Unravelling the Role of Uncommon Hydrogen Bonds in Cyclodextrin Ferrociphenol Supramolecular Complexes: A Computational Modelling and Experimental Study.

We sought to determine the cyclodextrins (CDs) best suited to solubilize a patented succinimido-ferrocidiphenol (SuccFerr), a compound from the ferrociphenol family having powerful anticancer activity but low water solubility. Phase solubility experiments and computational modelling were carried out on various CDs. For the latter, several CD-SuccFerr complexes were built starting from combinations of one or two CD(s) where the methylation of CD oxygen atoms was systematically changed to end up with a database of ca. 13 k models. Modelling and phase solubility experiments seem to indicate the predominance of supramolecular assemblies of SuccFerr with two CDs and the superiority of randomly methylated ß-cyclodextrins (RAMEßCDs). In addition, modelling shows that there are several competing combinations of inserted moieties of SuccFerr. Furthermore, the models show that ferrocene can contribute to high stabilization by making atypical hydrogen bonds between Fe and the hydroxyl groups of CDs (single bond with one OH or clamp with two OH of the same glucose unit).

Chasing unphysical TD-DFT excited states in transition metal complexes with a simple diagnostic tool.

Transition Metal Complexes (TMCs) are known for the rich variety of their excited states showing different nature and degrees of locality. Describing the energies of these excited states with the same degree of accuracy is still problematic when using time-dependent density functional theory in conjunction with the most current density functional approximations. In particular, the presence of unphysically low lying excited states possessing a relevant Charge Transfer (CT) character may significantly affect the spectra computed at such a level of theory and, more relevantly, the interpretation of their photophysical behavior. In this work, we propose an improved version of the MAC index, recently proposed by the authors and collaborators, as a simple and computationally inexpensive diagnostic tool that can be used for the detection and correction of the unphysically predicted low lying excited states. The analysis, performed on five prototype TMCs, shows that spurious and ghost states can appear in a wide spectral range and that it is difficult to detect them only on the basis of their CT extent. Indeed, both delocalization of the excited state and CT extent are criteria that must be combined, as in the MAC index, to detect unphysical states.

Aggregation-Induced Emission: A Challenge for Computational Chemistry Taking TPA-BMO as an Example*.

A multi-environment computational approach is proposed to study the modulation of the emission behavior of the triphenylamine (Z)-4-benzylidene-2-methyloxazol-5(4H)-one (TPA-BMO) molecule [Tang et al., J. Phys. Chem. C 119, 21875 (2015)]. We aim at (1) proposing a realistic description of the molecule in several environments (solution, aggregate, polymer matrix), (2) modelling its absorption and emission properties, and (3) providing a qualitative understanding of the experimental observations by highlighting the photophysical phenomena leading to the emission modulation. To this purpose, we rely on (TD-)DFT calculations and classical Molecular Dynamics simulations, but also on the hybrid ONIOM QM/QM' approach and the in situ chemical polymerization methodology. In low-polar solvents, the investigation of the potential energy surfaces and the modulation of the emission quantum yield can be attributed to possible photophysical energy dissipation caused by low-frequency vibrational modes. In the aggregate and in the polymer matrix, the emission modulation can be qualitatively interpreted in terms of the possible restriction of the intramolecular vibrations. For these two systems, our study highlights that a careful modelling of the environment is far from trivial but is fundamental to model the optical properties of the fluorophore.

Bioluminescent Nanoluciferase-Furimamide Complex: A Theoretical Study on Different Protonation States.

Luminescence of furimamide is 150 times brighter than oxidized luciferins in firefly and renilla luciferase. However, we do not have a clear understanding of the structure, function, and dynamic behavior of the nanoluciferase-furimamide complex. Here, for the first time, the absorption and emission properties of eight different possible light emitter forms of furimamide were investigated using the time-dependent density functional theory (TD-DFT) method in the gas phase and aqueous solution. The emission oscillator strengths in the gas phase showed that emission transition may be forbidden for some forms, and fluorescence would not occur. Besides, the charge transfer (CT) as well as the orbitals involved in the transitions were analyzed. Furthermore, molecular docking results showed that furimamide is situated inside the central cavity (ß-barrel) of nanoluciferase. Analysis of the trajectory of molecular dynamics (MD) simulations suggested a less compact structure of protein in the presence of furimamide in comparison to its apo form. The quantum mechanical/molecular mechanical (QM/MM) spectroscopic properties of one form in the binding site of nanoluciferase were investigated. The evolution of the excited states (ESs) of furimamide in the binding pocket of the protein confirmed that after photoexcitation and during the relaxation of the system, a crossing point between the first two singlet ESs exists. Thus, the initially populated S2 (a π→π* transition) becomes the first singlet excited state.

Following the evolution of excited states along photochemical reaction pathways.

Analyzing the behavior of potential energy surfaces (PESs) of diabatic excited states (ESs) becomes of crucial importance for a complete understanding of complex photochemical reactions. Since the definition of a compact representation for the transition density matrix, the use of the natural transition orbitals (NTOs) has become a routine practice in time-dependent density functional theory calculations. Their popularity has remarkably grown due to its simple orbital description of electronic excitations. Indeed, very recently, we have presented a new formalism used for the optimization of ESs by tracking the state of interest computing the NTO's overlap between consecutive steps of the procedure. In this new contribution, we generalize the use of this NTO's overlap-based state-tracking formalism for the analysis of all the desired diabatic states along any chemical reaction pathway. Determining the PES of the different diabatic states has been automatized by developing an extension of our recently presented algorithm, the so-called SDNTO: "Steepest Descent minimization using NTOs." This automatized overlap-based procedure allows an agile and convenient analysis of the evolution of the ESs avoiding the intrinsic ambiguity of visualizing orbitals or comparing physical observables. The analysis of two photochemical reactions of the same nature with different PES landscapes perfectly illustrates the utility of this new tool.

Atypical Lone Pair-π Interaction with Quinone Methides in a Series of Imido-Ferrociphenol Anticancer Drug Candidates.

Ferrociphenols, especially those possessing a heterocycle at the terminus of an aliphatic chain, display strong anticancer activity through a novel redox mechanism that generates active metabolites such as quinone methides (QMs). X-ray crystallography and UV/Vis spectroscopy reveal that the specific lone pair (lp)-π interaction between a carbonyl group of the imide and the quinone motif of the QM plays an important role in the exceptional cytotoxic behaviour of their imido-ferrociphenol precursors. This intramolecular lp-π interaction markedly enhanced the stability of the QMs and lowered the pKa values of the corresponding phenol/phenolate couples. As the first example of such a non-covalent interaction that stabilizes QMs remotely, it not only expands the scope of the lp-π interaction in supramolecular chemistry, but also represents a new mode of stabilization of a QM. This unprecedented application of lp-π interactions in imido-ferrociphenol anticancer drug candidates may also have great potential in drug discovery and organocatalyst design.

Excited state tracking during the relaxation of coordination compounds.

The ability to locate minima on electronic excited states (ESs) potential energy surfaces both in the case of bright and dark states is crucial for a full understanding of photochemical reactions. This task has become a standard practice for small- to medium-sized organic chromophores thanks to the constant developments in the field of computational photochemistry. However, this remains a very challenging effort when it comes to the optimization of ESs of transition metal complexes (TMCs), not only due to the presence of several electronic ESs close in energy, but also due to the complex nature of the ESs involved. In this article, we present a simple yet powerful method to follow an ES of interest during a structural optimization in the case of TMCs, based on the use of a compact hole-particle representation of the electronic transition, namely the natural transition orbitals (NTOs). State tracking using NTOs is unambiguously accomplished by computing the mono-electronic wave function overlap between consecutive steps of the optimization. Here, we demonstrate that this simple but robust procedure works not only in the case of the cytosine but also in the case of the ES optimization of a ruthenium nitrosyl complex which is very problematic with standard approaches. © 2019 The Authors. Journal of Computational Chemistry published by Wiley Periodicals, Inc.

Using density based indexes to characterize excited states evolution.

With the aim of offering new computational tools helping in the description of photochemical reactions and phenomena occurring at the excited state, we present in this work the capability of a density based index (Π) in locating decay channels from higher to lower excited states. The Π index, previously applied to disclose non-radiative decay channels from the first excited state to the ground state, is very simple in its formulation and can be evaluated, practically with no extra computational cost, and coupled to any quantum method able to provide excited states densities. Indeed, this index relies only on the knowledge of energetics and electron densities of the different electronic states involved in the decay. In the present work, we show the proficiency of the Π index in the general case of decay between excited states by applying it to two model systems well characterized both theoretically and experimentally. In both cases, this descriptor was successful in spotting the regions where excited states are more likely to decay, thus suggesting its potential interest for further application in the design of new compounds. © 2018 Wiley Periodicals, Inc.

Using Density Based Indexes and Wave Function Methods for the Description of Excited States: Excited State Proton Transfer Reactions as a Test Case.

To provide tools to interpret photochemical reactions, in this paper we demonstrate how a recently developed density-based index (DCT), up to now used in conjunction with time dependent density functional theory methods, can be extended to multiconfigurational methods. This index can guide chemists in the interpretation of photochemical reactions providing a measure of the spatial extent of a photoinduced charge transfer and, more generally, of charge transfer phenomena. This qualitative and quantitative description can be particularly relevant in the case of multiconfigurational calculations providing a simple tool for the interpretation of their complex outputs. To prove the potentiality of this approach we have considered a simple intramolecular excited state proton transfer reaction as study case and applied both wave function (CASSCF-CASPT2) and density-based methods in conjunction with a DCT analysis. Our results confirm that, also in the case of multiconfigurational methods, the DCT provides very useful information about the structural reorganization of a molecule at the excited state.

Prevalencia de fibrilación auricular y características de la fibrilación auricular no valvular en la población general. Registro AFINVA / Prevalence of atrial fibrillation and features of non-valvular atrial fibrillation in general population

Resumen Fundamento y objetivos: La fibrilación auricular es la arritmia mantenida más común. El estudio pretende conocer la prevalencia de fibrilación auricular en la población general, y evaluar las características y el manejo de los casos con fibrilación auricular no valvular. Métodos: Estudio transversal exploratorio en una muestra de la población de un Departamento de Salud (n = 30.024) de sujetos mayores de 18 años con diagnóstico electrocardiográfico de fibrilación auricular en la historia clínica electrónica de atención primaria. Se analizan características clínicas, manejo y tratamiento. Resultados: De un total de 629 pacientes con diagnóstico de fibrilación auricular, lo que representa una prevalencia del 2,1% (8,06% en > 65 años), fueron seleccionados para el estudio 505 casos con fibrilación auricular no valvular. La edad media fue 77,4 ± 10 años, 55% mujeres. Se objetivó cardiopatía estructural en el 32% de casos e insuficiencia cardiaca en el 29,5%. El 72% de pacientes recibía tratamiento anticoagulante, 60% con antivitamina K y 12% con anticoagulantes directos. Entre los primeros, solo el 53% mantenía un tiempo en rango terapéutico ≥ 65% según el método de Rosendaal. La forma de presentación persistente-permanente fue más frecuente (60,8%), seguida de la paroxística (39,2%). Conclusiones: La prevalencia de fibrilación auricular fue del 2,1%, aumentando con la edad, con elevada proporción de cardiopatía concomitante. La proporción de pacientes anticoagulados y la calidad de la anticoagulación son deficientes, revelándose así la necesidad de mejor monitorización y mayor utilización de nuevos anticoagulantes directos en los casos indicados.

Abstract Background and objectives: Atrial fibrillation is the most common type of constant arrhythmia. The study aims to know the prevalence of atrial fibrillation in the general population and to assess the features and management of non-valvular atrial fibrillation. Methods: Cross-sectional exploratory study of a population sample from a Health department (n=30.024) of individuals over 18 years with electrocardiographic diagnosis of atrial fibrillation in the primary care electronic medical records. Clinical features, management and treatments are analyzed. Results: Out of a total of 629 patients with an atrial fibrillation diagnosis, which represents a 2.1% prevalence (8.06% in >65 years), 505 cases with non-valvular atrial fibrillation were selected for the study. Average age was 77.4 ± 10 years, 55% female patients. Structural heart disease was detected in 32% of the cases, and cardiac failure in 29.5% of the cases. 72% of the patients were receiving anticoagulation therapy, 60% with antivitamin K drugs and 12% with direct anticoagulants. Among the former group, only 53% kept a time within the therapeutic range ≥65% according to the Rosendaal method. The most frequent presentation was persistentpermanent (60.8%), followed by paroxysmal (39.2%). Conclusions: Prevalence of atrial fibrillation was 2.1%, increasing with age, with a high proportion of accompanying heart disease. The proportion of anticoagulated patients and the quality of anticoagulation were poor, thus revealing the need for improved monitoring and wider use of new direct anticoagulants in the indicated cases.

Establishing the Two-Photon Linkage Isomerization Mechanism in the Nitrosyl Complex trans-[RuCl(NO)(py)4](2+) by DFT and TDDFT.

The density functional theory calculations presented in this work allow the first rationalization of the full linkage photoisomerization mechanism of trans-[RuCl(NO)(py)4](2+), in both the forward and reverse directions. These mechanisms are consistent with the experimental data establishing that blue-light irradiation triggers the forward process, while red or IR photons trigger the reverse process. Characterization of the singlet and lowest triplet potential energy surfaces shows that, despite the unfavorable thermodynamic character of the forward process, the topologies of the surfaces and particularly some crucial surface crossings enable the isomerization. In the forward Ru-NO → Ru-ON direction, a sequential two-photon absorption mechanism is unraveled that involves a sideways-bonded metastable state. In contrast, in the reverse reaction, two mechanisms are proposed involving either one or two photons.