32 results on '"Gracia-Mora I"'
Search Results
2. Acute toxicity assessment and subacute of compound alpha injectable (5-chloro-2-(methylthio)-6-(1-naphthyloxy)-1H-benzimidazole) in rats.
- Author
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Zapata-Arenas, Abel, Gracia-Mora, I., Castillo, R., Lezama-Ramírez, J., Rico-Morales, H., Bustamante-García, R., and Ibarra-Velarde, F.
- Subjects
- *
ACUTE toxicity testing , *EGG quality , *EGG products industry , *ECONOMIC efficiency , *COST effectiveness - Abstract
The objective of this work was to evaluate the acute and subacute toxicity of the injectable alpha compound to Hsd Han: WIST rats. For the acute toxicity assessment, rats were inoculated with doses of 2 000, 1 000, 500, 100, or 10 mg/kg alpha compound intramuscularly. The results of histopathological analysis did not show apparent changes with the doses used. Notably, 2 animals died after treatment with the 2 000 mg/kg dose, and one animal died in the 1 000 mg/kg group. In the subacute toxicity study, neither male nor female rats inoculated with repeated doses of 8, 24, and 40 mg/kg alpha compound showed significant changes in percent body weight (P = 0.5930). Among the females, significant differences were observed for the serum biochemical parameters glucose and cholesterol in the group inoculated with 8 mg/kg compared to the control. The hematocrit values in the 8, 24 and 40 mg/kg groups and the platelet count in the 24 mg/kg group were significantly different (P = 0.0110) among the females compared to the control group. For the male rats, significant differences were found in erythrocyte count and mean corpuscular volume (MCV) in the groups treated with 8 and 40 mg/kg. However, these values are normal according to the literature. The histopathological evaluations did not show apparent changes, so it is concluded that the alpha compound has a wide margin of safety after injection. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Characterization of physical interaction between Casiopeina III-ia and chitosan. Toward a Cas III-ia drug delivery system
- Author
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Miranda-Calderón, J.E., Medina-Torres, L., Tinoco-Mendez, M., Moreno-Esparza, R., Ruiz-Ramirez, L., Gracia-Mora, J., Gracia-Mora, I., and Bernad-Bernad, M.J.
- Published
- 2011
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4. Casiopeinas, metal-based drugs a new class of antineoplastic and genotoxic compounds
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Ruiz-Ramírez, L., primary, de la Rosa, M.E., additional, Gracia-Mora, I., additional, Mendoza, A., additional, Pérez, G., additional, Ferrer-Sueta, G., additional, Tovar, A., additional, Breña, M., additional, Gutierrez, P., additional, Cruces Martínez, M.P., additional, Pimentel, E., additional, and Natarajan, A.T., additional
- Published
- 1995
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5. Synthesis, characterization and biological activity of some mixed complexes of Cu(II) and Zn(II) with antibiotics of the nalidixic acid family and NN ligands.
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Mendoza-Díaz, G., primary, Garciá-Nieto, R.M., additional, Gracia-Mora, I., additional, Arias-Negrete, S., additional, Ruíz-Ramírez, L., additional, Cosenza, I.L., additional, Ireta, J., additional, Moreno-Esparza, R., additional, Pannell, K.H., additional, and Cervantes-Lee, F., additional
- Published
- 1991
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6. Anti-toxoplasma activity and DNA-binding of copper(II) and zinc(II) coordination compounds with 5-nitroimidazole-based ligands.
- Author
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Navarro-Peñaloza R, Anacleto-Santos J, Rivera-Fernández N, Sánchez-Bartez F, Gracia-Mora I, Caballero AB, Gamez P, and Barba-Behrens N
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- Copper chemistry, Zinc chemistry, DNA chemistry, Ligands, Crystallography, X-Ray, Coordination Complexes chemistry, Toxoplasma metabolism, Ornidazole, Nitroimidazoles
- Abstract
Tetrahedral copper(II) and zinc(II) coordination compounds from 5-nitroimidazole derivatives, viz. 1-(2-chloroethyl)-2-methyl-5-nitroimidazole (cenz) and ornidazole 1-(3-chloro-2-hydroxypropyl)-2-methyl-5-nitroimidazole (onz), were synthesized and spectroscopically characterized. Their molecular structures were determined by X-ray diffraction studies. The complexes [Cu(onz)
2 X2 ], [Zn(onz)2 X2 ], [Cu(cenz)2 X2 ] and [Zn(cenz)2 X2 ] (X- = Cl, Br), are stable in solution and exhibit positive LogD7.4 values that are in the range for molecules capable of crossing the cell membrane via passive difussion. Their biological activity against Toxoplasma gondi was investigated, and IC50 and lethal dose (LD50 ) values were determined. The ornidazole copper(II) compounds showed very good antiparasitic activity in its tachyzoite morphology. The interaction of the coordination compounds with DNA was examined by circular dichroism, fluorescence (using intercalating ethidium bromide and minor groove binding Hoechst 33258) and UV-Vis spectroscopy. The copper(II) compounds interact with the minor groove of the biomolecule, whereas weaker electrostatic interactions take place with the zinc(II) compounds. The spectroscopic data achieved for the two series of complexes (namely with copper(II) and zinc(II) as metal center) agree with the respective DNA-damage features observed by gel electrophoresis., (© 2023. The Author(s).)- Published
- 2024
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7. Caveats of chimpanzee ChAdOx1 adenovirus-vectored vaccines to boost anti-SARS-CoV-2 protective immunity in mice.
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Cervantes-Torres J, Cabello-Gutiérrez C, Ayón-Núñez DA, Soldevila G, Olguin-Alor R, Diaz G, Acero G, Segura-Velázquez R, Huerta L, Gracia-Mora I, Cobos L, Pérez-Tapia M, Almagro JC, Suárez-Güemes F, Bobes RJ, Fragoso G, Sciutto E, and Laclette JP
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- Humans, Animals, Mice, Pan troglodytes, ChAdOx1 nCoV-19, COVID-19 Vaccines genetics, SARS-CoV-2, Adenoviridae genetics, Vaccination, Antibodies, Viral, Antibodies, Neutralizing, Adenovirus Vaccines, COVID-19 prevention & control, Vaccines
- Abstract
Several COVID-19 vaccines use adenovirus vectors to deliver the SARS-CoV-2 spike (S) protein. Immunization with these vaccines promotes immunity against the S protein, but against also the adenovirus itself. This could interfere with the entry of the vaccine into the cell, reducing its efficacy. Herein, we evaluate the efficiency of an adenovirus-vectored vaccine (chimpanzee ChAdOx1 adenovirus, AZD1222) in boosting the specific immunity compared to that induced by a recombinant receptor-binding domain (RBD)-based vaccine without viral vector. Mice immunized with the AZD1222 human vaccine were given a booster 6 months later, with either the homologous vaccine or a recombinant vaccine based on RBD of the delta variant, which was prevalent at the start of this study. A significant increase in anti-RBD antibody levels was observed in rRBD-boosted mice (31-61%) compared to those receiving two doses of AZD1222 (0%). Significantly higher rates of PepMix™- or RBD-elicited proliferation were also observed in IFNγ-producing CD4 and CD8 cells from mice boosted with one or two doses of RBD, respectively. The lower efficiency of the ChAdOx1-S vaccine in boosting specific immunity could be the result of a pre-existing anti-vector immunity, induced by increased levels of anti-adenovirus antibodies found both in mice and humans. Taken together, these results point to the importance of avoiding the recurrent use of the same adenovirus vector in individuals with immunity and memory against them. It also illustrates the disadvantages of ChAdOx1 adenovirus-vectored vaccine with respect to recombinant protein vaccines, which can be used without restriction in vaccine-booster programs. KEY POINTS: • ChAdOx1 adenovirus vaccine (AZD1222) may not be effective in boosting anti-SARS-CoV-2 immunity • A recombinant RBD protein vaccine is effective in boosting anti-SARS-CoV-2 immunity in mice • Antibodies elicited by the rRBD-delta vaccine persisted for up to 3 months in mice., (© 2024. The Author(s).)
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- 2024
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8. Naturally occurring deamidated triosephosphate isomerase is a promising target for cell-selective therapy in cancer.
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Enríquez-Flores S, Flores-López LA, De la Mora-De la Mora I, García-Torres I, Gracia-Mora I, Gutiérrez-Castrellón P, Fernández-Lainez C, Martínez-Pérez Y, Olaya-Vargas A, de Vos P, and López-Velázquez G
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- Female, Glycolysis, Humans, Proteins metabolism, Pyruvaldehyde metabolism, Sulfhydryl Compounds, Breast Neoplasms, Triose-Phosphate Isomerase metabolism
- Abstract
Human triosephosphate isomerase (HsTIM) is a central glycolytic enzyme and is overexpressed in cancer cells with accelerated glycolysis. Triple-negative breast cancer is highly dependent on glycolysis and is typically treated with a combination of surgery, radiation therapy, and chemotherapy. Deamidated HsTIM was recently proposed as a druggable target. Although thiol-reactive drugs affect cell growth in deamidated HsTIM-complemented cells, the role of this protein as a selective target has not been demonstrated. To delve into the usefulness of deamidated HsTIM as a selective target, we assessed its natural accumulation in breast cancer cells. We found that deamidated HsTIM accumulates in breast cancer cells but not in noncancerous cells. The cancer cells are selectively programmed to undergo cell death with thiol-reactive drugs that induced the production of methylglyoxal (MGO) and advanced glycation-end products (AGEs). In vivo, a thiol-reactive drug effectively inhibits the growth of xenograft tumors with an underlying mechanism involving deamidated HsTIM. Our findings demonstrate the usefulness of deamidated HsTIM as target to develop new therapeutic strategies for the treatment of cancers and other pathologies in which this post translationally modified protein accumulates., (© 2022. The Author(s).)
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- 2022
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9. AS1411 Nucleolin-Specific Binding Aptamers Reduce Pathological Angiogenesis through Inhibition of Nucleolin Phosphorylation.
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Iturriaga-Goyon E, Vivanco-Rojas O, Magaña-Guerrero FS, Buentello-Volante B, Castro-Salas I, Aguayo-Flores JE, Gracia-Mora I, Rivera-Huerta M, Sánchez-Bartés F, and Garfias Y
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- Animals, Aptamers, Nucleotide pharmacology, Cell Movement drug effects, Cell Proliferation drug effects, Disease Models, Animal, Gene Expression Regulation drug effects, Human Umbilical Vein Endothelial Cells, Humans, Intravitreal Injections, Mice, MicroRNAs genetics, Oligodeoxyribonucleotides pharmacology, Phosphoproteins antagonists & inhibitors, Phosphoproteins genetics, Phosphorylation drug effects, RNA-Binding Proteins antagonists & inhibitors, RNA-Binding Proteins genetics, Retinal Neovascularization chemically induced, Retinal Neovascularization genetics, Retinal Neovascularization metabolism, Nucleolin, Aptamers, Nucleotide administration & dosage, Oligodeoxyribonucleotides administration & dosage, Oxygen adverse effects, Phosphoproteins metabolism, RNA-Binding Proteins metabolism, Retinal Neovascularization drug therapy
- Abstract
Proliferative retinopathies produces an irreversible type of blindness affecting working age and pediatric population of industrialized countries. Despite the good results of anti-VEGF therapy, intraocular and systemic complications are often associated after its intravitreal use, hence novel therapeutic approaches are needed. The aim of the present study is to test the effect of the AS1411, an antiangiogenic nucleolin-binding aptamer, using in vivo, ex vivo and in vitro models of angiogenesis and propose a mechanistic insight. Our results showed that AS1411 significantly inhibited retinal neovascularization in the oxygen induced retinopathy (OIR) in vivo model, as well as inhibited branch formation in the rat aortic ex vivo assay, and, significantly reduced proliferation, cell migration and tube formation in the HUVEC in vitro model. Importantly, phosphorylated NCL protein was significantly abolished in HUVEC in the presence of AS1411 without affecting NFκB phosphorylation and -21 and 221-angiomiRs, suggesting that the antiangiogenic properties of this molecule are partially mediated by a down regulation in NCL phosphorylation. In sum, this new research further supports the NCL role in the molecular etiology of pathological angiogenesis and identifies AS1411 as a novel anti-angiogenic treatment.
- Published
- 2021
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10. Anti-proliferative, pro-apoptotic and anti-invasive effect of the copper coordination compound Cas III-La through the induction of reactive oxygen species and regulation of Wnt/β-catenin pathway in glioma.
- Author
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Castillo-Rodríguez RA, Palencia G, Anaya-Rubio I, Pérez JCG, Jiménez-Farfán D, Escamilla-Ramírez Á, Zavala-Vega S, Cruz-Salgado A, Cervantes-Rebolledo C, Gracia-Mora I, Ruiz-Azuara L, and Trejo-Solis C
- Abstract
Gliomas are the most aggressive neoplasms that affect the central nervous system, being glioblastoma multiforme (GBM) the most malignant. The resistance of GBM to therapies is attributed to its high rate of cell proliferation, angiogenesis, invasion, and resistance to apoptosis; thus, finding alternative therapeutic approaches is vital. In this work, the anti-proliferative, pro-apoptotic, and anti-invasive effect of the copper coordination compound Casiopeina III-La (Cas III-La) on human U373 MG cells was determined in vitro and in vivo . Our results indicate that Cas III-La exerts an anti-proliferative effect, promoting apoptotic cell death and inactivating the invasive process by generating reactive oxygen species (ROS), inactivating GSK3β, activating JNK and ERK, and promoting the nuclear accumulation of β-catenin. The inhibition of ROS generation by N-acetyl-l-cysteine not only recovered cell migration and viability, but also reduced β-catenin accumulation and JNK and ERK activation. Additionally, Cas III-La significantly reduced tumor volume, cell proliferation and mitotic indices, and increased the apoptotic index in mice xenotransplanted with U373 glioma cells. Thus, Cas III-La is a promising agent to treat GBM., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)
- Published
- 2021
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11. Toxicity Evaluation of a Novel Rapamycin Liposomal Formulation After Subconjunctival and Intravitreal Injection.
- Author
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Salas-Ambrosio PJ, Bernad-Bernad MJ, Linares-Alba MA, García-Santisteban R, Tonix-Aburto LA, Ornelas-Lobato GJ, Gracia-Mora I, Rivera-Huerta M, Sánchez-Bartez F, Rico-Morales H, and García-Sánchez GA
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- Animals, Chorioallantoic Membrane metabolism, Conjunctiva metabolism, Disease Models, Animal, Drug Compounding, Electroretinography methods, Erythrocytes drug effects, Erythrocytes metabolism, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents toxicity, Intravitreal Injections, Liposomes administration & dosage, Liposomes therapeutic use, Male, Mice, Micronucleus Tests, Rabbits, Retina drug effects, Retina physiopathology, Safety, Sirolimus administration & dosage, Sirolimus toxicity, Autoimmune Diseases drug therapy, Eye Diseases immunology, Immunosuppressive Agents pharmacokinetics, Liposomes pharmacokinetics, Sirolimus pharmacokinetics
- Abstract
Purpose: Safety and toxicity evaluation of a novel, liposome-encapsulated rapamycin formulation, intended for autoimmune ocular disorders. Methods: The formulation was assessed by micronucleus polychromatic erythrocyte production, irritability by Hen's Egg Test-Chorioallantoic Membrane (HET CAM), sterility, and pyrogenicity testing. Subconjunctival (SCJ) and intravitreal (IVT) administration of the formulation were performed to evaluate subacute and acute toxicity, respectively. Differences between groups in biochemical and hematological parameters were evaluated by analysis of variance and t -tests. Numeric score was assigned to histopathological classification. Electroretinography (ERG) testing was also performed. Data were analyzed by a 1 way no parametric Kruskal-Wallis and the Mann-Whitney tests. Significance was considered when P < 0.05. Results: No significant toxicity directly related to the preparation was detected. Micronucleus count, mucous irritation score, and pyrogenicity results were negative. Pathology demonstrated no damage related to the formulation after SCJ injection. After IVT injection, only lens injury associated with technique was observed. Retinal function was also conserved in ERG. Conclusions: The preparation evaluated offers a good toxicity and safety profile when injected in a SCJ or IVT manner in an animal model. A clinical trial conducted in humans is highly warranted, as it could reveal an alternative immunosuppressive treatment for ophthalmological immune-mediated pathologies.
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- 2021
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12. Coordination compounds with heterocyclic ester derivatives. Structural characterization and anti-proliferative activity.
- Author
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Navarro-Peñaloza R, Vázquez-Palma AB, López-Sandoval H, Sánchez-Bartéz F, Gracia-Mora I, and Barba-Behrens N
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- Animals, Antineoplastic Agents pharmacology, Apoptosis drug effects, Carbamates chemistry, Cell Line, Tumor, Chelating Agents pharmacology, Coordination Complexes chemistry, Crystallography, X-Ray methods, Humans, Imidazoles chemistry, In Situ Nick-End Labeling methods, Ligands, Mice, Molecular Structure, Cell Proliferation drug effects, Cobalt chemistry, Coordination Complexes pharmacology, Copper chemistry, Esters chemistry, Zinc chemistry
- Abstract
A series of new coordination compounds of cobalt(II), copper(II) and zinc(II) with heterocyclic ester derivatives (ethyl 4-methyl-5-imidazole-carboxylate (emizco), 1-(2-(phenylsulphonyl)ethyl)-4-imidazole carboxylate (semizco)) and methyl 5-(propylthio)-2-benzimidazolecarbamate (albendazole, abz) were synthesized. They were fully characterized by different techniques such as IR, UV-Vis-NIR, elemental analysis, molar conductivity and magnetic susceptibility. Additionally, X-ray crystal structures of semizco and its [Co(semizco)
2 Cl2 ]·2CH3 CN 10, [Co(smmizco)2 Br2 ]·2CH3 CN 11 and [Cu(semizco)2 Br2 ] 15 coordination compounds are analyzed. These compounds present lone pair SO⋯π interactions between the sulfone and the imidazolic ring. These ligands showed three coordination modes: monodentate, through an imidazolic nitrogen atom, or a bidentate chelating mode by a nitrogen and an oxygen atom from the ester group. The different coordination modes and the number of coordinated ligands gave rise to tetrahedral and octahedral compounds, or for [Cu(semizco)(μ-Br)Br]n ·0.5H2 O 7 a square base pyramidal geometry. A cytotoxic study was carried out with the free ligands and their copper(II) and zinc(II) halide coordination compounds on HeLa (cervix-uterine), MCF-7 (breast), HCT-15 (colon), PC3 (prostate) human carcinoma cell lines and L929 mouse fibroblast (healthy cells). A TUNEL assay (terminal deoxynucleotidyl transferase dUTP nick end labeling) was performed with the most active copper(II) compounds to determine if cell death was by apoptosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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13. Exposure to bisphenol A: current levels from food intake are toxic to human cells.
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Hernández-Hernández KL, Tapia-Orozco N, Gimeno M, Espinosa-García AM, García-García JA, Araiza-Olivera D, Sánchez-Bartez F, Gracia-Mora I, Gutierrez-Aguilar M, and García-Arrazola R
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- 3T3-L1 Cells drug effects, Animals, Food Contamination, Humans, Inhibitory Concentration 50, MCF-7 Cells drug effects, Mice, PC-3 Cells drug effects, Benzhydryl Compounds adverse effects, Benzhydryl Compounds toxicity, Cell Line drug effects, Phenols adverse effects, Phenols toxicity
- Abstract
In the present work, cell lines of different origin were exposed to BPA levels from food intake reported elsewhere. Specifically, we used an in vitro assay to determine cytotoxicity of BPA in three cell lines: MCF7 (breast cancer), PC3 (prostate cancer) and 3T3-L1 (mouse fibroblast). Cytotoxic effects were observed at concentrations higher than 50 μg/mL which is above the involuntary exposure level of BPA described before in fresh, canned and frozen foods and beverages. Furthermore, medial inhibitory concentrations (IC50) of 85.17 μg/mL and 88.48 μg/mL were observed for PC3 and 3T3-L1, respectively, and a slightly lower IC50 of 64.67 μg/mL for MCF7. These results highlight BPA's toxicity potential at current levels from food intake. The cell line-dependent divergent response to BPA reported herein is discussed.
- Published
- 2019
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14. Preclinical evidences of safety of a new synthetic adjuvant to formulate with the influenza human vaccine: absence of subchronic toxicity and mutagenicity.
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Cervantes-Torres J, Gracia-Mora I, Segura-Velazquez R, Montero-Montoya R, Espinosa-Aguirre J, E Gonsebatt M, Camacho-Carranza R, Rivera-Huerta M, Sanchez-Bartez F, Tinoco-Méndez M, Ostrosky-Wegman P, Fragoso G, and Sciutto E
- Subjects
- Animals, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Female, Humans, Influenza, Human prevention & control, Injections, Subcutaneous, Male, Mutagenicity Tests, Peptides, Cyclic immunology, Rats, Wistar, Salmonella typhimurium drug effects, Salmonella typhimurium genetics, Toxicity Tests, Chronic, Adjuvants, Immunologic toxicity, Chromosome Aberrations drug effects, DNA Damage, Influenza Vaccines immunology, Peptides, Cyclic toxicity
- Abstract
Context: Influenza is a severe, life-threatening viral disease that can be prevented by vaccination. However, the anti-influenza human vaccine failed to show the required efficacy both in infants under 5 years old and in the elder population, who are among those with the highest risk of developing severe complications after influenza infection. Therefore, it is of high importance to improve the vaccine efficacy and ensure its safety in these susceptible populations. GK-1, a novel 18-aa peptide adjuvant, has been proved to increase the immunogenicity of the human influenza vaccine in both young and aged mice. Objective: A preclinical study of the toxicity profile of GK-1 following the World Health Organization guidelines to support its use was herein conducted. Material and methods: GK-1 was synthetically produced following Good Manufacturing Practices. The toxicological evaluation of GK-1 peptide was performed in rats after repeated dose-ranging trials by the subcutaneous route. The mutagenic potential of GK-1 was assessed by the micronucleus, chromosomal aberration, and Ames tests, in accordance with OECD Guidelines. Results: GK-1 did not show toxic effects at doses up to 12.5mg/kg, corresponding to 25 times the dose intended for human use. No indications of mutagenic potential were observed. GK-1 after dermal administration was well tolerated locally. Conclusion: The efficacy of GK-1 to improve influenza vaccine protection, along with the absence of toxicity and mutagenicity, as reported herein, support the evaluation of this peptide in a clinical trial as a novel adjuvant for human use.
- Published
- 2019
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15. Process signatures in glatiramer acetate synthesis: structural and functional relationships.
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Campos-García VR, Herrera-Fernández D, Espinosa-de la Garza CE, González G, Vallejo-Castillo L, Avila S, Muñoz-García L, Medina-Rivero E, Pérez NO, Gracia-Mora I, Pérez-Tapia SM, Salazar-Ceballos R, Pavón L, and Flores-Ortiz LF
- Abstract
Glatiramer Acetate (GA) is an immunomodulatory medicine approved for the treatment of multiple sclerosis, whose mechanisms of action are yet to be fully elucidated. GA is comprised of a complex mixture of polypeptides with different amino acid sequences and structures. The lack of sensible information about physicochemical characteristics of GA has contributed to its comprehensiveness complexity. Consequently, an unambiguous determination of distinctive attributes that define GA is of highest relevance towards dissecting its identity. Herein we conducted a study of characteristic GA heterogeneities throughout its manufacturing process (process signatures), revealing a strong impact of critical process parameters (CPPs) on the reactivity of amino acid precursors; reaction initiation and polymerization velocities; and peptide solubility, susceptibility to hydrolysis, and size-exclusion properties. Further, distinctive GA heterogeneities were correlated to defined immunological and toxicological profiles, revealing that GA possesses a unique repertoire of active constituents (epitopes) responsible of its immunological responses, whose modification lead to altered profiles. This novel approach established CPPs influence on intact GA peptide mixture, whose physicochemical identity cannot longer rely on reduced properties (based on complete or partial GA degradation), providing advanced knowledge on GA structural and functional relationships to ensure a consistent manufacturing of safe and effective products.
- Published
- 2017
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16. Suppression of the tert-butylhydroquinone toxicity by its grafting onto chitosan and further cross-linking to agavin toward a novel antioxidant and prebiotic material.
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Hernández-Valdepeña MA, Pedraza-Chaverri J, Gracia-Mora I, Hernández-Castro R, Sánchez-Bartez F, Nieto-Sotelo J, Montiel C, Shirai K, and Gimeno M
- Subjects
- Agave chemistry, Animals, Mice, Antioxidants chemistry, Chitosan chemistry, Hydroquinones chemistry, Inulin chemistry, Prebiotics analysis
- Abstract
The enzyme-mediated grafting of tert-butylhydroquinone (TBHQ) onto chitosan and further crosslinking to agave inulin (agavin) has been successfully achieved in a mild and non-toxic two-step route. The resulting products were characterized by nuclear magnetic resonance (NMR) and Infra-red spectroscopies to assess the molecular structure. The study of acute oral toxicity in mice revealed no adverse short-term effects of consumption in the synthesized materials with non-toxicity evidence until 2000 mg/kg through an oral acute administration. Importantly, this study proves that the compound maintains the radical scavenging capacity of the phenolic antioxidant upon ferric-reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays with a measured half-maximal inhibitory concentration (IC50) for the best case of 1.54 g/L based on inhibition of 2,2'-azino-bis(3-ethylbenzothiazoline)-6-sulfonic acid diammonium salt (ABTS). Additionally, the novel compound presented high prebiotic activities as ascertained in the presence of lactic acid bacteria (LAB)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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17. Redox-active and DNA-binding coordination complexes of clotrimazole.
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Betanzos-Lara S, Chmel NP, Zimmerman MT, Barrón-Sosa LR, Garino C, Salassa L, Rodger A, Brumaghim JL, Gracia-Mora I, and Barba-Behrens N
- Subjects
- Apoptosis drug effects, Circular Dichroism, Cobalt chemistry, Coordination Complexes chemical synthesis, Coordination Complexes toxicity, Copper chemistry, Crystallography, X-Ray, DNA metabolism, DNA Damage drug effects, HeLa Cells, Humans, Microscopy, Atomic Force, Molecular Conformation, Nickel chemistry, Nucleic Acid Denaturation, Oxidation-Reduction, Ultraviolet Rays, Zinc chemistry, Clotrimazole chemistry, Coordination Complexes chemistry, DNA chemistry, Metals chemistry
- Abstract
DNA interactions of anticancer mononuclear Cu(2+), Co(2+), Zn(2+), and Ni(2+) complexes with the biologically active ligand clotrimazole (clotri) are reported. To fully characterize DNA binding modes for these complexes of the formulae [M(clotri)2Cl2]·nH2O (1-4), [M(clotri)2Br2]·nH2O (5,6), [M(clotri)3NO3]NO3·nH2O (9), and [M(clotri)3(NO3)2] (10), circular dichroism (CD) and linear dichroism (LD) spectroscopy, UV melting experiments, atomic force microscopy (AFM) and ethidium bromide (EtBr) displacement methods were used. Results indicate mixed electrostatic interactions, possibly through groove binding, that result in accretion and coiling of DNA. Electrochemical studies indicate that the Cu(2+) complex 9 readily reduces to the reactive-oxygen-species-generating Cu(+), which oxidatively damages DNA. There is a subtle correlation between log P values, calculated electrostatic potentials, and cytotoxicity of the complexes. The extent of cell-nucleus DNA-metal adduct formation in the HeLa cervix-uterine carcinoma cell line does not necessarily correlate with cytotoxicity, indicating that the nature of DNA lesions may be crucial to activity.
- Published
- 2015
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18. 2,6-Bis(2,6-diethylphenyliminomethyl)pyridine coordination compounds with cobalt(II), nickel(II), copper(II), and zinc(II): synthesis, spectroscopic characterization, X-ray study and in vitro cytotoxicity.
- Author
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Martinez-Bulit P, Garza-Ortíz A, Mijangos E, Barrón-Sosa L, Sánchez-Bartéz F, Gracia-Mora I, Flores-Parra A, Contreras R, Reedijk J, and Barba-Behrens N
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents toxicity, Cell Line, Tumor, Cobalt chemistry, Coordination Complexes chemical synthesis, Copper chemistry, Crystallography, X-Ray, Humans, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Nickel chemistry, Spectroscopy, Near-Infrared, X-Ray Diffraction, Zinc chemistry, Antineoplastic Agents chemistry, Coordination Complexes chemistry, Coordination Complexes toxicity, Pyridines chemistry
- Abstract
Coordination compounds with cobalt(II), nickel(II), copper(II) and zinc(II) and the ligand 2,6-bis(2,6-diethylphenyliminomethyl)pyridine (L) were synthesized and fully characterized by IR and UV-Vis-NIR spectroscopy, elemental analysis, magnetic susceptibility and X-ray diffraction for two representative cases. These novel compounds were designed to study their activity as anti-proliferative drugs against different human cancer cell lines. The tridentate ligand forms heptacoordinated compounds from nitrate metallic salts, where the nitrate acts in a chelating form to complete the seven coordination positions. In vitro cell growth inhibition was measured for Co(II), Cu(II) and Zn(II) complexes, as well as for the free ligand. Upon coordination, the IC50 value of the transition-metal compounds is improved compared to the free ligand. The copper(II) and zinc(II) compounds are the most promising candidates for further in vitro and in vivo studies. The activity against colon and prostate cell lines merits further research, in views of the limited therapeutic options for such cancer types., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2015
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19. Cytotoxic copper(II), cobalt(II), zinc(II), and nickel(II) coordination compounds of clotrimazole.
- Author
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Betanzos-Lara S, Gómez-Ruiz C, Barrón-Sosa LR, Gracia-Mora I, Flores-Álamo M, and Barba-Behrens N
- Subjects
- Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Line, Tumor, Coordination Complexes pharmacology, Crystallography, X-Ray, DNA Fragmentation drug effects, Gene Expression drug effects, Humans, Ligands, Magnetic Resonance Spectroscopy, Microscopy, Confocal, Models, Molecular, Molecular Structure, Antineoplastic Agents chemical synthesis, Clotrimazole chemistry, Cobalt chemistry, Coordination Complexes chemical synthesis, Copper chemistry, Nickel chemistry, Zinc chemistry
- Abstract
Sixteen novel mononuclear Cu(II), Co(II), Zn(II), and Ni(II) complexes of the biologically active ligand clotrimazole (clotri) of the forms [M(clotri)(2)Cl(2)]·nH(2)O (1-4), [M(clotri)(2)Br(2)]·nH(2)O (5-7), [M(clotri)(3)Br(2)] (8), [M(clotri)(3)NO(3)]NO(3)·nH(2)O (9, 11), [M(clotri)(3)(NO(3))(2)]·nH(2)O (10), and [M(clotri)(3)(OH(2))(2)NO(3)]NO(3)·nH(2)O (12) were synthesized and fully characterized. Dinuclear [Cu(2)(clotri)(4)μ(2)-Cl(4)]·2H(2)O (1a) and [Cu(2)(clotri)(4)μ(2)-Br(2)]·2H(2)O (5b) as well as tetranuclear [Cu(4)(clotri)(4)μ(4)-Br(6)μ(4)-O] (5a) complexes were also isolated. Complexes 1-7, 9, and 11 present a tetrahedral geometry; complex 8 exhibits a pentacoordinated structure; complexes 1a, 10 and 12 an octahedral geometry. X-ray crystal structures of [Cu(clotri)(2)Cl(2)](1), [Cu(clotri)(2)(EtOH)Cl(2)](1·EtOH), [Zn(clotri)(2)Cl(2)] (3), [Zn(clotri)(2)Br(2)] (7), and [Cu(4)(clotri)(4)μ(4)-Br(6)μ(4)-O] (5a) were obtained. Complexes 1-12 were tested for cytotoxic activity against the human carcinoma cell lines HeLa (cervix-uterine), PC3 (prostate), and HCT-15 (colon) displaying IC(50) values <30 μM. Confocal microscopy and nuclear dying (DAPI) for complex 1 showed condensation of cromatin and nuclear membrane fragmentation. Immunocytochemical detection/expression of biomarkers suggests that complexes 1 and 9 induce cell death via apoptosis. TUNEL assay detected DNA fragmentation in HeLa cells, resulting from apoptotic signaling cascades induced by Cu(II) complexes 1 and 9. (1)H NMR studies of the Zn(II) complexes showed that they can bind to nucleotides., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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20. Casiopeina II-gly and bromo-pyruvate inhibition of tumor hexokinase, glycolysis, and oxidative phosphorylation.
- Author
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Marín-Hernández A, Gallardo-Pérez JC, López-Ramírez SY, García-García JD, Rodríguez-Zavala JS, Ruiz-Ramírez L, Gracia-Mora I, Zentella-Dehesa A, Sosa-Garrocho M, Macías-Silva M, Moreno-Sánchez R, and Rodríguez-Enríquez S
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Energy Metabolism drug effects, Glycogen metabolism, Humans, Lactates metabolism, Lymphocytes drug effects, Phosphofructokinase-1 metabolism, Pyruvate Kinase metabolism, Rats, Antineoplastic Agents pharmacology, Glycolysis drug effects, Hexokinase metabolism, Organometallic Compounds pharmacology, Oxidative Phosphorylation drug effects, Pyruvates pharmacology
- Abstract
The copper-based drug Casiopeina II-gly (CasII-gly) shows potent antineoplastic effect and diminishes mitochondrial metabolism on several human and rodent malignant tumors. To elucidate whether CasII-gly also affects glycolysis, (a) the flux through the complete pathway and the initial segment and (b) the activities of several glycolytic enzymes of AS-30D hepatocarcinoma cells were determined. CasII-gly (IC₅₀ = 0.74-6.7 μM) was more effective to inhibit 24-72 h growth of several human carcinomas than 3-bromopyruvate (3BrPyr) (IC₅₀ = 45-100 μM) with no apparent effect on normal human-proliferating lymphocytes and HUVECs. In short-term 60-min experiments, CasII-gly increased tumor cell lactate production and glycogen breakdown. CasII-gly was 1.3-21 times more potent than 3BrPyr and cisplatin to inhibit tumor HK. As CasII-gly inhibited the soluble and mitochondrial HK activities and the flux through the HK-TPI glycolytic segment, whereas PFK-1, GAPDH, PGK, PYK activities and HPI-TPI segment flux were not affected, the data suggested glycogenolysis activation induced by HK inhibition. Accordingly, glycogen-depleted as well as oligomycin-treated cancer cells became more sensitive to CasII-gly. The inhibition time-course of HK by CasII-gly was slower than that of OxPhos in AS-30D cells, indicating that glycolytic toxicity was secondary to mitochondria, the primary CasII-gly target. In long-term 24-h experiments with HeLa cells, 5 μM CasII-gly inhibited OxPhos (80%), glycolysis (40%), and HK (42%). The present data indicated that CasII-gly is an effective multisite anticancer drug simultaneously targeting mitochondria and glycolysis.
- Published
- 2012
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21. Diversity in the supramolecular interactions of 5,6-dichloro-2-(trifluoromethyl)-1H-benzimidazole with modified cyclodextrins: Implications for physicochemical properties and antiparasitic activity.
- Author
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Rojas-Aguirre Y, Castillo I, Hernández DJ, Nogueda-Torres B, Márquez-Navarro A, Villalobos JC, Sánchez-Bartéz F, Sánchez-Torres L, Gracia-Mora I, Castillo R, and Hernández-Luis F
- Abstract
The molecular interactions of 5,6-dichloro-2-(trifluoromethyl)-1H-benzimidazole (G2), an antiprotozoa with poor aqueous solubility, with 2-hydroxypropyl-α-cyclodextrin (HPαCD), methyl-β-cyclodextrin (MβCD) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) were examined. The aqueous solubility enhancement by cyclodextrins (CDs) was evidenced in phase-solubility diagrams, and the stoichiometry of G2/CD systems was determined by Job's plots. Two-dimensional NMR spectroscopic data revealed that a different mode of interaction took place between G2 and CDs in solution. With HPαCD, a non-inclusion complex was generated. In the case of MβCD, a typical host-guest system was obtained and with HPβCD a partial inclusion complex through the narrow side of the macrocycle was formed. ESI-mass spectrometric data confirmed the stoichiometry and mode of interaction of these systems in solution. Solid-state characterization (scanning calorimetry and powder X-ray diffraction) supported the inclusion complex formation. The leishmanicidal activity, trypanocidal activity and non-toxic profile of G2/MβCD showed the advantages of using this inclusion complex to promote the biological assays extension of G2., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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22. Casiopeína IIgly-induced oxidative stress and mitochondrial dysfunction in human lung cancer A549 and H157 cells.
- Author
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Kachadourian R, Brechbuhl HM, Ruiz-Azuara L, Gracia-Mora I, and Day BJ
- Subjects
- Apoproteins metabolism, Cell Line, Tumor, Cell Survival, Chelating Agents chemical synthesis, Copper chemistry, DNA Damage, DNA, Mitochondrial metabolism, Electron Spin Resonance Spectroscopy, Electron Transport drug effects, Flow Cytometry, Glutathione metabolism, Heme Oxygenase-1 metabolism, Humans, Hydrogen Peroxide chemistry, Hydrogen Peroxide toxicity, Iron chemistry, Lung Neoplasms pathology, Mitochondrial Diseases metabolism, Organometallic Compounds chemical synthesis, Reactive Oxygen Species metabolism, Reverse Transcriptase Polymerase Chain Reaction, Chelating Agents toxicity, Mitochondrial Diseases chemically induced, Organometallic Compounds toxicity, Oxidative Stress drug effects
- Abstract
Casiopeínas are a series of mixed chelate copper complexes that are being evaluated as anticancer agents. Their effects in the cell include oxidative damage and mitochondrial dysfunction, yet the molecular mechanisms leading to such effects remain unclear. We tested whether [Cu(4,7-dimethyl-phenanthroline)(glycinate)]NO(3) (Casiopeína IIgly or Cas IIgly) could alter cellular glutathione (GSH) levels by redox cycling with GSH to generate ROS and cellular oxidative stress. Cas IIgly induced a dramatic drop in intracellular levels of GSH in human lung cancer H157 and A549 cells, and is able to use GSH as source of electrons to catalyze the Fenton reaction. In both cell lines, the toxicity of Cas IIgly (2.5-5 microM) was potentiated by the GSH synthesis inhibitor l-buthionine sulfoximine (BSO) and diminished by the catalytic antioxidant manganese(III) meso-tetrakis(N,N'-diethylimidazolium-2-yl)porphyrin (MnTDE-1,3-IP(5+)), thus supporting an important role for oxidative stress. Cas IIgly also caused an over-production of reactive oxygen species (ROS) in the mitochondria and a depolarization of the mitochondrial membrane. Moreover, Cas IIgly produced mitochondrial DNA damage that resulted in an imbalance of the expression of the apoproteins of the mitochondrial respiratory chain, which also can contribute to increased ROS production. These results suggest that Cas IIgly initiates multiple possible sources of ROS over-production leading to mitochondrial dysfunction and cell death., ((c) 2009 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2010
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23. Cytotoxic activity, X-ray crystal structures and spectroscopic characterization of cobalt(II), copper(II) and zinc(II) coordination compounds with 2-substituted benzimidazoles.
- Author
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Sánchez-Guadarrama O, López-Sandoval H, Sánchez-Bartéz F, Gracia-Mora I, Höpfl H, and Barba-Behrens N
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Benzimidazoles pharmacology, Cell Line, Tumor, Cell Survival, Chelating Agents chemical synthesis, Chelating Agents pharmacology, Crystallography, X-Ray, Drug Design, Drug Screening Assays, Antitumor, Growth Inhibitors chemical synthesis, Growth Inhibitors pharmacology, HeLa Cells, Humans, Inhibitory Concentration 50, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Structure, Organometallic Compounds chemical synthesis, Organometallic Compounds pharmacology, Spectrophotometry, Spectroscopy, Near-Infrared, Structure-Activity Relationship, Antineoplastic Agents chemistry, Benzimidazoles chemistry, Chelating Agents chemistry, Cobalt chemistry, Copper chemistry, Growth Inhibitors chemistry, Organometallic Compounds chemistry, Zinc chemistry
- Abstract
Herein we present the synthesis, structural and spectroscopic characterization of coordination compounds of cobalt(II), copper(II) and zinc(II) with 2-methylbenzimidazole (2mbz), 2-phenylbenzimidazole (2phbz), 2-chlorobenzimidazole (2cbz), 2-benzimidazolecarbamate (2cmbz) and 2-guanidinobenzimidazole (2gbz). Their cytotoxic activity was evaluated using human cancer cell lines, PC3 (prostate), MCF-7 (breast), HCT-15 (colon), HeLa (cervic-uterine), SKLU-1 (lung) and U373 (glioblastoma), showing that the zinc(II) and copper(II) compounds [Zn(2mbz)(2)Cl(2)].0.5H(2)O, [Zn(2cmbz)(2)Cl(2)].EtOH, [Cu(2cmbz)Br(2)].0.7H(2)O and [Cu(2gbz)Br(2)] had significant cytotoxic activity. The isostructural cobalt(II) complexes showed not significant activity. The cytotoxic activity is related to the presence of halides in the coordination sphere of the metal ion. Recuperation experiments with HeLa cells, showed that the cells recuperated after removing the copper(II) compounds and, on the contrary, the cells treated with the zinc(II) compounds did not. These results indicate that the mode of action of the coordination compounds is different.
- Published
- 2009
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24. Antiproliferative activity and QSAR study of copper(II) mixed chelate [Cu(N-N)(acetylacetonato)]NO3 and [Cu(N-N)(glycinato)]NO3 complexes, (Casiopeínas).
- Author
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Bravo-Gómez ME, García-Ramos JC, Gracia-Mora I, and Ruiz-Azuara L
- Subjects
- Animals, Cell Proliferation drug effects, Drug Design, HeLa Cells, Humans, Inhibitory Concentration 50, Male, Mice, Quantitative Structure-Activity Relationship, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Copper chemistry, Organometallic Compounds chemistry, Organometallic Compounds pharmacology
- Abstract
Mixed chelate copper(II) complexes patented and mark title registered as Casiopeínas are antineoplastic agents with general formulas [Cu(N-N)(alpha-l-amino acidato)]NO(3) and [Cu(N-N)(O-O)]NO(3), where the N-N donor is an aromatic substituted diimine (1,10-phenanthroline (phen) or 2,2'-bipyridine (bpy)) and the O-O donor is acetylacetonate (acac) or salicylaldehydate (salal). In the present work, the series of complexes [Cu(N-N)(acac)]NO(3) and [Cu(N-N)(gly)]NO(3) with several substituents on the diimine ligand were selected to perform a quantitative structure-activity relationship (QSAR) study. Two main analysis were performed: (1) the study of the influence of the substituents on diimine ligand on physicochemical properties such as half-wave potential (E(1/2)) and their relationship with medial lethal dose (LD50) or medial inhibitory concentration (IC50) on several tumor cell lines and (2) the study of the influence of the secondary ligand when acac is changed for glycinate (gly). Results showed that the presence of the central fused aromatic ring in the phen containing complexes is necessary to preserve the antiproliferative activity. The QSAR equations showed a strong relationship between the IC50 and E(1/2); the most active complexes are the weaker oxidants. The change of secondary ligand from acac to gly has less influence on biological activity than the changes on the diimine ligand.
- Published
- 2009
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25. Synthesis, structure and biological activities of cobalt(II) and zinc(II) coordination compounds with 2-benzimidazole derivatives.
- Author
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López-Sandoval H, Londoño-Lemos ME, Garza-Velasco R, Poblano-Meléndez I, Granada-Macías P, Gracia-Mora I, and Barba-Behrens N
- Subjects
- Benzimidazoles chemistry, Cell Line, Tumor, Crystallography, X-Ray, Escherichia coli drug effects, HeLa Cells, Humans, Microbial Sensitivity Tests, Micrococcus luteus drug effects, Nuclear Magnetic Resonance, Biomolecular, Organometallic Compounds chemistry, Proteus vulgaris drug effects, Pseudomonas aeruginosa drug effects, Salmonella typhi drug effects, Spectrophotometry, Infrared, Staphylococcus aureus drug effects, Anti-Infective Agents chemical synthesis, Anti-Infective Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Benzimidazoles chemical synthesis, Benzimidazoles pharmacology, Cobalt chemistry, Cobalt pharmacology, Organometallic Compounds chemical synthesis, Organometallic Compounds pharmacology, Zinc chemistry, Zinc pharmacology
- Abstract
In this work we present the synthesis, structural and spectroscopic characterisation of a series of cobalt(II) and zinc(II) coordination compounds with benzimidazole (bz) and its 2-benzimidazole derivatives: 2-aminobenzimidazole (2ab), albendazole (abz) and tris(2-benzimidazolylmethyl)amine (ntb). The compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus, Micrococcus luteus, Salmonella typhi, Pseudomonas aeruginosa, Escherichia coli and Proteus vulgaris. Their cytotoxic activity was also evaluated using human cancer lines, HeLa, HCT-15 and SKLU-1. The halide tetrahedral compounds [Co(bz)2Br2] 3, [Zn(2ab)2Cl2].0.5H2O 11, [Co(abz)Cl2(H2O)].3H2O 14, [Co(abz)Br2(H2O)] 15, [Zn(abz)Cl2(H2O)].3H2O 17 and [Zn(abz)Br2(H2O)].H2O 18 displayed similar minimal inhibition concentration (MIC) values against Micrococcus luteus and Escherichia coli, comparable to those of amoxicillin and chloramphenicol. Additionally, 11 showed a wide range of activity towards Gram(+) and Gram(-) microorganisms. The tetradentate ntb and its trigonal bipyramidal cobalt(II) and zinc(II) compounds were active, regardless of the anion present in the complex. Compound [Co(abz)Cl2(H2O)].3H2O 14 showed promising activity in HeLa cells, while [Co(ntb)Br]Br.H2O 21 inhibited Hela and HCT-15 cell lines.
- Published
- 2008
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26. Casiopeína IIgly induced cytotoxicity to HeLa cells depletes the levels of reduced glutathione and is prevented by dimethyl sulfoxide.
- Author
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Alemón-Medina R, Muñoz-Sánchez JL, Ruiz-Azuara L, and Gracia-Mora I
- Subjects
- Antineoplastic Agents antagonists & inhibitors, Antioxidants metabolism, Cell Death drug effects, Cytosol drug effects, Cytosol ultrastructure, Fluorescent Dyes, HeLa Cells, Humans, Organometallic Compounds antagonists & inhibitors, Oxidation-Reduction, Oxidative Stress drug effects, Rhodamine 123, Antineoplastic Agents toxicity, Cell Survival drug effects, Dimethyl Sulfoxide pharmacology, Glutathione metabolism, Organometallic Compounds toxicity
- Abstract
The newly synthesized copper coordination compound Casiopeína IIgly (Cas IIgly) is a promising alternative drug in the treatment of cancer, since it has shown cytotoxicity and genotoxicity in different tumour models. Given its enhanced effects after ascorbic acid-mediated copper reduction, Cas IIgly's activity is thought to be related to oxidative damage. In the present work, oxidized Cas IIgly failed to induce cytosolic oxidative damage in HeLa cells (only 0.9% of the cell population), and in 2.3% of the treated cells when previously reduced, as evaluated through the oxidation of dihydrorhodamine 123 (DHR 123). However, it showed cytotoxicity, since HeLa cells treated with 10-80 microg/mL Cas IIgly proliferated only at 30% of their normal rate, and at 15% when treated with reduced Cas IIgly. This cytotoxicity is strongly abolished in the presence of the hydroxyl scavenger dimethyl sulfoxide. The decrease, from 3994 to 530 nanograms of reduced glutathione (GSH) per million cells after treatment with 80 microg/mL Casiopeína IIgly, indicates that this drug causes the expenditure of this naturally occurring antioxidant. These results altogether suggest that, albeit Cas IIgly induced cytotoxicity is not related to cytosolic DHR 123 oxidation, it may be related to oxidative damage.
- Published
- 2008
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27. Casiopeina III-ia induces apoptosis in HCT-15 cells in vitro through caspase-dependent mechanisms and has antitumor effect in vivo.
- Author
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Carvallo-Chaigneau F, Trejo-Solís C, Gómez-Ruiz C, Rodríguez-Aguilera E, Macías-Rosales L, Cortés-Barberena E, Cedillo-Peláez C, Gracia-Mora I, Ruiz-Azuara L, Madrid-Marina V, and Constantino-Casas F
- Subjects
- Animals, Blotting, Western, Body Weight drug effects, Cell Cycle drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Dose-Response Relationship, Drug, Humans, Male, Mice, Mice, Nude, Organometallic Compounds chemistry, bcl-2-Associated X Protein metabolism, Apoptosis drug effects, Caspases metabolism, Colonic Neoplasms prevention & control, Organometallic Compounds pharmacology, Xenograft Model Antitumor Assays
- Abstract
The aim of this study was to evaluate the in vitro and in vivo effects of the new chemotherapy agent Casiopeina III-ia [(4,4'-dimethyl-2,2'-bipiridine)(acetylacetonate) Copper (II) nitrate] on HCT-15 (p53-/-) colon cellular line. In vitro, the drug reduced the viability and induced necrosis and apoptosis in a dose dependent manner, without affecting cell cycle phases. Apoptosis was related to Bax increasing levels, suggesting a caspase-dependent mechanism of death, as verified by nucleosomal fragmentation of DNA. In vivo, the antitumor activity of Casiopeina III-ia was tested in HCT-15 cells transplanted to nude mice. In this study we will show that the novel antineoplastic agent Casiopeina III-ia is active on this colon tumor line, setting out as a good candidate for the treatment of colon tumors refractory to chemotherapy.
- Published
- 2008
- Full Text
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28. Assessment of acute respiratory and cardiovascular toxicity of casiopeinas in anaesthetized dogs.
- Author
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Leal-García M, García-Ortuño L, Ruiz-Azuara L, Gracia-Mora I, Luna-Delvillar J, and Sumano H
- Subjects
- Anesthesia, Animals, Dogs, Female, Heart physiopathology, Lung pathology, Lung physiopathology, Lung ultrastructure, Male, Myocardium pathology, Myocardium ultrastructure, Pulmonary Edema chemically induced, Pulmonary Edema pathology, Toxicity Tests, Acute, Antineoplastic Agents toxicity, Heart drug effects, Lung drug effects, Organometallic Compounds toxicity
- Abstract
The 99 lethal dose in an acute toxicity study of two anticancer novel molecules named casiopeinas((R)) in dogs was calculated to be 200 mg/m(2) for casiopeina III-ia and 160 mg/m(2) for casiopeina IIgly. Considering therapeutic dose ranges from 3.6 to 18 mg/m(2) for the former and 1.2 to 3 mg/m(2) for the latter, true therapeutic margin of safety varies from 4.7 to 23.6 mg/m(2) and from 20 to 50 mg/m(2), respectively. For both casiopeinas intravenous administration of the corresponding lethal dose in 100 ml of 5% dextrose solution in a time period of 30 min. induced death after an almost uneventful latency time period of 30-50 min. Then, after an apparently sudden onset, changes in blood gases indicated respiratory distress (PO(2) from 82.5% to 26.5% for casiopeina III-ia and from 88.6% to 37.5% for casiopeina IIgly; end-tidal CO(2) from 38 to 8.1 mmHg for the first and from 35.1 to 11.2 mmHg for the second, this was almost simultaneously confirmed by the onset of tachypnoea (from 16 to almost 60 breaths/min. for both casiopeinas) and by a drop in arterial blood pressure (from 117 to 51 mmHg for casiopeina III-ia and from 108 to 49 mmHg for casiopeina IIgly). Reflex tachycardia occurs at the beginning of intravenous administration followed by bradycardia a few minutes later (from 158 to 63 beats/min. for casiopeina III-ia and from 148 to 56 beats/min. for casiopeina IIgly). Finally, cardiac arrest occurred no later than 25 min. towards the end of these events lung oedema appeared as fluid dripping from the endotracheal tube. Death occurred in a mean of 15 +/- 5 min. S.D. from the beginning of the end of the latency period. For both casiopeina's data allow the speculation that lung oedema is caused by a joined toxicity to the lung capillary bed, and particularly to the heart. Carvedilol premedication for 8 days delayed the outcome of lung oedema by approximately 8 hr but could not prevent it.
- Published
- 2007
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29. Cas IIgly induces apoptosis in glioma C6 cells in vitro and in vivo through caspase-dependent and caspase-independent mechanisms.
- Author
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Trejo-Solís C, Palencia G, Zúñiga S, Rodríguez-Ropon A, Osorio-Rico L, Luvia ST, Gracia-Mora I, Marquez-Rosado L, Sánchez A, Moreno-García ME, Cruz A, Bravo-Gómez ME, Ruiz-Ramírez L, Rodríguez-Enriquez S, and Sotelo J
- Subjects
- Acetylcysteine pharmacology, Active Transport, Cell Nucleus, Animals, Antioxidants pharmacology, Apoptosis, Blotting, Western, Caspase 3, Cell Line, Tumor, Cell Proliferation, Chromatin metabolism, DNA Fragmentation, Dose-Response Relationship, Drug, In Vitro Techniques, Lipid Peroxidation, Membrane Potentials, Mitochondria pathology, Nucleosomes metabolism, Protein Transport, Rats, Rats, Wistar, Reactive Oxygen Species, Subcellular Fractions, Caspases metabolism, Copper pharmacology, Glioma drug therapy, Organometallic Compounds chemistry, Organometallic Compounds pharmacology
- Abstract
In this work, we investigated the effects of Casiopeina II-gly (Cas IIgly)--a new copper compound exhibiting antineoplastic activity--on glioma C6 cells under both in vitro and in vivo conditions, as an approach to identify potential therapeutic agents against malignant glioma. The exposure of C6 cells to Cas IIgly significantly inhibited cell proliferation, increased reactive oxygen species (ROS) formation, and induced apoptosis in a dose-dependent manner. In cultured C6 cells, Cas IIgly caused mitochondrio-nuclear translocation of apoptosis induction factor (AIF) and endonuclease G at all concentrations tested; in contrast, fragmentation of nucleosomal DNA, cytochrome c release, and caspase-3 activation were observed at high concentrations. Administration of N-acetyl-L-cystein, an antioxidant, resulted in significant inhibition of AIF translocation, nucleosomal DNA fragmentation, and caspase-3 activation induced by Cas IIgly. These results suggest that caspase-dependent and caspase-independent pathways both participate in apoptotic events elicited by Cas IIgly. ROS formation induced by Cas IIgly might also be involved in the mitochondrio-nuclear translocation of AIF and apoptosis. In addition, treatment of glioma C6-positive rats with Cas IIgly reduced tumor volume and mitotic and cell proliferation indexes, and increased apoptotic index. Our findings support the use of Cas IIgly for the treatment of malignant gliomas.
- Published
- 2005
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30. Toxic effects of copper-based antineoplastic drugs (Casiopeinas) on mitochondrial functions.
- Author
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Marín-Hernández A, Gracia-Mora I, Ruiz-Ramírez L, and Moreno-Sánchez R
- Subjects
- Adenosine Triphosphate metabolism, Animals, Copper chemistry, Cytochrome c Group metabolism, Membrane Potentials drug effects, Mitochondria physiology, Mitochondrial Swelling drug effects, Organometallic Compounds chemistry, Rats, Rats, Wistar, Respiration drug effects, Antineoplastic Agents pharmacology, Mitochondria drug effects, Organometallic Compounds pharmacology
- Abstract
To elucidate some of the subcellular and biochemical mechanisms of toxicity of metal-based antineoplastic drugs, mitochondria and cells were exposed to Casiopeinas), a new class of copper-based compounds with high antineoplastic activity. The rates of respiration and swelling, the H(+) gradient, and the activities of succinate (SDH) and 2-oxoglutarate dehydrogenases (2-OGDH) and ATPase were measured in mitochondria isolated from rat liver, kidney, heart, and hepatoma AS-30D. Also, oligomycin-sensitive respiration and ATP content in hepatoma AS-30D cells were determined. Casiopeinas) (CS) II-gly and III-i inhibited the rates of state 3 and uncoupled respiration in mitochondria. CS II was 10 times more potent than CS III. The sensitivity to CS II was 4-5-fold higher in mitochondria incubated with 2-OG than with succinate. Thus, at low concentrations (< or =10 nmol (mg protein)(-1); 10 microM), CS II disturbed mitochondrial functions only when 2-OG was present, due to a specific inhibition of 2-OGDH. At high concentrations (> or =15nmol (mg protein)(-1)), CS II-induced stimulation of basal respiration, followed by a strong inhibition, which correlated with K(+)-dependent swelling and cytochrome c release, respectively; K(+)-channel openers induce a similar mitochondrial response. Mitochondria from liver, kidney and hepatoma showed a similar sensitivity towards CS II, whereas heart mitochondria were more resistant. Oxidative phosphorylation and ATP content were also decreased in tumor cells by CS II. The data suggested that CS affected several different mitochondrial sites, bringing about inhibition of respiration and ATP synthesis, which could compromise energy-dependent processes such as cellular duplication.
- Published
- 2003
- Full Text
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31. Development and validation of a liquid chromatographic method for Casiopeina IIIi in rat plasma.
- Author
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Fuentes-Noriega I, Ruiz-Ramírez L, Tovar Tovar A, Rico-Morales H, and Gracia-Mora I
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Calibration, Male, Organometallic Compounds pharmacokinetics, Rats, Rats, Wistar, Sensitivity and Specificity, Spectrophotometry, Ultraviolet, Antineoplastic Agents blood, Chromatography, Liquid methods, Organometallic Compounds blood
- Abstract
A sensitive and specific liquid chromatographic method using extraction with zinc sulfate has been developed for the determination of Casiopeina IIIi and validated over the linear range 5-100 microg/ml in 1 ml of rat plasma. The analysis was performed on a Symmetry C(18) (5 microm) column. The mobile phase was methanol: 0.01 M phosphate buffer pH 6.5 (40:60, v/v). The column effluent was monitored at 262 nm. The results showed that the assay is sensitive at 5 microg/ml. Maximum intra-day coefficient of variation was 10.6%. The recovery obtained in plasma was 87.2%. The method was used to perform protein binding studies by equilibrium dialysis in rat plasma and was found to be satisfactory.
- Published
- 2002
- Full Text
- View/download PDF
32. Knigth's Move in the Periodic Table, From Copper to Platinum, Novel Antitumor Mixed Chelate Copper Compounds, Casiopeinas, Evaluated by an in Vitro Human and Murine Cancer Cell Line Panel.
- Author
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Gracia-Mora I, Ruiz-Ramírez L, Gómez-Ruiz C, Tinoco-Méndez M, Márquez-Quiñones A, Lira LR, Marín-Hernández A, Macías-Rosales L, and Bravo-Gómez ME
- Abstract
We synthesized a novel anticancer agents based on mixed chelate copper (II) complexes, named Casiopeínas((R)) has of general formula [Cu(N-N)(N-O)H(2)O]NO(3) (where, N-N = diimines as 1,10- phenanthroline, 2,2-bipyridine, or substituted and N-O=aminoeidate or [Cu(N-N)(O-O)H(2)O]NO(3) (where NN= diimines as 10-phenanthroline, 2,2-bipyridine or substituted Casiopeínas I, II, IV, V, VI, VII VIII and O-O=acetylacetonate, salicylaldehidate Casiopínas III). We evaluated the in vitro antitumor activity using a human cancer cell panel and some nurine cancer cells. Eleven Casiopeinas are evaluated in order to acquire some structure-activity correlations and some monodentated Casiopeinäs analogues; cisplatinum was used as control drug. The 50% growth inhibition observed is, in all cases reach with concentrations of Casiopeina's 10 or 100 times lower than cisplatinum. In a previous work we reported the induction of apoptosis by Casiopeina II. The results indicate that Casiopeinass are a promising new anticancer drug candidates to be developed further toward clinical trials.
- Published
- 2001
- Full Text
- View/download PDF
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