Formation of dendrimer-guest complexes as a strategy to increase the solubility of a phenazine N, N′-dioxide derivative with antitumor activity

Poly(amidoamine) and Poly(propylenimine) dendrimers with different generations and peripheral groups were studied as solubility enhancers and nanocarriers for 7-bromo-2-hydroxy-phenazine N5,N10-dioxide. This compound possesses potential antitumoral and anti-trypanosomal activity, but its low solubility in physiological media precludes its possible application as therapeutic drug. The amino terminated dendrimers association with the active compounds as observed trough NMR studies showed that electrostatic interactions are essential in the solubilization enhancement process. The obtaining of a stable and no cytotoxic formulation makes the drug-carried association a suitable strategy for the generation of a drug delivery system for phenazine derivatives.EEA Marcos JuárezFil: Dib, Nahir. Universidad Nacional de Río Cuarto. Departamento de Física y Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernández, Luciana. Universidad Nacional de Río Cuarto. Departamento de Física y Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Santo, Marisa. Universidad Nacional de Río Cuarto. Departamento de Física y Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Otero, Luis. Universidad Nacional de Río Cuarto. Departamento de Física y Departamento de Química; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alustiza, Fabrisio Eduardo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Marcos Juárez; ArgentinaFil: Liaudat, Ana Cecilia. Universidad Nacional de Río Cuarto. Departamento de Biología Molecular; ArgentinaFil: Bosch, Pablo. Universidad Nacional de Río Cuarto. Departamento de Biología Molecular; ArgentinaFil: Lavaggi, María Laura. Universidad de la República. Facultad de Ciencias. Facultad de Química. Departamento de Química Orgánica; UruguayFil: Cerecetto, Hugo. Universidad de la República. Facultad de Ciencias. Facultad de Química. Departamento de Química Orgánica; UruguayFil: González, Mercedes Florencia. Universidad de la República. Facultad de Ciencias. Facultad de Química. Departamento de Química Orgánica; Urugua

New copper-based complexes with quinoxaline 'N POT.1', 'N POT.4'-dioxide derivatives, potential antitumoral agents

Taking into account our previous studies on cytotoxic metal compounds, new copper complexes with 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives as ligands were synthesized and characterized by different spectroscopic methods. The hypoxic selective cytotoxicity towards V79 cells and the superoxide dismutase-like activity of the complexes were determined and related to physicochemical properties of the compounds. In particular, the copper(II) complex with 3-amino-6-chloro-7-fluoroquinoxaline-2-carbonitrile N1,N4-dioxide showed cytotoxic selectivity in hypoxia being the most lipophilic compound of the series. On the contrary, the complex with 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide was cytotoxic but not selective and that with 3-amino-7-chloro-6-methoxy-quinoxaline-2-carbonitrile N1,N4-dioxide was not cytotoxic towards V79 cells neither in oxia nor in hypoxia in the assayed conditions. The σm Hammett substituent electronic descriptor was related to the effect in hypoxic conditions and the SOD-like activity was correlated to the effect in normoxia.Comisión Honoraria de Lucha Contra el Cáncer (CHLCC)Comisión Sectorial de Investigación Científica (CSIC)PEDECIB

Garbage in, garbage out: how reliable training data improved a virtual screening approach against SARS-CoV-2 MPro

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence.Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy –performed in a large and diverse chemolibrary– complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening.Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC50 ≤ 25 μM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC50 = 0.12–20 μM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC50 7–45 μM).Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known “garbage in, garbage out” machine learning principle

Aportes para el monitoreo participativo de la calidad del agua del río Tacuarembó en el noreste uruguayo

Implementing participatory processes to involve different social actors linked to local environmental problems can be helpful to improve the understanding of their causes and to empower citizens facing collective decision–making. The importance of this citizen participation is reflected in the experience carried out in Tranqueras (Rivera, Uruguay) where different actors were summoned to carry out participatory monitoring of the water quality of the Tacuarembó river. The process involved several workshops for the visualization of environmental problems and the design of a participatory sampling and analysis of water quality. This experience generated a teaching–learning space between the community and the University that raises the reflection of the relevance of the epistemological dimension of environmental problems and the way in which their knowledge is generated and the different perspectives of how environmental problems are addressed.A implementação de processos participativos para envolver diferentes atores sociais ligados a problemas ambientais locais pode ajudar a melhorar a compreensão de suas causas e capacitar os cidadãos para a toma de decisões coletivas. A importância dessa participação cidadã é mostrada na experiência realizada em Tranqueras (Rivera, Uruguai), onde diferentes atores foram convocados para realizar o monitoramento participativo da qualidade da água do rio Tacuarembó. O processo envolveu a realização de oficinas para a visualização de problemas ambientais e o desenho de uma amostragem, coleta participativa e análise da qualidade da água. Essa experiência gerou um espaço de ensino–aprendizagem entre a comunidade e a Universidade que suscita a reflexão sobre a relevância da dimensão epistemológica dos problemas ambientais, a maneira como seus conhecimentos são gerados e as diferentes perspectivas com as quais os problemas ambientais são abordados.Implementar procesos participativos para involucrar a diferentes actores sociales vinculados a problemas ambientales locales puede contribuir a mejorar la comprensión de las causas de estos y empoderar a los ciudadanos frente a la toma de decisiones colectivas. La importancia de esta participación ciudadana se refleja en la experiencia llevada a cabo en Tranqueras (Rivera, Uruguay), donde se convocó a distintos actores para efectuar un monitoreo participativo de la calidad de agua del río Tacuarembó. El proceso implicó la realización de talleres para la visualización de problemáticas ambientales y el diseño de un muestreo, colecta participativa y análisis de la calidad del agua. Esta experiencia generó un espacio de intercambio de saberes entre la comunidad y la Universidad que conduce a la reflexión sobre la relevancia de la dimensión epistemológica de los problemas ambientales, la forma en que se llega a su conocimiento y las distintas perspectivas con las que se abordan

Structural modifications on the phenazine N,N′-dioxide-scaffold looking for new selective hypoxic cytotoxins

We have identified phenazine 5,10-dioxides as prodrugs for antitumour therapy that undergo hypoxic-selective bioreduction to form cytotoxic species. Here, we investigated some structural modifications in order to find new selective hypoxic cytotoxins and to establish the structural requirements for adequate activity. Three different chemical-series were prepared and the clonogenic survival of V79 cells on aerobic and anaerobic conditions was determined. Electrochemical- and DNA-interaction studies were done for the most relevant derivatives. The new fluoro-derivative 7-fluoro-2-aminophenazine 5,10-dioxide displayed selective toxicity towards hypoxic V79 cells having adequate hypoxic cytotoxicity ratio (HCR = 6.8) and being the most potent hypoxic cytotoxins (P = 2.5 μM) described for this family of bioreductive agents. The reduction potential of the N-oxide moiety in this new fluoro-derivative was in the range for adequate bioreduction property. According to the fluorescence studies,

Study of benzo[a]phenazine 7,12-dioxide as selective hypoxic cytotoxin-scaffold. Identification of aerobic-antitumoral activity through DNA fragmentation

Phenazine 5,10-dioxides are prodrugs for antitumor therapy that undergo hypoxic-selective bioreduction to form cytotoxic species. Here we investigate the expanded system benzo[a]phenazine 7,12-dioxides as selective hypoxic cytotoxin-scaffold. The clonogenic survival of V79 cells on aerobic and anaerobic conditions, conduct us to study antiproliferative activity on Caco-2 tumoral cells in normoxia. Electrochemical, DNA-interaction and DNA-damage studies were performed to establish the mode of action. The results demonstrated the potential biological properties of the studied scaffold being derivatives 6-10 structural hits for further chemical-modifications to become into therapeutics for solid tumors. Compounds 6 and 8 with cytotoxicity against V79 cells in both conditions (aerobia and anaerobia) were also cytotoxic against Caco-2 tumoral cells in aerobiosis. © 2010 Elsevier Ltd. All rights reserved

Oxidovanadium(IV) and dioxidovanadium(V) complexes of tridentate salicylaldehyde semicarbazones: Searching for prospective antitrypanosomal agents

As a contribution to the identification of the relevant species for biological activity and the understanding of structure–activity relationships of [VIVO(L-2H)(NN)] antitrypanosomal complexes (NN is a bidentate polypyridyl DNA intercalator; L is a tridentate salicylaldehyde semicarbazone derivative), new [VVO2(L-2H)] complexes and [VIVO(L-2H)(NN)] complexes including bipy or dppz (dipyrido[3,2-a: 2′,3′-c]phenazine) co-ligands are prepared and characterized in the solid state and in solution. Their activity is evaluated on Trypanosoma cruzi. The lipophilicity, as structural descriptor related to bioactivity, of the whole [VIVO(L-2H)(NN)] series is determined. Furthermore, the antiproliferative effect of those new compounds showing activity against T. cruzi is evaluated on the genetically related parasite T. brucei with the aim to develop broad spectrum agents. The new [VIVO(L-2H)(dppz)] complexes are about ten to fifteen times more toxic to T. cruzi than the bipy analogues and show quite good in vitro activity on T. brucei brucei. They are shown to interact with DNA, suggesting that this biomolecule may be the parasite target. The stability of the VIVO-complexes in solution is accessed by several techniques. Globally the data suggest that the relevant species for biological activity are the [VIVO(L-2H)(NN)] compounds, their order of activity being dependent on the NN nature, but not much on the substitution on the salicylaldehyde semicarbazone moiety. A parabolic relationship between biological response and lipophilicity (determined as RM = log [(1 / Rf) − 1] by a TLC method) is obtained. From this correlation an optimum RM value, close to 1.44, was found, which may be used as design guide for future development of antitrypanosomal compounds.Fil: Fernández, Mariana. Universidad de la República; UruguayFil: Becco, Lorena. Universidad de la República; UruguayFil: Correia, Isabel. Universidade Técnica de Lisboa; PortugalFil: Benítez, Julio. Universidad de la República; UruguayFil: Piro, Oscar Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; ArgentinaFil: Echeverría, Gustavo Alberto. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Medeiros, Andrea. Universidad de la República; Uruguay. Instituto Pasteur de Montevideo; UruguayFil: Comini, Marcelo. Instituto Pasteur de Montevideo; UruguayFil: Lavaggi, María Laura. Universidad de la República; UruguayFil: González, Mercedes. Universidad de la República; UruguayFil: Cerecetto, Hugo. Universidad de la República; UruguayFil: Moreno, Virtudes. Universidad de Barcelona; EspañaFil: Costa Pessoa, Joao. Universidade Técnica de Lisboa; PortugalFil: Garat, Beatriz. Universidad de la República; UruguayFil: Gambino, Dinorah. Universidad de la República; Urugua