Síntesis, caracterización de complejos de Pd(II) con ligantes tiosemicarbazonas, sus compuestos de inclusión en β- Ciclodextrina con posible actividad biológica

En el presente trabajo de investigación se estudió la síntesis, caracterización de complejos de Pd(II) con ligantes pirazolil-tiosemicarbazonas y sus compuestos de inclusión parcial y/o asociación en β-ciclodextrina con posible actividad biológica. Se presenta una primera sección general de antecedentes que recopila generalidades del metal empleado, ligantes tiosemicarbazonas, propiedades fisicoquímicas y biológicas de complejos de paladio(II) con ligantes tiosemicarbazona con diferentes sustituyentes y finalmente las características de la β-ciclodextrina y algunos compuestos de inclusión. Asimismo, en la segunda sección se describe la metodología, donde se realiza una descripción detallada de las condiciones de reacción empleadas y de los instrumentos utilizados para la caracterización de precursores y productos finales. Posteriormente, se presenta el capítulo de resultados y discusión, el cual consta de seis secciones en las que se incluyen, metodologías sintéticas empleadas, análisis de datos espectroscópicos, propiedades físicas y químicas de los productos obtenidos y resultados de las pruebas biológicas realizadas. / Abstract. In the present work of investigation we studied the synthesis, characterization of complexes of Pd (II) with pyrazolyl thiosemicarbazones ligands and their partial inclusion compounds and /or association in β-cyclodextrin with possible biological activity In the first section we present a general overview of the metal used, thiosemicarbazones ligands, physicochemical and biological properties complexes of palladium(II) with thiosemicarbazone ligands with different substituents and finally the characteristics of the β-cyclodextrin and some inclusion compounds. Likewise, in the second section describes the methodology, also perform a detailed description of reaction conditions employed and of the instruments used for characterization of precursors and final products. Subsequently, the chapter presents results and discussion, which consists of six sections that include, synthetic methodologies employed, spectroscopic data analysis, physical and chemical properties of the obtained products and results of biological tests performed.Maestrí

Efecto citotóxico de los compuestos de inclusión de paladio (II) en la beta-ciclodextrina

Introduction: Thiosemicarbazones and palladium (II) complexes have antineoplastic activities with mild side effects, for which they are considered new alternative antineoplastic drugs. However, the IC50 ranges of these complexes vary due to differences in their structure and solubility and their sensitivities for various cellular targets. Beta-cyclodextrin is an additive used to improve the solubility and stability of various drugs for therapeutic use, but the combination of beta-cyclodextrin with palladium (II) complexes and thiosemicarbazones has not been tested yet.Objective: To study the cytotoxic effect of palladium (II) inclusion complexes in beta-cyclodextrin.Materials and methods: We tested the cytotoxic activity of palladium complexes combined with beta-cyclodextrin in the breast cancer cell line MCF-7 using a sulforhodamine B assay.Results: We tested the antiproliferative activity of palladium (II) complexes with and without the ligands MePhPzTSC and Ph2PzTSC and with and without beta-cyclodextrin in MCF-7 cells and compared them to that of cisplatin. All combinations showed antiproliferative activity; however, the activity was greater for the combinations that included beta-cyclodextrin: ([Pd (MePhPzTSC) 2] • ß-CD and [Pd (Ph2PzTSC) 2] • ß-CD), at concentrations of 0.14 and 0.49 μM, respectively. The IC50 for this complex was 5-fold lower than that of the ligand-free combinations (1.4 and 2.9 μM, respectively). The IC50 for free palladium (II) complex was 0.571.24 μM and that for cisplatin was 6.87 μM.Conclusions: Beta-cyclodextrin significantly enhanced the cytotoxic activities of palladium (II) complexes and thiosemicarbazones probably by improving their solubility and bioavailability. The addition of beta-cyclodextrin is a possible strategy for designing new anticancer drugs.Introducción. Las tiosemicarbazonas y sus complejos de paladio (II) poseen actividad antineoplásica con pocos efectos secundarios, por lo cual se las considera como una nueva alternativa terapéutica. Sin embargo, existen diferencias en los rangos de la concentración inhibitoria media (CI50) asociada a la divergencia estructural y la solubilidad de los complejos, así como a la sensibilidad de los blancos celulares. La inclusión de fármacos en la beta-ciclodextrina con fines terapéuticos ha mejorado su solubilidad y estabilidad, pero los efectos de su combinación con los complejos de paladio (II) y las tiosemicarbazonas no se han comprobado aún.Objetivo. Estudiar el efecto citotóxico de los complejos de paladio en la beta-ciclodextrina.Materiales y métodos. La actividad citotóxica de los complejos de paladio en la beta-ciclodextrina se evaluó en la línea celular de cáncer de mama (MCF-7), empleando el método de la sulforodamina B.Resultados. Los ligandos MePhPzTSC y Ph2PzTSC, sus complejos de paladio (II) libres e incluidos en la beta-ciclodextrina y el cisplatino mostraron actividad citotóxica en la línea celular MCF-7; sin embargo, la citotoxicidad fue mayor con la inclusión en la beta-ciclodextrina ([Pd(MePhPzTSC)2]•ß-CD y [Pd(Ph2PzTSC)2]•ß-CD). La concentración inhibitoria media (CI50) para estos complejos se obtuvo en concentraciones de 0,14 y 0,49 μM, y con dosis hasta cinco veces inferiores comparadas con las concentraciones de los ligandos libres (1,4 y 2,9 μM), de los complejos de paladio (II) libres (0,57 y 1,24 μM) y del cisplatino (6,87 μM).Conclusiones. El uso de la beta-ciclodextrina mejoró significativamente la actividad citotóxica de las tiosemicarbazonas y sus complejos de paladio (II), lo cual probablemente está asociado al incremento de la solubilidad y biodisponibilidad del compuesto, estrategia que se puede sugerir para el diseño de futuros fármacos antineoplásicos

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Estudos de complexos metálicos de ligantes bioativos derivados de estilbeno e de benzo-gama-pirona

Exportado OPUSMade available in DSpace on 2019-08-12T06:53:39Z (GMT). No. of bitstreams: 1 tesis_lenka_victoria_tamayo.pdf: 11920730 bytes, checksum: 786f226e20338104d3d5caea5d8982ab (MD5) Previous issue date: 14O presente trabalho envolveu o estudo de complexos de cobre(II) e prata(I) de ligantes bioativos derivados de estilbeno e de benzo-Y-pirona. Foram sintetizadas trans-4-estilbenocarboxaldeído-acetilhidrazona HStAc (1), trans-4-estilbenocarboxaldeído-fenilhidrazona HStPh (2), trans-4- estilbenocarboxaldeído-para-cloro-fenilhidrazona HStpClPh (3), trans-4-estilbenocarboxaldeído- para-nitro-fenilhidrazona HStpNO2Ph (4), trans-4-estilbenocarboxaldeído- para-toluil-hidrazona HStpT (5), trans-4-estilbeno-carboxaldeídobenzilhidrazona HStBz (6) e trans-4-estilbenocarboxaldeído-para-hidroxifenilhidrazona HStpOHPh (7) assim como os complexos [Cu(HStAc)2Cl2] (8), [Cu(HStpClPh)2Cl2] (9), [Cu(HStpNO2Ph)2Cl2] (10), [Cu(HStpT)2Cl2] (11), [Cu(HStBz)2Cl2] (12) e [Cu(HStpOHPh)2Cl2] (13). Cálculos teóricos revelaram que os diferentes isômeros apresentam energias muito próximas, tornando inviável determinar qual seria a geometria mais provável para os complexos. Os ligantes (1-7) e os complexos (8-13) apresentaram fraca atividade antimicrobiana e fraca atividade citotóxica contra células tumorais. As hidrazonas e seus complexos mostraram ser capazes de capturar in vitro espécies radicalares de nitrogênio e oxigênio. Os complexos (12) e (13) interagem com as albuminas do soro bovino (BSA) e do soro humano (HSA) sugerindo que poderiam ser transportados por essas proteínas. Os complexos [Cu(Nar)(Fen)(OH2)]2·2ClO4·2H2O (17) e [Cu(Hsp)(Fen)(OH2)]2·2ClO4 (18) contendo naringenina (Nar) ou hesperetina (Hsp) e o co-ligante 1,10-fenantrolina foram obtidos. Seus espectros de RPE no estado sólido sugerem tratar-se de espécies binucleares. Em solução de DMSO/água a 37 ¿C ocorre predominância de espécies mononucleares. Os complexos (17) e (18) foram estudados quanto às suas atividades citotóxicas frente a células de carcinoma de pulmão A549 e não tumorais LL24 (fibroblastos de pulmão humano) e HUVEC (Human Umbilical Vein Endothelial Cells). O complexo (18) exibe maior atividade citotóxica contra células A549 do que o complexo (17). Ambos provocam alterações morfológicas típicas de apoptose em células A549. O tratamento de células A549 com os complexos não resultou em redução do potencial de membrana mitocondrial, demonstrado que os compostos agem através de mecanismo v independente de despolarização de mitocôndria. Células A549 tratadas com (17) e (18) apresentaram redução na produção de ROS, indicando que os compostos exibem atividade antioxidante. Os complexos interagem com o DNA, e com BSA e HSA. Os complexos (17) e (18) devem ser investigados como candidatos a fármacos antineoplásicos para o tratamento de adenocarcinoma do pulmão humano. No presente trabalho foram também obtidas 3-formil-6-metilcromonafenilhidrazona HCrPh (19) e 3-formil-6-metilcromona-para-cloro-fenilhidrazona HCrpClPh (20). As hidrazonas (19) e (20) não apresentaram atividade antimicrobiana e revelaram baixa citotoxicidade frente a células tumorais B16-F10 (melanoma metastático murino) e frente a células não tumorais Melan-a (melanócito murino). Após a complexação à prata(I), com formação de [Ag(HCrPh)2]NO3¿2H2O (21) e [Ag(HCrpClPh)2]NO3 (22) a ação antifúngica melhora consideravelmente. Os complexos (21) e (22) foram mais citotóxicos que os ligantes livres frente a células B16-F10, induzindo redução da viabilidade celular de 25 e 40% respectivamente. Nas mesmas condições a cisplatina e AgNO3 induziram uma redução de 11% e 9% da viabilidade celular, respectivamente. Assim, a complexação das hidrazonas com prata(I) leva a um aumento da atividade citotóxica. Os complexos de prata(I) revelaram-se menos ativos frente às células sadias de melanócitos Melan-a em comparação com a cisplatina, indicando que provocam menos dano celular em células normais, o que é muito importante na busca de novos agentes quimioterápicos. Assim, a coordenação das hidrazonas à prata(I) constituiu importante estratégia para fazer aumentar a atividade citotóxica das hidrazonas frente a células tumorais sem contudo aumentar seu efeito citotóxico frente a células normais. O complexo (22) interage com DNA, BSA e HSA. O presente trabalho representa uma importante contribuição à Química Medicinal Inorgânica na procura de novos compostos potencialmente úteis como candidatos a protótipos de fármacos e metalofármacos antimicrobianos e antitumorais.The present work comprised an investigation on copper(II) and silver(I)complexes containing bioactive ligands derived from stilbene and benzo-Y-pyrone. Trans-4-stilbenecarboxaldehyde-acetylhydrazone HStAc (1), trans-4-stilbenecarboxaldehyde-phenylhydrazone HStPh (2), trans-4-stilbenecarboxaldehydepara-chloro-phenylhydrazone HStpClPh (3), trans-4-stilbenecarboxaldehyde-paranitro-phenylhydrazone HStpNO2Ph (4), trans-4-stilbenecarboxaldehyde-para-toluichydrazoneHStpT (5), trans-4-stilbenecarboxaldehyde-benzylhydrazone HStBz (6) and trans-4-stilbenecarboxaldehyde-para-hydroxy-phenylhydrazone HStpOHPh (7) were prepared, as well as complexes [Cu(HStAc)2Cl2] (8), [Cu(HStpClPh)2Cl2] (9), [Cu(HStpNO2Ph)2Cl2] (10), [Cu(HStpT)2Cl2] (11), [Cu(HStBz)2Cl2] (12) and [Cu(HStpOHPh)2Cl2] (13). Due to the small differences in energy of the possible isomers theoretical calculations did not allow to determine the exact geometry of thecomplexes. The ligands (1-7) and complexes (8-13) showed weak antimicrobial activity against bacteria and fungi as well as poor cytotoxic effects against tumor cells. The hydrazones and their complexes demonstrated in vitro free radical scavenging activity for reactive oxygen and nitrogen species. Complexes (12) and (13) interact with bovine (BSA) and human serum (HSA), albumin indicating that they could be transported by these proteins.Complexes Cu(Nar)(Fen)(OH2)]22ClO4·2H2O (17) and [Cu(Hsp)(Fen)(OH2)]22ClO4 (18) containing naringenin (Nar) or hesperetin (Hsp ) and 1,10-phenanthroline as co-ligand were synthesized. The EPR spectra of complexes (17-18) in powder suggested formation of binuclear species. However, in DMSO solution the monomeric species should be largely predominant at 37 oC in DMSO/water. The cytotoxic activities of complexes (17) and (18) were evaluated against A549lung adenocarcinoma cells, normal lung fibroblasts (LL-24) and human umbilical vein endothelial cells (HUVEC). Complex (18) exhibited higher cytotoxic activity against A549 cells than complex (17). Both complexes promoted typical apoptotic morphological changes in A549 cells. A549 cells treated with the complexes did not show reduced mitochondrial membrane potential indicating that apoptosis induced bythe complexes is not associated to mitochondrial depolarization. A549 cells treated with the complexes showed reduction of ROS production, indicating that the compounds have antioxidant activity. The two complexes interact with DNA and with BSA and HSA. Thus, these complexes should be investigated as promising antineoplastic drugs candidates for the treatment of human lung adenocarcinoma.In addition, in the present work, 3-formyl-6-methylchromone-phenyl hydrazone (HCrPh, 19) and 3-formyl-6-methylchromone-para-chloro-phenyl hydrazone(HCrpClPh, 20) were also obtained. Hydrazones (19) and (20) did not present antimicrobial activity and showed low cytotoxic activity against on B16-F10 (metastatic melanoma) and Melan-a (nontumorigenic melanocyte) cells. However, upon coordination to silver(I), with formation of [Ag(HCrPh)2]NO32H2O (21) and [Ag(HCrpClPh)2]NO3 (22) improved antifungal activity was observed. Complexes (20)and (21) were more cytotoxic than the free ligands against B16-F10 cells, promoting reduction in cell viability of 25% and 40% respectively. Under the same conditions cisplatin and silver nitrate induced a reduction in cell viability of 11% and 9%, respectively. Hence, complexation of 3-formyl-6-methylchromone derived-hydrazones with silver(I) improves cytotoxic activity against tumor cells. The silver(I) complexes were less active on non-malignant Melan-a cells than cisplatin, indicating that they induced less cell damage in normal cells, which is a very important characteristic of new chemotherapeutic drug candidates. Hence, coordination of the hydrazones to silver(I) constituted an important strategy for increasing cytotoxic activity against solid tumorcells without increasing cytotoxic effects against normal cells. Complex (22) interacts with DNA and with BSA and HSA

SYNTHESIS, CHARACTERIZATION AND ANTIMICROBIAL ACTIVITY OF A Pd(II) COMPLEX WITH A 1,3-DIPHENYLPYRAZOLE-4-CARBOXALDEHYDE THIOSEMICARBAZONE LIGAND

This article describes the synthesis and characterization of a new complex, [Pd(Ph2PzTSC)2], formed between palladium(II) and 1,3-diphenylpyrazole-4-carboxaldehyde thiosemicarbazone ligand as a strategy for antimicrobial activity improvement the synthesized complex. The metal coordination leads to an improvement of ligand pharmacological activities and synergistic effects involving both metal ion as the ligand. The bidentate ligand is coordinated to metal ion through the azomethine nitrogen atoms and the sulphur in the form of thiol by deprotonation of the NH-C=S group. The antimicrobial activity of these new compounds was evaluated against gram-negative (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa) and gram-positive (Staphylococcus aureus and Bacillus thuringiensis) bacteria and two yeasts strains (Candida albicans and Saccharomyces cerevisiae). A comparison between the antimicrobial activity of the complex and that of the free ligand revealed that the coordination of Pd(II) improved the activity

Síntesis, caracterización y actividad Antimicrobial de un complejo de pd(ii) con Ligante 1,3-difenilpirazol-4-carboxaldehído Tiosemicarbazona

En este artículo se describe la síntesis y caracterización de un nuevo complejo de paladio(II), [Pd(Ph2PzTSC)2], con el ligante 1,3-difenilpirazol-4-carboxaldehído tiosemicarbazona (Ph2PzTSC) como una estrategia para mejorar la actividad antimicrobiana del complejo formado. La coordinación del ion metálico y el efecto sinérgico entre estos, conduce a mejorar la actividad biológica del complejo. El ligante se coordina al ion metálico de modo bidentado a través del átomo de nitrógeno del azometino y del azufre en forma de tiol, por la desprotonación del grupo NH-C=S. La actividad antimicrobiana de estos compuestos fueevaluada frente a bacterias Gram-negativas(Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa) yGram-positivas(Staphylococcus aureus, Bacillus thuringensis) y dos levaduras (Candida albicans y Saccharomyces cerevisiae). Cuando fueron comparados los resultados de la actividad antimicrobiana con la actividad del ligante libre, se observó que la coordinación del Pd(II) mejoró la actividad.This article describes the synthesis and characterization of a new complex, [Pd(Ph2PzTSC)2], formed between palladium(II) and 1,3-diphenylpyrazole-4-carboxaldehyde thiosemicarba-zone ligand as a strategy for antimicrobial activity improve-ment the synthesized complex. The metal coordination leads to an improvement of ligand pharmacological activities and synergistic effects involving both metal ion as the ligand. The bidentate ligand is coordinated to metal ion through the azomethine nitrogen atoms and the sulphur in the form of thiol by deprotonation of the NH-C=S group. The antimicro-bial activity of these new compounds was evaluated against gram-negative (Escherichia coli, Klebsiella pneumoniaeand Pseudomonas aeruginosa) and gram-positive (Staphy-lococcus aureus and Bacillus thuringiensis) bacteria and two yeasts strains (Candida albicans and Saccharomyces cerevisiae). A comparison between the antimicrobial activity of the complex and that of the free ligand revealed that the coordination of Pd(II) improved the activity.Incluye referencias bibliográfica

Synthesis, Characterization, and Antimicrobial Activity oF The Ligand 3-Methylpyrazole- 4-Carboxaldehyde Thiosemicarbazone and Its Pd(II) Complex

<div><p></p><p>The synthesis and characterization of a new palladium(II) complex [Pd(MePhPzTSC)₂] and its corresponding ligand 3-methylpyrazole-4-carboxaldehyde thiosemicarbazone (MePhPzTSC) are described. The bidentate ligand is coordinated to Pd(II) through the azomethine nitrogen atoms and sulfur in the form of thiol by deprotonation of the NH-C = S. The antimicrobial activity of these new compounds was evaluated against gram-negative (<i>Escherichia coli, Klebsiella pneumoniae,</i> and <i>Pseudomonas aeruginosa</i>) and gram-positive (<i>Staphylococcus aureus and Bacillus thuringiensis</i>) bacteria and two yeast strains (<i>Candida albicans</i> and <i>Saccharomyces cerevisiae</i>). Coordination of the ligand to the metallic ion showed improved antimicrobial activity compared to the free ligand. For the gram-positive bacteria the antimicrobial activity of the complex was higher than that of the positive control used.</p> <p>[Supplemental materials are available for this article. Go to the publisher's online edition of <i>Phosphorus, Sulfur, and Silicon and the Related Elements</i> to view the following free supplemental files: Additional figures and tables]</p> </div

Copper(II) complexes with naringenin and hesperetin: cytotoxic activity against A 549 human lung adenocarcinoma cells and investigation on the mode of action

Copper(II) complexes [Cu(H (2) O) (2) (L1)(phen)](ClO (4) ) (1) and [Cu(H (2) O)(L2)(phen)](ClO (4) ) (2) (HL1 = naringenin; HL2 = hesperetin) were obtained, in which an anionic flavonoid ligand is attached to the metal center along with 1,10-phenanthroline (phen) as co-ligand. Complexes (1) and (2) were assayed for their cytotoxic activity against A549 lung carcinoma and against normal lung fibroblasts (LL-24) and human umbilical vein endothelial cells (HUVEC). We found IC50 = 16.42 A mu M (1) and IC50 = 5.82 A mu M (2) against A549 tumor cells. Complexes (1) and (2) exhibited slight specificity, being more cytotoxic against malignant than against non-malignant cells. 1 and 2 induced apoptosis on A549 cells in a mitochondria-independent pathway, and showed antioxidant activity. The antioxidant effect of the complexes could possibly improve their apoptotic action, most likely by a PI3K-independent reduction of autophagy. Complexes (1) and (2) interact in vitro with calf thymus DNA by an intercalative binding mode. EPR data indicated that 1 and 2 interact with human serum albumin (HSA) forming mixed ligand species