and aryl phosphine complexes. The presence of a thiazolidine ring did not improve the cytotoxicity. The study of the cytotoxic activity revealed effective antitumor activities for the gold(I) complexes, being more active than cisplatin in all the tested tumor cell lines. Gold(I) compounds (1), (2), (3), (4) and (6) exhibited relevant antitubercular activity even when compared with first line drugs such as rifampicin.


Asunto(s)
Carbohidratos/química , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/química , Oro/química , Carbohidratos/administración & dosificación , Carbohidratos/síntesis química , Cisplatino/administración & dosificación , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Oro/administración & dosificación , Células HeLa , Humanos , Ligandos , Pulmón/efectos de los fármacos , Pulmón/patología , Células MCF-7 , Espectroscopía de Resonancia Magnética , Rifampin/administración & dosificación , Relación Estructura-Actividad
15.
Anticancer Drugs ; 24(2): 131-9, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23011234

RESUMEN

Liposome encapsulation of platinum (Pt) drugs has emerged as a promising strategy to overcome their toxicity and cellular Pt resistance. The aim of the present work was to examine the impact of liposome encapsulation of a novel antitumor lipophilic Pt complex, dichloro-(N-dodecyl)-propanediamine-platinum(II) complex (DDPP), on its pharmacological profile as an antitumor agent. Biological assays included acute toxicity and histopathological evaluations, pharmacokinetics, and growth inhibition of B16-F1 tumor cells in C57Bl/6 mice. Comparison was made with cisplatin and free DDPP dissolved in castor oil. DDPP encapsulated in pegylated liposomes showed reduced acute toxicity in mice following intraperitoneal administration, compared with the free complex. Free DDPP at 5 mg Pt/kg induced histopathological alterations in the liver, in contrast to liposomal DDPP and cisplatin. Interestingly, the marked loss of body weight following the treatment of mice with cisplatin was not observed after liposomal DDPP at the same Pt dose. Liposomal DDPP was found to inhibit tumor growth significantly, when administered at 5 mg Pt/kg/day for 3 days, similar to cisplatin, but in contrast to the free complex. Pharmacokinetic studies after intraperitoneal and intravenous administrations at 5 mg Pt/kg indicated greater and more prolonged Pt levels in the plasma, liver, spleen, and kidneys from liposomal DDPP, compared with free DDPP or cisplatin. The tumor concentration of Pt increased after liposomal DDPP over the 24-h period, whereas it decreased after cisplatin. In conclusion, the encapsulation of DDPP in pegylated liposomes reduced the drug toxicity and enhanced its antitumoral activity in mice, as a result of improved drug pharmacokinetics.


Asunto(s)
Antineoplásicos/administración & dosificación , Liposomas/administración & dosificación , Compuestos Organoplatinos/administración & dosificación , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Cisplatino/farmacocinética , Cisplatino/farmacología , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Inyecciones Intraperitoneales , Liposomas/química , Masculino , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C57BL , Neoplasias/tratamiento farmacológico , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacocinética , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Distribución Tisular
16.
J Inorg Biochem ; 115: 13-9, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22922288

RESUMEN

A series of novel platinum(II) complexes derived from N-alkyl-ethanediamine and N-alkyl-propanediamine ligands were prepared and characterized. These complexes contain a long chain aliphatic diamine where the carbon length is variable and present a hydroxyl group in two different positions. The complexes with the ethanediamine derivatives were prepared from K(2)PtCl(4). Interestingly, the propanediamine derivatives did not react well with this platinum salt under the experimental conditions normally employed and could only be obtained from the more reactive K(2)PtI(4). A theoretical molecular modeling study was performed to understand this difference in reactivity and it showed that the conformation around the diamine plays an important role in the ring closure step of complex formation. The complexes had their cytotoxicity investigated in B16F1, CT26, B16F10, and MDA cell lines. Some of them demonstrated superior activity when compared to cisplatin and carboplatin. We were also able to confirm a structure-activity relationship between cytotoxicity and carbon chain length.


Asunto(s)
Antineoplásicos/síntesis química , Citotoxinas/síntesis química , Compuestos Organoplatinos/síntesis química , Platino (Metal)/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Citotoxinas/química , Citotoxinas/farmacología , Etilenodiaminas/química , Humanos , Ratones , Compuestos Organoplatinos/química , Compuestos Organoplatinos/farmacología
17.
Metallomics ; 4(5): 433-40, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22454083

RESUMEN

It has been reported recently that Sb(III) competes with Zn(II) for its binding to the CCHC zinc finger domain of the HIV-1 NCp7 protein, suggesting that zinc finger proteins may be molecular targets for antimony-based drugs. Here, the interaction of Sb(III) with a CCCH zinc finger domain, which is considered to play a crucial role in the biology of kinetoplastid protozoa, has been characterized for the first time. The binding characteristics of Sb(III) were compared between a CCCH-type peptide derived from a kinetoplastid protein and two different CCHC-type zinc finger peptides. The formation of 1 : 1 Zn-peptide and Sb-peptide complexes from the different peptides was demonstrated using circular dichroism, UV absorption, fluorescence spectroscopies and ESI-MS. Titration of the Zn-peptide complexes with SbCl(3) was performed at pH 6 and 7, exploiting the intrinsic fluorescence of the peptides. The differential spectral characteristics of the peptides allowed for competition experiments between the different peptides for binding of Zn(II). The present study establishes that Sb(III) more effectively displaces Zn(II) from the CCCH peptide than CCHC ones, as a result of both the greater stability of the Sb-CCCH complex (compared to Sb-CCHC complexes) and the lower stability of the Zn-CCCH complex (compared to Zn-CCHC complexes). Comparison of the binding characteristics of Sb(III) or Zn(II) between the CCHC-type peptides with different amino acid sequences supports the model that not only the conserved zinc finger motif, but also the sequence of non-conserved amino acids determines the binding affinity of Sb(III) and Zn(II). These data suggest that the interaction of Sb(III) with CCCH-type zinc finger proteins may modulate, or even mediate, the pharmacological action of antimonial drugs.


Asunto(s)
Antimonio/metabolismo , Proteínas Protozoarias/metabolismo , Dedos de Zinc , Zinc/metabolismo , Secuencia de Aminoácidos , Antimonio/química , Dicroismo Circular , Leishmania major/química , Leishmania major/metabolismo , Datos de Secuencia Molecular , Péptidos , Unión Proteica , Proteínas Protozoarias/química , Espectrometría de Masa por Ionización de Electrospray , Trypanosoma brucei brucei/química , Trypanosoma brucei brucei/metabolismo , Zinc/química
18.
Chem Biol Drug Des ; 75(4): 407-11, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20102368

RESUMEN

This work describes the synthesis and characterization of three novel complexes derived from N-benzyl-ethylenediamine and oxalate. Precursor compounds were synthesized by reacting N-benzyl-ethylenediamine with K(2)PtCl(4). Subsequent substitution of chlorides by oxalate led to the final products. Elemental analysis and the infrared, (1)H, (13)C, and (195)Pt NMR spectra of these complexes were provided. The cytotoxic activities were investigated against human non-small cell lung carcinoma (A(549)), mouse non-metastatic cell skin melanoma (B16-F1), mouse metastatic cell skin melanoma (B16-F10), human cell breast adenocarcinoma (MDA-MB-231) and normal cell lines such as baby hamster cell kidney (BHK-21), hamster cell ovary (CHO) and compared to cisplatin and carboplatin under the same experimental conditions. The presence of oxalate as a leaving group conferred an interesting cytotoxicity profile to the complexes in the tested cell lines.


Asunto(s)
Antineoplásicos/síntesis química , Complejos de Coordinación/síntesis química , Etilenodiaminas/química , Compuestos Organoplatinos/síntesis química , Oxalatos/química , Animales , Antineoplásicos/química , Antineoplásicos/toxicidad , Células CHO , Línea Celular Tumoral , Complejos de Coordinación/química , Complejos de Coordinación/toxicidad , Cricetinae , Cricetulus , Humanos , Ratones , Compuestos Organoplatinos/química , Compuestos Organoplatinos/toxicidad
19.
J Inorg Biochem ; 102(4): 767-72, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18190963

RESUMEN

This work describes the synthesis and characterization of four new ligands derived from 1,3-propanediamine in addition to the preparation and characterization of their respective platinum(II) complexes by reaction with K(2)PtCl(4). These ligands were obtained by the reaction of the corresponding alkyl mesylate with 1,3-propanediamine. We have prepared compounds having different carbon chains lengths in an attempt to correlate this factor, which influences the lipophilicity of the compounds, with cytotoxic activity. Octanol/water partition coefficients, the effect of the four complexes on the growth of two tumoral cell lines, and their cellular uptake were investigated. Increasing lipophilicity enhances the rate of cellular uptake and, consequently, the cytotoxic activity.


Asunto(s)
Carbono/química , Diaminas/química , Diaminas/farmacología , Compuestos de Platino/química , Compuestos de Platino/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectroscopía de Resonancia Magnética , Espectrofotometría Infrarroja
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