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Antibacterial fluoroquinolones (FQs) are frequently used in treating infections. However, the value of FQs is debatable due to their association with severe adverse effects (AEs). The Food and Drug Administration (FDA) issued safety warnings concerning their side-effects in 2008, followed by the European Medicine Agency (EMA) and regulatory authorities from other countries. Severe AEs associated with some FQs have been reported, leading to their withdrawal from the market. New systemic FQs have been recently approved. The FDA and EMA approved delafloxacin. Additionally, lascufloxacin, levonadifloxacin, nemonoxacin, sitafloxacin, and zabofloxacin were approved in their origin countries. The relevant AEs of FQs and their mechanisms of occurrence have been approached. New systemic FQs present potent antibacterial activity against many resistant bacteria (including resistance to FQs). Generally, in clinical studies, the new FQs were well-tolerated with mild or moderate AEs. All the new FQs approved in the origin countries require more clinical studies to meet FDA or EMA requirements. Post-marketing surveillance will confirm or infirm the known safety profile of these new antibacterial drugs. The main AEs of the FQs class were addressed, highlighting the existing data for the recently approved ones. In addition, the general management of AEs when they occur and the rational use and caution of modern FQs were outlined.
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"Drug repositioning" is a modern strategy used to uncover new applications for out-of-date drugs. In this context, nalidixic acid, the first member of the quinolone class with limited use today, has been selected to obtain nine new metal complexes with lanthanide cations (La3+, Sm3+, Eu3+, Gd3+, Tb3+); the experimental data suggest that the quinolone acts as a bidentate ligand, binding to the metal ion via the keto and carboxylate oxygen atoms, findings that are supported by DFT calculations. The cytotoxic activity of the complexes has been studied using the tumoral cell lines, MDA-MB-231 and LoVo, and a normal cell line, HUVEC. The most active compounds of the series display selective activity against LoVo. Their affinity for DNA and the manner of binding have been tested using UV-Vis spectroscopy and competitive binding studies; our results indicate that major and minor groove binding play a significant role in these interactions. The affinity towards serum proteins has also been evaluated, the complexes displaying higher affinity towards albumin than apotransferrin.
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The widespread use of antibiotics has resulted in the emergence of drug-resistant populations of microorganisms. Clearly, one can see the need to develop new, more effective, antimicrobial agents that go beyond the explored 'chemical space'. In this regard, their unique modes of action (e.g., reactive oxygen species (ROS) generation, redox activation, ligand exchange, depletion of substrates involved in vital cellular processes) render metal complexes as promising drug candidates. Several Ru (II/III) complexes have been included in, or are currently undergoing, clinical trials as anticancer agents. Based on the in-depth knowledge of their chemical properties and biological behavior, the interest in developing new ruthenium compounds as antibiotic, antifungal, antiparasitic, or antiviral drugs has risen. This review will discuss the advantages and disadvantages of Ru (II/III) frameworks as antimicrobial agents. Some aspects regarding the relationship between their chemical structure and mechanism of action, cellular localization, and/or metabolism of the ruthenium complexes in bacterial and eukaryotic cells are discussed as well. Regarding the antiviral activity, in light of current events related to the Covid-19 pandemic, the Ru (II/III) compounds used against SARS-CoV-2 (e.g., BOLD-100) are also reviewed herein.
RESUMEN
"Drug repositioning" is a current trend which proved useful in the search for new applications for existing, failed, no longer in use or abandoned drugs, particularly when addressing issues such as bacterial or cancer cells resistance to current therapeutic approaches. In this context, six new complexes of the first-generation quinolone oxolinic acid with rare-earth metal cations (Y3+, La3+, Sm3+, Eu3+, Gd3+, Tb3+) have been synthesized and characterized. The experimental data suggest that the quinolone acts as a bidentate ligand, binding to the metal ion via the keto and carboxylate oxygen atoms; these findings are supported by DFT (density functional theory) calculations for the Sm3+ complex. The cytotoxic activity of the complexes, as well as the ligand, has been studied on MDA-MB 231 (human breast adenocarcinoma), LoVo (human colon adenocarcinoma) and HUVEC (normal human umbilical vein endothelial cells) cell lines. UV-Vis spectroscopy and competitive binding studies show that the complexes display binding affinities (Kb) towards double stranded DNA in the range of 9.33 × 104 - 10.72 × 105. Major and minor groove-binding most likely play a significant role in the interactions of the complexes with DNA. Moreover, the complexes bind human serum albumin more avidly than apo-transferrin.
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Antibacterianos/farmacología , Complejos de Coordinación/síntesis química , Complejos de Coordinación/farmacología , ADN/metabolismo , Metales de Tierras Raras/farmacología , Ácido Oxolínico/síntesis química , Ácido Oxolínico/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Complejos de Coordinación/química , Teoría Funcional de la Densidad , Fluorescencia , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Cinética , Metales de Tierras Raras/química , Conformación Molecular , Ácido Oxolínico/química , Unión Proteica/efectos de los fármacos , Albúmina Sérica Humana/química , Espectrofotometría Ultravioleta , Espectroscopía Infrarroja por Transformada de Fourier , TemperaturaRESUMEN
Quinolones comprise a series of synthetic bactericidal agents with a broad spectrum of activity and good bioavailability. An important feature of these molecules is their capacity to bind metal ions in complexes with relevant biological and analytical applications. Interestingly, lanthanide ions possess extremely attractive properties that result from the behavior of the internal 4f electrons, behavior which is not lost upon ionization, nor after coordination. Subsequently, a more detailed discussion about metal complexes of quinolones with lanthanide ions in terms of chemical and biological properties is made. These complexes present a series of characteristics, such as narrow and highly structured emission bands; large gaps between absorption and emission wavelengths (Stokes shifts); and long excited-state lifetimes, which render them suitable for highly sensitive and selective analytical methods of quantitation. Moreover, quinolones have been widely prescribed in both human and animal treatments, which has led to an increase in their impact on the environment, and therefore to a growing interest in the development of new methods for their quantitative determination. Therefore, analytical applications for the quantitative determination of quinolones, lanthanide and miscellaneous ions and nucleic acids, along with other applications, are reviewed here.
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Elementos de la Serie de los Lantanoides/farmacología , Quinolonas/farmacología , Sitios de Unión , Ciprofloxacina/farmacología , ADN/metabolismo , Topoisomerasa de ADN IV/metabolismo , Elementos de la Serie de los Lantanoides/química , Quinolonas/químicaRESUMEN
Four novel monocationic Ru(II) polypyridyl complexes were synthesized with the general formula [Ru(DIP)2flv]X, where DIP is 4,7-diphenyl-1,10-phenanthroline, flv stands for the flavonoid ligand (5-hydroxyflavone in [Ru(DIP)2(5-OHF)](PF6), genistein in [Ru(DIP)2(gen)](PF6), chrysin in [Ru(DIP)2(chr)](OTf), and morin in [Ru(DIP)2(mor)](OTf)), and X is the counterion, PF6-, and OTf Ì (triflate, CF3SO3Ì ), respectively. Following the chemical characterization of the complexes by 1H and 13C NMR, mass spectrometry, and elemental analysis, their cytotoxicity was tested against several cancer cell lines. The most promising complex, [Ru(DIP)2(gen)](PF6), was further investigated for its biological activity. Metabolic studies revealed that this complex severely impaired mitochondrial respiration and glycolysis processes, contrary to its precursor, Ru(DIP)2Cl2, which showed a prominent effect only on the mitochondrial respiration. In addition, its preferential accumulation in MDA-MB-435S cells (a human melanoma cell line previously described as mammary gland/breast; derived from metastatic site: pleural effusion), which are used for the study of metastasis, explained the better activity in this cell line compared to MCF-7 (human, ductal carcinoma).
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Antineoplásicos/farmacología , Complejos de Coordinación/farmacología , Flavonoides/farmacología , Piridinas/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Complejos de Coordinación/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Flavonoides/síntesis química , Glucólisis/efectos de los fármacos , Humanos , Ligandos , Mitocondrias/efectos de los fármacos , Piridinas/síntesis química , Rutenio/químicaRESUMEN
In the present work, we attempted to develop new metal coordination complexes of the natural flavonoid 5-hydroxyflavone with Sm(III), Eu(III), Gd(III), Tb(III). The resultant hydroxo complexes have been characterized by a variety of spectroscopic techniques, including fluorescence, FT-IR, UV-Vis, EPR and mass spectral studies. The general chemical formula of the complexes is [Ln(C15H9O3)3(OH)2(H2O)x]·nH2O, where Ln is the lanthanide cation and x = 0 for Sm(III), x = 1 for Eu(III), Gd(III), Tb(III) and n = 0 for Sm(III), Gd(III), Tb(III), n = 1 for Eu(III), respectively. The proposed structures of the complexes were optimized by DFT calculations. Theoretical calculations and experimental determinations sustain the proposed structures of the hydroxo complexes, with two molecules of 5-hydroxyflavone acting as monoanionic bidentate chelate ligands. The interaction of the complexes with calf thymus DNA has been explored by fluorescence titration and UV-Vis absorption binding studies, and revealed that the synthesized complexes interact with DNA with binding constants (Kb) ~ 104. Human serum albumin (HSA) and transferrin (Tf) binding studies have also been performed by fluorescence titration techniques (fluorescence quenching studies, synchronous fluorescence spectra). The apparent association constants (Ka) and thermodynamic parameters have been calculated from the fluorescence quenching experiment at 299 K, 308 K, and 318 K. The quenching curves indicate that the complexes bind to HSA with smaller affinity than the ligand, but to Tf with higher binding affinities than the ligand.
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Complejos de Coordinación/química , Flavonoides/química , Elementos de la Serie de los Lantanoides/química , Metales/química , Unión Competitiva , ADN/química , Fluorescencia , Humanos , Elementos de la Serie de los Lantanoides/síntesis química , Ligandos , Modelos Químicos , Estructura Molecular , Mapeo de Interacción de Proteínas , Espectroscopía Infrarroja por Transformada de Fourier , Relación Estructura-ActividadRESUMEN
The deleterious effects of ionizing radiation are a major concern of the modern world. In the last decades, outstanding interest has been given to developing new therapeutic tools designed for protection against the toxic effects of ionizing radiation. Deinococcus spp. are among the most radioresistant organisms on Earth, being able to survive extreme doses of radiation, 1000-fold higher than most vertebrates. The molecular mechanisms underlying DNA repair and biomolecular protection, which are responsible for the remarkable radioresistance of Deinococcus bacteria, have been a debatable subject for the last 60 years. This paper is focused on the most recent findings regarding the molecular background of radioresistance and on Deinococcus bacteria response to oxidative stress. Novel proteins and genes involved in the highly regulated DNA repair processes, and enzymatic and non- enzymatic antioxidant systems are presented. In addition, a recently proposed mechanism that may contribute to oxidative damage protection in Deinococcus bacteria is discussed. A better understanding of these molecular mechanisms may draw future perspectives for counteracting radiation-related toxicity.