Suchergebnisse

[EN] Binding of the inmunodrepresive agent mycophenolate mofetil (MMP) and its pharmacologically active metabolite mycophenolic acid (MPA) to human serum albumin (HSA) and ¿1-acid glycoprotein (HAAG) has been investigated by an integrated approach involving selective excitation of the drug fluorophore, following their UV-A triggered fluorescence and docking studies. The formation of the protein/ligand complexes was evidenced by a dramatic enhancement of the fluorescence intensity and a hypsochromic shift of the emission band. In HSA, competitive studies using oleic acid as site I probe revealed site I as the main binding site of the ligands. Binding constants revealed that the affinity of the active metabolite by HSA is four-fold higher than its proactive form. Moreover, the affinity of MMP by HSA is three-fold higher than by HAAG. Docking studies revealed significant molecular binding differences in the binding of MMP and MPA to sub-domain IIA of HSA (site 1). For MPA, the aromatic moiety would be in close contact to Trp214 with the flexible chain pointing to the other end of the sub-domain; on the contrary, for MMP, the carboxylate group of the chain would be fixed nearby Trp214 through electrostatic interactions with residues Arg218 and Arg222. ; Financial support from the Spanish Ministry of Economy and Competiveness (CTQ2013-47872-C2-1-P, CTQ2016-78875-P, SAF2016-75638-R), the Xunta de Galicia (Centro singular de investigacion de Galicia accreditation 2016-2019, ED431G/09), the European Union (European Regional Development Fund-ERDF) and the Generalitat Valenciana (PROMETEO/2017/075) is gratefully acknowledged ; Vendrell-Criado, V.; González-Bello, C.; Miranda Alonso, MÁ.; Jiménez Molero, MC. (2018). A combined photophysical and computational study on the binding of mycophenolate mofetil and its major metabolite to transport proteins. Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy. 199:308-314. https://doi.org/10.1016/j.saa.2018.03.064 ; S ; 308 ; 314 ; 199

The efficiency of thymine (Thy) and uracil (Ura) to form cyclobutane pyrimidine dimers (CPDs) in solution, upon UV irradiation differs by one order of magnitude. This could to be partially related to the steric hindrance induced by the methyl at C5 in thymine. The aim of the present work is to establish the influence of a bulky moiety at this position on the photoreactivity of pyrimidines. With this purpose, photosensitization with benzophenone and acetone of a 5-tert-butyl uracil derivative (1) and the equivalent Thy (2) has been compared. Introduction of the tert-butyl group completely blocks CPD formation. Moreover, the mechanistic insight obtained by laser flash photolysis is in accordance with the observed photoreactivity. ; Financial support by the Spanish Government (CTQ2012-32621, CTQ2015-70164-P and contract JAE-Predoc 2011-00740 to V. V.-C.) and the Generalitat Valenciana (PROMETEOII/2013/005) is gratefully acknowledged. ; Vendrell Criado, V.; Lhiaubet, VL.; Yamaji, M.; Cuquerella Alabort, MC.; Miranda Alonso, MÁ. (2016). Blocking cyclobutane pyrimidine dimer formation by steric hindrance. Organic and Biomolecular Chemistry. 14(17):4110-4115. https://doi.org/10.1039/c6ob00382f ; S ; 4110 ; 4115 ; 14 ; 17

4110 4115 14 17 ; Senia ; The efficiency of thymine (Thy) and uracil (Ura) to form cyclobutane pyrimidine dimers (CPDs) in solution, upon UV irradiation differs by one order of magnitude. This could to be partially related to the steric hindrance induced by the methyl at C5 in thymine. The aim of the present work is to establish the influence of a bulky moiety at this position on the photoreactivity of pyrimidines. With this purpose, photosensitization with benzophenone and acetone of a 5-tert-butyl uracil derivative (1) and the equivalent Thy (2) has been compared. Introduction of the tert-butyl group completely blocks CPD formation. Moreover, the mechanistic insight obtained by laser flash photolysis is in accordance with the observed photoreactivity. Financial support by the Spanish Government (CTQ2012-32621, CTQ2015-70164-P and contract JAE-Predoc 2011-00740 to V. V.-C.) and the Generalitat Valenciana (PROMETEOII/2013/005) is gratefully acknowledged. Vendrell Criado, V.; Lhiaubet, VL.; Yamaji, M.; Cuquerella Alabort, MC.; Miranda Alonso, MÁ. (2016). Blocking cyclobutane pyrimidine dimer formation by steric hindrance. Organic and Biomolecular Chemistry. 14(17):4110-4115. doi:10.1039/c6ob00382f

[EN] Based on our previous investigations into the photophysical properties of the 5-methyl-2-pyrimidone (Pyo) chromophore, we now extend our studies to the photobehavior of the dimeric (6-4) thymine photoproducts (6-4 PP) to evaluate their capability to act as instrinsic DNA photosensitizers. The lesion presents significant absorption in the UVB/UVA region, weak fluorescence emission, a singlet-excited-state energy of approximately 351 kJ mol(-1), and a triplet-excited-state energy of 297 kJ mol(-1). Its triplet transient absorption has a maximum at 420-440 nm, a lifetime of around 7 mu s, and a high formation quantum yield, Phi(ISC) = 0.86. This species is efficiently quenched by thymidine. Its DNA photosensitizing properties are demonstrated by a series of experiments run on a pBR322 plasmid. The lesion photoinduces both single-strand breaks and the formation of cyclobutane thymine dimers. Altogether, these results show that, the substitution of the pyrimidone ring at C4 by a 5-hydroxy-5,6-dihydrothymine does not cancel out the photosensitization properties of the chromophore. ; Spanish Government (CTQ2015-70164-P, RIRAAF RETICS RD12/0013/0009, Prometeo II program, Severo Ochoa program/SEV-2012-0267 and JAE-Predoc 2011-00740 to V. V.-C.) is gratefully acknowledged. ; Vendrell Criado, V.; Rodríguez Muñiz, GM.; Lhiaubet ., VL.; Cuquerella Alabort, MC.; Miranda Alonso, MÁ. (2016). The (6-4) Dimeric Lesion as a DNA Photosensitizer. ChemPhysChem (Online). 17(13):1979-1982. https://doi.org/10.1002/cphc.201600154 ; S ; 1979 ; 1982 ; 17 ; 13

The aim of the present work is to determine the influence of C5 substitution on the photophysical properties of 2-thiopyrimidines (2-TPyr). For this purpose, 2-thiouracil, 5-t-butyl-2-thiouracil and 2-thiothymine (TU, BTU and TT, respectively) have been selected as target thionucleobases for the experimental studies and, in parallel, for DFT theoretical calculations. The UV spectra displayed by TU, BTU and TT in EtOH were very similar to each other. They showed a maximum around 275 nm and a shoulder at ca. 290 nm. The three 2-TPyr exhibited a strong phosphorescence emission; from the recorded spectra, triplet excited state energies of ca. 307, 304 and 294 kJ mol(-1) were determined for TU, BTU and TT, respectively. Laser excitation at 308 nm gave rise to a broad transient absorption band from 500 nm to 700 nm, which was in principle assigned to triplet-triplet absorption. This assignment was confirmed by energy transfer experiments using biphenyl (E-T = 274 kJ mol(-1)) as an acceptor. The triplet lifetimes were 70 ns, 1.1 mu s and 2.3 mu s, for TU, BTU and TT, respectively. The obtained photophysical data, both in phosphorescence and transient absorption measurements, point to significantly different properties of the TT triplet excited state in spite of the structural similarities. Theoretical calculations at the B3LYP/aug-cc-pVDZ/PCM level agree well with the experimental range of excited state energies and support the pi pi(star) nature of the lowest triplet states. ; Financial support by the Spanish Government (CTQ2009-13699, CTQ2012-32621, RyC-2007-00476 to V. L.-V., and contracts JAE-Predoc 2011-00740 and JAE-Doc 2010-06204 to V. V.-C. and J. A. S. respectively) and the computing facilities provided by the Theoretical Organic Chemistry group at the Universitat de Valencia (http://utopia.uv.es) are acknowledged. ; Vendrell Criado, V.; Sáez Cases, JA.; Lhiaubet, VL.; Cuquerella Alabort, MC.; Miranda Alonso, MÁ. (2013). Photophysical properties of 5-substituted 2-thiopyrimidines. Photochemical & ...

[EN] In this work, a molecular hydrogel made of gelator (S)-4-((3-methyl-1-(nonylamino)-1-oxobutan-2-yl)amino)-4-oxobutanoic acid (SVN) has been employed as soft container to modify the photochemical and photophysical behavior of the antipsychotic drug cyamemazine (CMZ). The interaction of CMZ with the gel network has been evidenced by fluorescence spectroscopy through a hypsochromic shift of the emission band (from lambda(max) = 521 nm in solution to lambda(max) = 511 nm in the gel) and an increase of the fluorescence lifetime (5.6 ns in PBS vs. 7.2 ns in the gel). In the laser flash photolysis experiments on CMZ/SVN systems, the CMZ triplet excited state ((3)CMZ*), monitored at lambda = 320 nm, has been more efficiently generated and became much longer-lived than in solution (2.7 mu s vs. 0.7 mu s); besides, photochemical ionization leading to the radical cation CMZ(+center dot) was disfavored. In the steady-state experiments, photooxidation of CMZ to afford the N,S-dioxide derivative CMZ-SONO has been retarded in the gel, which provides a more lipophilic and constrained microenvironment. Both the photophysical properties and the photoreactivity are in agreement with CMZ located in a less polar domain when entrapped in the supramolecular gel, as result of the interaction of the drug with the fibers of the supramolecular SVN gel. ; Financial support from the Spanish Government (CTQ2016-78875-P and CTQ2015-71004-R), the Generalitat Valenciana (PROMETEO/2017/075) and the European Union is gratefully acknowledged. ; Vendrell-Criado, V.; Angulo-Pachón, CA.; Miravet, JF.; Galindo, F.; Miranda Alonso, MÁ.; Jiménez Molero, MC. (2020). Photobehavior of the antipsychotic drug cyamemazine in a supramolecular gel protective environment. Journal of Photochemistry and Photobiology B Biology. 202:1-4. https://doi.org/10.1016/j.jphotobiol.2019.111686 ; S ; 1 ; 4 ; 202 ; Bourin, M., Dailly, E., & Hascöet, M. (2006). Preclinical and Clinical Pharmacology of Cyamemazine: Anxiolytic Effects and Prevention of Alcohol and ...

1 4 202 ; S ; [EN] In this work, a molecular hydrogel made of gelator (S)-4-((3-methyl-1-(nonylamino)-1-oxobutan-2-yl)amino)-4-oxobutanoic acid (SVN) has been employed as soft container to modify the photochemical and photophysical behavior of the antipsychotic drug cyamemazine (CMZ). The interaction of CMZ with the gel network has been evidenced by fluorescence spectroscopy through a hypsochromic shift of the emission band (from lambda(max) = 521 nm in solution to lambda(max) = 511 nm in the gel) and an increase of the fluorescence lifetime (5.6 ns in PBS vs. 7.2 ns in the gel). In the laser flash photolysis experiments on CMZ/SVN systems, the CMZ triplet excited state ((3)CMZ*), monitored at lambda = 320 nm, has been more efficiently generated and became much longer-lived than in solution (2.7 mu s vs. 0.7 mu s); besides, photochemical ionization leading to the radical cation CMZ(+center dot) was disfavored. In the steady-state experiments, photooxidation of CMZ to afford the N,S-dioxide derivative CMZ-SONO has been retarded in the gel, which provides a more lipophilic and constrained microenvironment. Both the photophysical properties and the photoreactivity are in agreement with CMZ located in a less polar domain when entrapped in the supramolecular gel, as result of the interaction of the drug with the fibers of the supramolecular SVN gel. Financial support from the Spanish Government (CTQ2016-78875-P and CTQ2015-71004-R), the Generalitat Valenciana (PROMETEO/2017/075) and the European Union is gratefully acknowledged. Vendrell-Criado, V.; Angulo-Pachón, CA.; Miravet, JF.; Galindo, F.; Miranda Alonso, MÁ.; Jiménez Molero, MC. (2020). Photobehavior of the antipsychotic drug cyamemazine in a supramolecular gel protective environment. Journal of Photochemistry and Photobiology B Biology. 202:1-4. https://doi.org/10.1016/j.jphotobiol.2019.111686 Bourin, M., Dailly, E., & Hascöet, M. (2006). Preclinical and Clinical Pharmacology of Cyamemazine: Anxiolytic Effects and Prevention of Alcohol and Benzodiazepine ...

[EN] Transient absorption spectroscopy in combination with in silico methods has been employed to study the interactions between human serum albumin (HSA) and the anti-psychotic agent chlorpromazine (CPZ) as well as its two demethylated metabolites (MCPZ and DCPZ). Thus, solutions containing CPZ, MCPZ or DCPZ and HSA (molar ligand:protein ratios between 1:0 and 1:3) were submitted to laser flash photolysis and the Delta A(max) value at lambda = 470 nm, corresponding to the triplet excited state, was monitored. In all cases, the protein-bound ligand exhibited higher Delta Amax values measured after the laser pulse and were also considerably longer-lived than the non-complexed forms. This is in agreement with an enhanced hydrophilicity of the metabolites, due to the replacement of methyl groups with H that led to a lower extent of protein binding. For the three compounds, laser flash photolysis displacement experiments using warfarin or ibuprofen indicated Sudlow site I as the main binding site. Docking and molecular dynamics simulation studies revealed that the binding mode of the two demethylated ligands with HSA would be remarkable different from CPZ, specially for DCPZ, which appears to come from the different ability of their terminal ammonium groups to stablish hydrogen bonding interactions with the negatively charged residues within the protein pocket (Glu153, Glu292) as well as to allocate the methyl groups in an apolar environment. DCPZ would be rotated 180 degrees in relation to CPZ locating the aromatic ring away from the Sudlow site I of HSA. (C) 2019 Elsevier B.V. All rights reserved. ; Financial support from Ministerio de Economia, Industria y Competitividad (CTQ2016-78875-P, SAF2016-75638-R, BES-2011-043706), Generalitat Valenciana (Prometeo 2017/075), Xunta de Galicia [Centro Singular de Investigacion de Galicia accreditation 2016-2019 (ED431G/09, ED431B 2018/04) and post-doctoral fellowship to E. L.] and European Union (European Regional Development Fund-ERDF) is gratefully acknowledged. I. A. ...