Excited-State Proton and Charge Transfer in Protonated Amino and Methylated Derivatives of 2-(2′-Hydroxyphenyl)benzimidazole

This is the peer-reviewed version of the following article: The Journal of Physical Chemistry B 2015, 119, 2475–2489, DOI: 10.1021/jp507917u, which has been published in final form at https://pubs.acs.org/doi/abs/10.1021/jp507917u. This article may be used for non-commercial purposes onlyWe studied the excited-state behavior of a family of mono- and diprotonated derivatives of 2-phenylbenzimidazole in different solvents, using steady-state and time-resolved fluorescence spectroscopy. The species investigated were 2-(4′-amino-2′-hydroxyphenyl)benzimidazole (1), the diethylamino analogue 2-(4′-N,N-diethylamino-2′-hydroxyphenyl)benzimidazole (2) and its N-methylated derivative 1-methyl-2-(4′-N,N-diethylamino-2′-hydroxyphenyl)benzimidazole (3). The O-methoxy derivatives of 2 and 3 (2-OMe and 3-OMe), and the simpler models 2-phenylbenzimidazole (4) and its 4′-amino (5) and 4′-dimethylamino (6) derivatives were also studied. We found that the dications of 1, 2, and 3 (protonated at the benzimidazole N3 and at the amino group) were strong photoacids, which were deprotonated at the hydroxyl group upon excitation in aqueous solution (totally for 2 and 3) to give a tautomer of the ground-state monocation. In contrast, no photodissociation was observed for the monocations of these species. Instead, some of the monocations studied behaved as molecular rotors, for which electronic excitation led to a twisted intramolecular charge transfer (TICT) state. The monocations of 2, 3, 2-OMe, 3-OMe, and 6, protonated at the benzimidazole N3, experienced a polarity- and viscosity-dependent radiationless deactivation associated with a large-amplitude rotational motion. We propose that this process is connected to an intramolecular charge transfer from the dimethylaminophenyl or diethylaminophenyl moiety (donor) to the protonated benzimidazole group (acceptor) of the excited monocation, which yields a twisted charge-transfer species. No fluorescence from this species was detected except for 3 and 3-OMe in low-viscosity solventsWe are indebted to the European Regional Development Fund, the Spanish Ministry of Economy and Competitiveness (Grant CTQ2010-17835), and the Xunta de Galicia (Grants GPC2013/052, CN2012/314, and EM2012/091) for financial support of our work. S.R. and J.L.P.L. are thankful for a MEC-FPU fellowship and a “Ramón y Cajal” contract, respectivelyS

Fluorescence of methylated derivatives of hydroxyphenylimidazopyridine. Resolution of strongly overlapping spectra and a new ESIPT dye showing very efficient radiationless deactivation

This is the peer-reviewed version of the following article: Fluorescence of methylated derivatives of hydroxyphenylimidazopyridine. Resolution of strongly overlapping spectra and a new ESIPT dye showing very efficient radiationless deactivation Alfonso Brenlla, Manoel Veiga, M. Carmen Ríos Rodríguez, Manuel Mosquera and Flor Rodríguez-Prieto Photochem. Photobiol. Sci., 2011, 10, 1622. DOI: 10.1039/c1pp05165b, which has been published in final form at http://pubs.rsc.org/en/content/articlelanding/2011/pp/c1pp05165b This article may be used for non-commercial purposes onlyThe ground- and excited-state behaviour of the isomeric species 2-(2′-methoxyphenyl)imidazo[4,5-b]pyridine (1-OMe) and 2-(2′-hydroxyphenyl)-4-methylimidazo[4,5-b]pyridine (1-NMe) in neutral and acid media has been studied by UV-vis absorption spectroscopy, steady-state and time-resolved fluorescence spectroscopy. The new dye 1-NMe is non-fluorescent in neutral media except in trifluoroethanol, where it shows a very weak fluorescence. 1-NMe also exhibits highly solvent-dependent fluorescence intensity in acidic media. We propose that the neutral species experiences a fast excited-state intramolecular proton transfer (ESIPT), relaxing afterwards by intramolecular twisting associated with internal charge transfer (TICT) and subsequent very fast internal conversion of the proton-transferred TICT structure. The behaviour of 1-NMe in acidic media is explained by the existence of a ground-state tautomeric equilibrium between species with intramolecular hydrogen bonds N–H⋯OH and N⋯HO. The first type of tautomers dissociates at the hydroxyl group in water and ethanol, but fluoresces in acetonitrile and trifluoroethanol due to the inability of these solvents to accept the proton. The second type of tautomers is non-emissive due to fast radiationless deactivation through an ESIPT-TICT process. The fluorescence of 1-OMe was investigated in neutral and acidic media, demonstrating the photobasic character of the pyridine nitrogen. A ground-state equilibrium between pyridinium and imidazolium cations was found for this species, showing overlapping absorption and fluorescence spectra. We devised a method to resolve the spectra by applying principal component global analysis to a series of excitation spectra taken at different emission wavelengths, which allowed estimation of the equilibrium constant between the cationsWe are indebted to the Spanish Ministry of Education and Science and the European Regional Development Fund (Grants CTQ2007-68057-C02-01/BQU and CTQ2010-17835) and the Xunta de Galicia (Grant IN845B-2010/094) for financial support of our work. A. Brenlla thanks the Fundación Segundo Gil Dávila for a postgraduate research grantS

Photoinduced Proton and Charge Transfer in 2‑(2′- Hydroxyphenyl)imidazo[4,5‑b]pyridine

This is the peer-reviewed version of the following article: The Journal of Physical Chemistry B 2013, 117, 884–896, DOI: 10.1021/jp311709c, which has been published in final form at https://pubs.acs.org/doi/abs/10.1021/jp311709c. This article may be used for non-commercial purposes onlyThis paper deals with the interplay between solvent properties and isomerism of 2-(2′-hydroxyphenyl)imidazo[4,5-b]pyridine (1), and the proton and charge-transfer processes that the different isomers undergo in the first-excited singlet state. We demonstrate the strong influence of these processes on the fluorescence properties of 1. We studied the behavior of 1 in several neutral and acidified solvents, by UV–vis absorption spectroscopy and by steady-state and time-resolved fluorescence spectroscopy. The fluorescence of 1 showed a strong sensitivity to the environment. This behavior is the result of conformational and isomeric equilibria and the completely different excited-state behavior of the isomers. For both neutral and cationic 1, isomers with intramolecular hydrogen bond between the hydroxyl group and the benzimidazole N undergo an ultrafast excited-state intramolecular proton transfer (ESIPT), yielding tautomeric species with very large Stokes shift. For both neutral and cationic 1, isomers with the OH group hydrogen-bonded to the solvent behave as strong photoacids, dissociating in the excited state in solvents with basic character. The pyridine nitrogen exhibits photobase character, protonating in the excited state even in some neutral solvents. An efficient radiationless deactivation channel of several species was detected, which we attributed to a twisted intramolecular charge-transfer (TICT) process, facilitated by deprotonation of the hydroxyl group and protonation of the pyridine nitrogenThis work has been supported by the Spanish Government and the European Regional Development Fund (Grant CTQ2010-17835) and the Xunta de Galicia (Grant CN 2012/314). A.B., M.V., and J.L.P.L. are thankful for a “Fundación Segundo Gil Dávila” fellowship, a MEC-FPU fellowship, and a “Ramon y Cajal” contract, respectivelyS

Moderately Strong Photoacid Dissociates in Alcohols with High Transient Concentration of the Proton-Transfer Contact Pair

This is the peer-reviewed version of the following article: The Journal of Physical Chemistry Letters 2014, 5, 989–994, DOI: 10.1021/jz5001648, which has been published in final form at https://pubs.acs.org/doi/abs/10.1021/jz5001648. This article may be used for non-commercial purposes onlyProton transfer from strong photoacids to hydroxylic solvents is much under debate. Experimentally, the main issue stems from relaxation and diffusion processes that are concomitant with ultrafast proton transfer and blur population dynamics. To overcome this, we propose a fast photodissociation reaction that, however, proceeds slower than solvent relaxation. Fluorescence spectroscopy of the cationic photoacid 2-(1′-hydroxy-2′-naphtyl)benzimidazolium reveals a two-stage mechanism: (a) reversible elementary proton transfer inside the solvent shell and (b) irreversible contact-pair splitting. The time evolution of the fluorescence signal is complex, yet this is explained quantitatively by simultaneous, spectrally overlapping emission of the acid, the conjugate base, and the contact proton-transfer pair. The latter attains high transient concentration in linear alcohols. Microscopic rate constants of dissociation are determinedWe thank the Spanish Government and the European Regional Development Fund (Grants CTQ2010-17835 and CTQ2010-17026) and the Xunta de Galicia (Grants CN 2012/314,EM2012/091, and GPC2013/052) for financial support of our work. J.L.P.L. thanks the Spanish Ministry of Economy and Competitiveness for funding through the Ramón y Cajal Programm 2009. M.V.G. and A.B. thank the Spanish Government and the “Segundo Gil-Dávila” Foundation, respectively, for financial supportS

Clinical and pathological features of Merkel cell carcinoma: A 4-year follow-up observational retrospective study in Spain

Background: Merkel cell carcinoma (MCC) is a malignant skin cancer with a 5-year survival rate of approximately 50%. Knowledge of MCC has increased in recent years mostly due to improved diagnosis techniques. In Spain there is lack of information regarding the incidence and tumour characteristics, and the treatment approaches are not standardised. The objective of this study was to provide information of the clinical and epidemiological characteristics of MCC patients in Spain. Methods: Retrospective, observational study involving 192 patients from 25 Spanish hospitals. Evaluated vari ables included overall survival and incidence rate of Merkel cell polyomavirus, in patients diagnosed from 2012 to 2016. Results: The Spanish incidence rate was estimated 0.32/100,000 inhabitants/year, with variations according to geographical regions, being slightly higher in areas with greater sunlight exposure. In total, 61.5% of tumours showed expansive growth (progressive growth of the tumour), 78.6% showed localisation in UV-exposed skin. 97.4% of patients were diagnosed by excisional biopsy. Surgery was the first line treatment in 96.6% of patients, radiotherapy in 24.6%, and chemotherapy in 6.3%. These treatments were not mutually exclusive. Median overall survival was 38.3 months (78.4% at 12 months and 60% at 24 months). MCPyV was present in 33.8% of patients. Conclusion: The incidence of MCC in Spain is one of the highest in Europe, with a slight predominance in men. The sample has shown that a biopsy is available for diagnosis in most cases. Moreover, the treatment is surgical when the tumour is localized and is associated with lymphadenectomy, and/or it is radiotherapy if widespread

A virtual reality approach to the Trier Social Stress Test: Contrasting two distinct protocols

Virtual reality adaptations of the Trier Social Stress Test (TSST-VR) constitute useful tools for studying the physiologic axes involved in the stress response. Here, we aimed to determine the most appropriate experimental approach to the TSST-VR when investigating the modulation of the axes involved in the stress response. We compared the use of goggles versus a screen projection in the TSST-VR paradigm. Forty-five healthy participants were divided into two groups: the first one (goggles condition; 13 females, 11 males) wore goggles while performing the TSST-VR; the second (screen condition; 15 females, six males) was exposed to the TSST-VR projected on a screen. Sympathetic reactivity to stress was measured by continuously recording skin conductance (SC), while the hypothalamic-pituitary-adrenal axis (HPA) was evaluated by sampling salivary cortisol throughout the experiment. At the end of the task, there was an increase in SC and cortisol level for both means of delivering the TSST-VR, although the increase in SC was greater in the goggles condition, while salivary cortisol was comparable in both groups. Immersion levels were reportedly higher in the screen presentation than in the goggles group. In terms of sex differences, females experienced greater involvement and spatial presence, though comparatively less experienced realism, than their male counterparts. These findings help us determine which protocol of the TSST-VR is most suitable for the stress response under study. They also emphasize the need to consider the sex of participants, as males and females show distinct responses in each protocol.This study is a part of a Thesis Doctoral and was supported by the I+D Project “PSI2010-15780” of the Spanish Ministry of Science and Innovation

The relationship between the menstrual cycle and cortisol secretion: Daily and stress-invoked cortisol patterns

The menstrual cycle involves significant changes in hormone levels, causing physical and psychological changes in women that are further influenced by stress. The aim of this study was to understand the relationship between menstrual cycle phase and salivary cortisol patterns during the day as well as the salivary cortisol response to the Virtual Reality Version of the Trier Social Stress Test (TSST-VR). Forty two women not taking oral contraceptives (24 in follicular phase and 18 in luteal phase) participated in the study. Five samples of salivary cortisol collected during the day and another five samples of cortisol during the TSST-VR were analyzed. Psychological stress measures and psychopathological symptomatology were also evaluated. A 2 × 4 mixed ANCOVA showed an interaction between the two groups on the TSST-RV invoked cortisol response to the [F(3,42) = 3.681; p = 0.023) where women in luteal phase showed higher cortisol post exposure levels (5.96 ± 3.76 nmol/L) than women in follicular phase (4.31 ± 2.23 nmol/L). No other significant differences were found. Our findings provide evidence that menstrual cycle phase tended to influence cortisol response to laboratory-induced mental stress, with more reactivity observed in the luteal phase.This study is a part of a Thesis Doctoral and was supported by the I+D Project “PSI2010-15780”, funded by the Spanish Ministry of Economy and Competitiveness

A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.<p></p> Methods: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.<p></p> Conclusion: Our results suggest a role of PPARG gene in the development of SSc

Evolutionary genomics of SARS-CoV-2: keys for viral success

Resumen del trabajo presentado al 44º Congreso de la Sociedad Española de Bioquímica y Biología Molecular, celebrado en Málaga del 6 al 9 de septiembre de 2022.Peer reviewe

Influence of Obesity and Metabolic Disease on Carotid Atherosclerosis in Patients with Coronary Artery Disease (CordioPrev Study)

Background Recent data suggest that the presence of associated metabolic abnormalities may be important modifiers of the association of obesity with a poorer prognosis in coronary heart disease. We determined the influence of isolated overweight and obesity on carotid intima media thickness (IMT-CC), and also assessed whether this influence was determined by the presence of metabolic abnormalities. Methods 1002 participants from the CordioPrev study were studied at entry. We determined their metabolic phenotypes and performed carotid ultrasound assessment. We evaluated the influence of obesity, overweight and metabolic phenotypes on the IMT-CC. Results Metabolically sick participants (defined by the presence of two or more metabolic abnormalities) showed a greater IMT-CC than metabolically healthy individuals (p = 4 * 10−6). Overweight and normal weight patients who were metabolically healthy showed a lower IMT-CC than the metabolically abnormal groups (all p<0.05). When we evaluated only body weight (without considering metabolic phenotypes), overweight or obese patients did not differsignificantly from normal-weight patients in their IMT-CC (p = 0.077). However, obesity was a determinant of IMT-CC when compared to the composite group of normal weight and overweight patients (all not obese). Conclusions In coronary patients, a metabolically abnormal phenotype is associated with a greater IMTCC, and may be linked to a higher risk of suffering new cardiovascular events. The protection conferred in the IMT-CC by the absence of metabolic abnormality may be blunted by the presence of obesit