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The aim of the present study was to evaluate the cytotoxic potential of a new complex of silver(I) with furosemide (Ag-FSE) over a panel of tumor and non-tumor human cells, as well as its genotoxicological safety. According to the results obtained, cell line derived from colorectal adenocarcinoma (Caco-2) was the most sensitive to the Ag-FSE complex, and among the non-tumor cells was the non-transforming fibroblasts known as GM07492A, which stimulated the characterization of cytotoxic properties against these cells. In addition to interfering with the cellular metabolic profile (evidenced by the resazurin method), Ag-FSE alters the integrity of cell membranes (results obtained by the Trypan blue assay) regardless of the cell line evaluated. However, interference with clonogenic capacity is dependent on the cell being tested; the cytotoxic activity evaluated by the clonogenic survival assay was evidenced against Caco-2 cells, but not against GM07492A cells. Furthermore, Ag-FSE did not induce an increase in the extent of DNA damage detectable by the comet assay, nor in the frequency of micronuclei compared to the negative control, demonstrating the absence of genotoxicity under the experimental conditions used. The data of the present study provide information on various biological aspects of the Ag-FSE complex and help in the generation of new drug candidates with potential to impact the health area, targeting cancer treatment. El objetivo del presente estudio fue evaluar el potencial citotóxico de un nuevo complejo de plata(I) con furosemida (Ag-FSE) en un panel de células tumorales y no tumorales humanas, así como su seguridad genotoxicológica. De acuerdo con los resultados obtenidos, la línea celular derivada del adenocarcinoma colorrectal (Caco-2) fue la más sensible al complejo Ag-FSE, y entre las células no tumorales se encontraban los fibroblastos no transformantes conocidos como GM07492A, lo que estimuló la caracterización. de las propiedades citotóxicas contra estas células. Además de interferir con el perfil metabólico celular (evidenciado por el método de resazurina), Ag-FSE altera la integridad de las membranas celulares (resultados obtenidos por el ensayo de azul de tripano) independientemente del linaje celular evaluado. Sin embargo, la interferencia con la capacidad clonogénica depende de la célula que se esté analizando; la actividad citotóxica evaluada por el ensayo de supervivencia clonogénica se evidenció frente a las células Caco-2, pero no frente a las células GM07492A. Además, Ag-FSE no indujo un aumento en la extensión del daño del ADN detectable por el ensayo Comet, ni en la frecuencia de micronúcleos en relación con el control negativo, lo que demuestra la ausencia de genotoxicidad en las condiciones experimentales utilizadas. Los datos del presente estudio brindan información sobre varios aspectos biológicos del complejo Ag-FSE y ayudan en la generación de nuevos candidatos a fármacos con potencial impacto en el área de la salud, con miras al tratamiento del cáncer. O objetivo do presente estudo foi avaliar o potencial citotóxico de um novo complexo de prata(I) com furosemida (Ag-FSE) sobre um painel de células humanas tumorais e não tumorais, bem como sua segurança genotoxicológica. De acordo com os resultados obtidos, a linhagem celular derivada do adenocarcinoma colorretal (Caco-2) foi a mais sensível ao complexo Ag-FSE, e dentre as células não tumorais foram fibroblastos não transformantes conhecidos como GM07492A, o que estimulou a caracterização das propriedades citotóxicas contra essas células. Além de interferir no perfil metabólico celular (evidenciado pelo método da resazurina), Ag-FSE altera a integridade das membranas celulares (resultados obtidos pelo ensaio do azul de Trypan) independentemente da linhagem celular avaliada. No entanto, a interferência na capacidade clonogênica depende da célula que está sendo testada; a atividade citotóxica avaliada pelo ensaio de sobrevivência clonogênica foi evidenciada contra células Caco-2, mas não contra células GM07492A. Além disso, Ag-FSE não induziu aumento na extensão do dano ao DNA detectável pelo ensaio Cometa, nem na frequência de micronúcleos em relação ao controle negativo, demonstrando ausência de genotoxicidade nas condições experimentais utilizadas. Os dados do presente estudo fornecem informações sobre diversos aspectos biológicos do complexo Ag-FSE e auxiliam na geração de novos candidatos a fármacos com potencial de impacto na área da saúde, visando o tratamento do câncer.

Made available in DSpace on 2022-04-29T08:38:47Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 This study aimed to encapsulate and characterise a potential anti-tuberculosis copper complex (CuCl2(INH)2.H2O:I1) into polymeric nanoparticles (PNs) of polymethacrylate copolymers (Eudragit®, Eu) developed by nanoprecipitation method. NE30D, S100 and, E100 polymers were tested. The physicochemical characterisations were performed by DLS, TEM, FTIR, encapsulation efficiency and, in vitro release studies. Encapsulation of I1 in PN-NE30D, PN-E100, and PN-S100 was 26.3%, 94.5%, 22.6%, respectively. The particle size and zeta potentials were 82.3 nm and −24.5 mV for PNs-NE30D, 304.4 nm and +18.7 mV for PNs-E100, and 517.9 nm and −6.9 mV for PNs-S100, respectively. All PDIs were under 0.5. The formulations showed an I1 controlled release at alkaline pH with 29.7% from PNs-NE30D, 7.9% from PNs-E100 and, 28.1% from PNs-S100 at 1 h incubation. PNs were stable for at least 3 months. Particularly, PNs-NE30D demonstrated moderate inhibition of M. tuberculosis and low cytotoxic activity. None of the PNs induced mutagenicity. Department of Biological Sciences and Health University of Araraquara (UNIARA) Department of Drugs and Medicines School of Pharmaceutical Sciences São Paulo State University (UNESP) Nanobiotechnology Laboratory Institute of Biological Sciences Department of Genetics and Morphology University of Brasilia Department of Biological Sciences School of Pharmaceutical Sciences São Paulo State University (UNESP) Facultad de Ciencias Exactas Departmento de Química CINDEFI Laboratorio de Nanobiomateriales Universidad Nacional de La Plata–CONICET (CCT La Plata) Max Planck Laboratory for Structural Biology Chemistry and Molecular Biophysics of Rosario (MPLbioR UNR-MPIbpC) Partner Laboratory of the Max Planck Institute for Biophysical Chemistry (MPIbpC MPG) Universidad Nacional de Rosario Centro de Estudios Interdisciplinarios (CEI) Laboratorio de Química Fina (UNL-CONICET) Universidad Nacional del Litoral (UNL) INTEC Department of Drugs and Medicines School of Pharmaceutical Sciences São Paulo State University (UNESP) Department of Biological Sciences School of Pharmaceutical Sciences São Paulo State University (UNESP)

The development of new drugs based on metal complexes requires a detailed analysis of their biological endpoints. In this study, we report the genotoxic profile and influence on cell proliferation and death of the oxovanadium(IV) complex with orotic acid ([VO(C

Made available in DSpace on 2020-12-12T02:01:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-06-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) ASCRS Research Foundation Considering the promising previous results of Cu (II) complexes with isoniazid active ligand against Mycobacterium tuberculosis, the main causative agent of tuberculosis, novel biological assays evaluating its toxicogenic potential were performed to ensure the safe use. The genotoxicity/mutagenicity of the complexes CuCl2(INH)2.H2O (I1), Cu(NCS)2(INH)2.5H2O (I2) and Cu(NCO)2(INH)2.4H2O (I3) was evaluated by the Comet, Micronucleus-cytome and Salmonella microsome (Ames test) assays. The cell viability using resazurin assay indicated that I1, I2 e I3 had moderate to low capacity to reduce the viability of colorectal cells (Caco-2), liver cells (HepG2), lung cells (GM 07492-A and A549) and endothelial cells (HU-VE-C). On genotoxicity/mutagenicity, I1 complex did not induce sizable levels of DNA damage in HepG2 cells (Comet assay), and gene (Ames test) and chromosomal (Micronucleus-cytome assay) mutations. Already, I2 and I3 complexes were considered mutagenic in the highest concentrations used. In light of the above, these results contribute to valuable data on the safe use of Cu(II) complexes. Considering the absence of mutagenicity and cytotoxicity of I1, this complex is a potential candidate for the development of a new drug to the treatment tuberculosis, while I2 and I3 require caution in its use. UNIARA- University of Araraquara Department of Biological Sciences and Health UNESP-São Paulo State University Faculty of Pharmaceutical Sciences of Araraquara- Department of Biological Sciences UNESP-São Paulo State University Faculty of Pharmaceutical Sciences of Araraquara- Department of Biological Sciences FAPESP: 2013/09265-7 ASCRS Research Foundation: 2017/16278-9 FAPESP: 2017/16278-9 ASCRS Research Foundation: D:\MYFILES\ELSEVIER\YRTPH\00104653\S-CESTRUCTURING\gs3

Made available in DSpace on 2020-12-12T02:31:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-03-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Universidade Estadual de Campinas ASCRS Research Foundation Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) This manuscript presents three silver(I) complexes with fluoroanthranilic acid (fa) isomers, [Ag(4fa)]n, [Ag(5fa)]n and [Ag(6fa)]n, which were named as Ag4fa, Ag5fa and Ag6fa, respectively. The 1:1 metal/ligand molar composition of the complexes was determined by elemental, thermal and high-resolution mass spectrometric (ESI(+)-MS) analyses. Infrared and 1H, 13C and {15N,1H} nuclear magnetic resonance spectroscopy evidenced the coordination of the fluoroanthranilic acid isomers to silver via the nitrogen atom of the amino group and by the oxygen atoms of the carboxylate group. The structure of the Ag5fa complex was determined by single crystal X-ray diffraction analysis. The complex forms an extended polymeric structure organized in layers with coordination by the amino and carboxylate moieties. Antibacterial activity assays showed that the silver complexes were active against M. tuberculosis (MIC90 between 2.6 and 4.2 µg/mL) and also over S. aureus, B. cereus, E. coli and P. aeruginosa (MIC = 62.25 µg/mL) strains. The complexes have also shown in vitro cytotoxicity over cancer cell lines and selectivity (SI) especially against epithelial colorectal adenocarcinoma cells (IC50 = 2.1 µg/mL and SI > 3). Also, the silver complexes are non-mutagenic, which is essential when considering the development of new bioactive compounds for therapeutic purposes. Inorganic Chemistry Department Institute of Chemistry University of Campinas – UNICAMP, P.O. Box 6154 Biological and Health Sciences Department University of Araraquara – UNIARA School of Pharmaceutical Sciences São Paulo State University – UNESP School of Pharmaceutical Sciences São Paulo State University – UNESP FAPESP: 2017/16278-9 FAPESP: 2017/25995-6 FAPESP: 2018/00163-0 FAPESP: 2018/12062-4 FAPESP: 2018/14512-7 CNPq: 407012/2018-4