Gustavo Espino
University of Burgos
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Inorganic Chemistry | 2013
Natalia Busto; Valladolid J; Marta Martínez-Alonso; Lozano Hj; Félix A. Jalón; Blanca R. Manzano; Ana M. Rodríguez; María del Carmen Carrión; Tarita Biver; Jorge Leal; Gustavo Espino; Begoña García
The synthesis and full characterization of the new aqua-complex [(η(6)-p-cymene)Ru(OH2)(κ(2)-N,N-2-pydaT)](BF4)2, [2](BF4)2, and the nucleobase derivative [(η(6)-p-cymene)Ru(9-MeG)(κ(2)-N,N-2-pydaT)](BF4)2, [4](PF6)2, where 2-pydaT = 2,4-diamino-6-(2-pyridyl)-1,3,5-triazine and 9-MeG = 9-methylguanine, are reported here. The crystal structures of both [4](PF6)2 and the chloro complex [(η(6)-p-cymene)RuCl(κ(2)-N,N-2-pydaT)](PF6), [1](PF6), have been elucidated by X-ray diffraction. The former provided relevant information regarding the interaction of the metallic fragment [(η(6)-p-cymene)Ru(κ(2)-N,N-2-pydaT)](2+) and a simple model of DNA. NMR and kinetic absorbance studies have proven that the aqua-complex [2](BF4)2 binds to the N7 site of guanine in nucleobases, nucleotides, or DNA. A stable bifunctional interaction (covalent and partially intercalated) between the [(η(6)-p-cymene)Ru(κ(2)-N,N-2-pydaT)](2+) fragment and CT-DNA has been corroborated by kinetic, circular dichroism, viscometry, and thermal denaturation experiments. The reaction mechanism entails the very fast formation of the Ru-O-(PO3) linkage prior to the fast intercalation of the 2-pydaT fragment. Then, a Ru-N7-(G) covalent bond is formed at the expense of the Ru-O-(PO3) bond, yielding a bifunctional complex. The dissociation rate of the intercalated fragment is slow, and this confers additional interest to [2](BF4)2 in view of the likely correlation between slow dissociation and biological activity, on the assumption that DNA is the only biotarget. Furthermore, [2](BF4)2 displays notable pH-dependent cytotoxic activity in human ovarian carcinoma cells (A2780, IC50 = 11.0 μM at pH = 7.4; IC50 = 6.58 μM at pH = 6.5). What is more, complex [2](BF4)2 is not cross-resistant with cisplatin, exhibiting a resistance factor, RF(A2780cis), of 0.28, and it shows moderate selectivity toward the cancer cell lines, in particular, A2780cis (IC50 = 3.0 5 ± 0.08 μM), relative to human lung fibroblast cells (MRC-5; IC50 = 24 μM), the model for healthy cells.
Inorganic Chemistry | 2014
Marta Martínez-Alonso; Natalia Busto; Félix A. Jalón; Blanca R. Manzano; José M. Leal; Ana M. Rodríguez; Begoña García; Gustavo Espino
The ligands 2-pyridin-2-yl-1H-benzimidazole (HL(1)), 1-methyl-2-pyridin-2-ylbenzimidazole (HL(2)), and 2-(1H-imidazol-2-yl)pyridine (HL(3)) and the proligand 2-phenyl-1H-benzimidazole (HL(4)) have been used to prepare five different types of new ruthenium(II) arene compounds: (i) monocationic complexes with the general formula [(η(6)-arene)RuCl(κ(2)-N,N-HL)]Y [HL = HL(1), HL(2), or HL(3); Y = Cl or BF4; arene = 2-phenoxyethanol (phoxet), benzene (bz), or p-cymene (p-cym)]; (ii) dicationic aqua complexes of the formula [(η(6)-arene)Ru(OH2)(κ(2)-N,N-HL(1))](Y)2 (Y = Cl or TfO; arene = phoxet, bz, or p-cym); (iii) the nucleobase derivative [(η(6)-arene)Ru(9-MeG)(κ(2)-N,N-HL(1))](PF6)2 (9-MeG = 9-methylguanine); (iv) neutral complexes consistent with the formulation [(η(6)-arene)RuCl(κ(2)-N,N-L(1))] (arene = bz or p-cym); (v) the neutral cyclometalated complex [(η(6)-p-cym)RuCl(κ(2)-N,C-L(4))]. The cytototoxic activity of the new ruthenium(II) arene compounds has been evaluated in several cell lines (MCR-5, MCF-7, A2780, and A2780cis) in order to establish structure-activity relationships. Three of the compounds with the general formula [(η(6)-arene)RuCl(κ(2)-N,N-HL(1))]Cl differing in the arene moiety have been studied in depth in terms of thermodynamic dissociation constants, aquation kinetic constants, and DNA binding measurements. The biologically most active compound is the p-cym derivative, which strongly destabilizes the DNA double helix, whereas those with bz and phoxet have only a small effect on the stability of the DNA double helix. Moreover, the inhibitory activity of several compounds toward CDK1 has also been evaluated. The DNA binding ability of some of the studied compounds and their CDK1 inhibitory effect suggest a multitarget mechanism for their biological activity.
Chemistry-an Asian Journal | 2012
Natalia Busto; Jesús Valladolid; Cristina Aliende; Félix A. Jalón; Blanca R. Manzano; Ana M. Rodríguez; J. Gaspar; Célia Martins; Tarita Biver; Gustavo Espino; José M. Leal; Begoña García
The reactions of two diaminotriazine ligands 2,4-diamino-6-(2-pyridyl)-1,3,5-triazine (2-pydaT) and 6-phenyl-2,4-diamino-1,3,5-triazine (PhdaT) with ruthenium-arene precursors led to a new family of ruthenium(II) compounds that were spectroscopically characterized. Four of the complexes were cationic, with the general formula [(η(6)-arene)Ru(κ(2)-N,N-2-pydaT)Cl]X (X=BF(4), TsO; arene=p-cymene: 1·BF(4), 1·TsO; arene=benzene: 2·BF(4), 2·TsO). The neutral cyclometalated complex [(η(6)-p-cymene)Ru(κ(2)-C,N-PhdaT*)Cl] (3) was also isolated. The structures of complexes 2·BF(4) and 3·H(2)O were determined by X-ray diffraction. Complex 1·BF(4) underwent a partial reversible-aquation process in water. UV/Vis and NMR spectroscopic measurements showed that the reaction was hindered by the addition of NaCl and was pH-controlled in acidic solution. At pH 7.0 (sodium cacodylate) Ru-Cl complex 1·BF(4) was the only species present in solution, even at low ionic strength. However, in alkaline medium (KOH), complex 1·BF(4) underwent basic hydrolysis to afford a Ru-OH complex (5). Fluorimetric studies revealed that the interaction of complex 1·BF(4) with DNA was not straightforward; instead, its main features were closely linked to ionic strength and to the [DNA]/complex ratio. The bifunctional complex 1·BF(4) was capable of interacting concurrently through both its p-cymene and 2-pydaT groups. Cytotoxicity and genotoxicity studies showed that, contrary to the expected behavior, the complex species was biologically inactive; the formation of a Ru-OH complex could be responsible for such behavior.
Supramolecular Chemistry | 2012
Gustavo Espino; Félix A. Jalón; Blanca R. Manzano; Mercedes Pérez-Manrique; Kurt Mereiter; David Quiñonero
The reaction of [RuCl2(cod)(bpzm)] [cod = 1,5-cyclooctadiene, bpzm = bis(pyrazol-1-yl)methane] with 2-diphenylphosphino-1-methylimidazole (dpim) and crystallisation from CHCl3 yielded crystals of cis-[RuCl(κ2-N,N-bpzm)(κ1-P-dpim)(κ2-P,N-dpim)][Cl(CHCl3)4]·CHCl3, (1√(CHCl3)5), in which the Cl− counteranion was solvated by four CHCl3 molecules and interacted with the most positive region of the cation. The structure of the anionic entity and the presence of non-covalent interactions were studied. Theoretical calculations allowed the evaluation of the stability of [Cl(CHCl3) n ]− aggregates. A pronounced stability was found for aggregates with n = 6 with an increasing charge transfer from the chloride ion to the CHCl3 molecules from n = 1 to 6. A literature survey on the occurrence of anionic species [Cl(CXCl3) n (HB) m ]− (X = H or D; HB = hydrogen bonds with the cation) in solid state structures was carried out and the findings correlated with the results of computational studies. A stabilisation effect of a Cl…Cl interaction was demonstrated by a natural bond orbitals (NBO) analysis.
European Journal of Medicinal Chemistry | 2018
Cristina Pérez-Arnaiz; María Isabel Acuña; Natalia Busto; Igor Echevarría; Marta Martínez-Alonso; Gustavo Espino; Begoña García; Fernando Domínguez
Two pairs of Rh(III) and Ir(III) biscyclometallated complexes with thiabendazole (L1), named [Ir-a]Cl and [Rh-a]Cl, and N-benzyl-thiabendazole (L2), named [Ir-b]Cl and [Rh-b]Cl, have been designed and synthesized to explore the photophysical and biological effects that arise from changing both the metal center and the ancillary ligand. In the dark, the four metal complexes exhibit greater cytotoxicity than cisplatin against human colon (SW480) and human lung (A549) adenocarcinoma cell lines. Moreover, the pair of complexes bearing the ligand L2 is markedly more cytotoxic and present higher uptake values than complexes with L1, thereby their biological properties were studied further to determine their mechanism of action. Interestingly, in spite of the different metal center both the [Ir-b]Cl and [Rh-b]Cl complexes are responsible for the loss of mitochondrial functionality and the activation of apoptotic cell death pathways. Moreover, the photodynamic activity of the four complexes, [Ir-a,b]Cl and [Rh-a,b]Cl, was tested using visible blue light (460 nm) under soft irradiation conditions (20 min, 5.5 mW cm-2). While the Rh complexes are not photopotentiated, the phototoxicity index (IC50 non-irradiated/IC50 irradiated) of [Ir-a]Cl and [Ir-b]Cl complexes was 15.8 and 3.6, respectively. We also demonstrate that only the Ir derivatives are capable of photocatalyzing the oxidation of S-containing l-amino acids under blue light irradiation, [Ir-a]Cl being more active than [Ir-b]Cl, which provides a reasonable mechanism for their biological action (oxidative stress could be selectively promoted through a photocatalytic action) upon irradiation. This different PDT behaviour depending on the metal center and the ancillary substituent may be useful for future rational design of metal-based photosensitizers.
Chemistry: A European Journal | 2018
Marta Martínez-Alonso; Natalia Busto; Larry Danilo Aguirre; Leticia Berlanga; María del Carmen Carrión; José V. Cuevas; Ana M. Rodríguez; Arancha Carbayo; Blanca R. Manzano; Enrique Ortí; Félix A. Jalón; Begoña García; Gustavo Espino
In this paper, the synthesis, comprehensive characterization and biological and photocatalytic properties of two series of neutral IrIII biscyclometalated complexes of general formula [Ir(C^N)2 (N^O)], where the N^O ligands are 2-(benzimidazolyl)phenolate-N,O (L1, series a) and 2-(benzothiazolyl)phenolate-N,O (L2, series b), and the C^N ligands are 2-(phenyl)pyridinate or its derivatives, are described,. Complexes of types a and b exhibit dissimilar photophysical and biological properties. In vitro cytotoxicity tests conclusively prove that derivatives of series a are harmless in the dark against SW480 cancer cells (colon adenocarcinoma), but express enhanced cytotoxicity versus the same cells after stimulation with UV or blue light. In contrast, complexes of type b show a very high cytotoxic activity in the dark, but low photosensitizing ability. Thus, the ancillary N^O ligand is the main factor in terms of cytotoxic activity both in the dark and upon irradiation. However, the C^N ligands play a key role regarding cellular uptake. In particular, the complex of formula [Ir(dfppy)2 (L1)] (dfppy=2-(4,6-difluorophenyl)pyridinate) [3 a] has been identified as both an efficient photosensitizer for 1 O2 generation and a potential agent for photodynamic therapy. These capabilities are probably related to a combination of its notable cellular internalization, remarkable photostability, high photoluminescence quantum yield, and long triplet excited-state lifetime. Both types of complexes exhibit notable catalytic activity in the photooxidation of thioanisole and S-containing aminoacids with full selectivity.
Organometallics | 2012
Cristina Aliende; Mercedes Pérez-Manrique; Félix A. Jalón; Blanca R. Manzano; Ana M. Rodríguez; Gustavo Espino
Journal of the American Chemical Society | 2005
Félix A. Jalón; Blanca R. Manzano; Agustfn Caballero; M. Carmen Carrión; Lucfa Santos; Gustavo Espino; Miquel Moreno
ACS Catalysis | 2014
M. Carmen Carrión; Margarita Ruiz-Castañeda; Gustavo Espino; Cristina Aliende; Lucía Santos; Ana M. Rodríguez; Blanca R. Manzano; Félix A. Jalón; Agustí Lledós
Journal of Inorganic Biochemistry | 2012
Cristina Aliende; Mercedes Pérez-Manrique; Félix A. Jalón; Blanca R. Manzano; Ana M. Rodríguez; José V. Cuevas; Gustavo Espino; Ma Ángeles Martínez; Anna Massaguer; Marta González-Bártulos; Rafael de Llorens; Virtudes Moreno