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1.
J Biol Inorg Chem ; 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32193613

RESUMO

Topoisomerase IIα (topo2α) is an essential nuclear enzyme involved in DNA replication, transcription, recombination, chromosome condensation, and highly expressed in many tumors. Thus, topo2α-targeting has become a very efficient and well-established anticancer strategy. Herein, we investigate the cytotoxic and DNA-damaging activity of thiomaltol-containing ruthenium-, osmium-, rhodium- and iridium-based organometallic complexes in human mammary carcinoma cell lines by means of several biological assays, including knockdown of topo2α expression levels by RNA interference. Results suggest that inhibition of topo2α is a key process in the cytotoxic mechanism for some of the compounds, whereas direct induction of DNA double-strand breaks or other DNA damage is mostly rather minor. In addition, molecular modeling studies performed for two of the compounds (with Ru(II) as the metal center) evinces that these complexes are able to access the DNA-binding pocket of the enzyme, where the hydrophilic environment favors the interaction with highly polar complexes. These findings substantiate the potential of these compounds for application as antitumor metallopharmaceuticals.

2.
Inorg Chem ; 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32142275

RESUMO

The development of new solar-to-fuel scenarios is of great importance, but the construction of molecular systems that convert sunlight into chemical energy represents a challenge. One specific issue is that the molecular systems have to be able to accumulate redox equivalents to mediate the photodriven transformation of relevant small molecules, which mostly involves the orchestrated transfer of multiple electrons and protons. Disulfide/dithiol interconversions are prominent 2e-/2H+ couples and can play an important role for redox control and charge storage. With this background in mind, a new photosensitizer [Ru(S-Sbpy)(bpy)2]2+ (12+) equipped with a disulfide functionalized bpy ligand (S-Sbpy, bpy = 2,2'-bipyridine) was synthesized and has been comprehensively studied, including structural characterization by X-ray diffraction. In-depth electrochemical studies show that the S-Sbpy ligand in 12+ can be reduced twice at moderate potentials (around -1.1 V vs Fc+/0), and simulation of the cyclic voltammetry (CV) traces revealed potential inversion (E2 > E1) and allowed to derive kinetic parameters for the sequential electron-transfer processes. However, reduction at room temperature also triggers the ejection of one sulfur atom from 12+, leading to the formation of [Ru(Sbpy)(bpy)2]2+(22+). This chemical reaction can be suppressed by decreasing the temperature from 298 to 248 K. Compared to the archetypical photosensitizer [Ru(bpy)3]2+, 12+ features an additional low energy optical excitation in the MLCT region, originating from charge transfer from the metal center to the S-Sbpy ligand (aka MSCT) according to time-dependent density functional theory (TD-DFT) calculations. Analysis of the excited states of 12+ on the basis of ground-state Wigner sampling and using charge-transfer descriptors has shown that bpy modification with a peripheral disulfide moiety leads to an energy splitting between charge-transfer excitations to the S-Sbpy and the bpy ligands, offering the possibility of selective charge transfer from the metal to either type of ligands. Compound 12+ is photostable and shows an emission from a 3MLCT state in deoxygenated acetonitrile with a lifetime of 109 ns. This work demonstrates a rationally designed system that enables future studies of photoinduced multielectron, multiproton PCET chemistry.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32052547

RESUMO

Photochemistry is a fascinating branch of chemistry concerned with molecules and light. However, the importance of simulating light-induced processes is reflected also in fields as diverse as biology, material science, or medicine. This Minireview highlights recent progress achieved in theoretical chemistry to calculate electronically excited states of molecules and simulate their photo-induced dynamics aspiring to reach experimental accuracy. We focus on emergent methods and give selected examples that illustrate the progress in recent years towards predicting complex electronic structure situations involving strong correlation, performing calculations for large molecules, describing multi-chromophoric systems, and simulating nonadiabatic molecular dynamics for long time scales, for molecules in gas phase or in complex biological environments.

4.
J Phys Chem Lett ; : 1443-1449, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-31918552

RESUMO

The response of a molecule to photoexcitation is governed by the coupling of its electronic states. However, if the energetic spacing between the electronically excited states at the Franck-Condon window becomes sufficiently small, it is infeasible to selectively excite and monitor individual states with conventional time-resolved spectroscopy, preventing insight into the energy transfer and relaxation dynamics of the molecule. Here, we demonstrate how the combination of time-resolved spectroscopy and extensive surface hopping dynamics simulations with a global fit approach on individually excited ensembles overcomes this limitation and resolves the dynamics in the n3p Rydberg states in acetone. Photoelectron transients of the three closely spaced states n3px, n3py, and n3pz are used to validate the theoretical results, which in turn allow retrieving a comprehensive kinetic model describing the mutual interactions of these states for the first time.

5.
ChemPhotoChem ; 3(9): 833-845, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31681833

RESUMO

Previous time-resolved spectroscopic experiments and static quantum-chemical calculations attributed nitronaphthalene derivatives one of the fastest time scales for intersystem crossing within organic molecules, reaching the 100 fs mark. Nonadiabatic dynamics simulations on three nitronaphthalene derivatives challenge this view, showing that the experimentally observed ∼100 fs process corresponds to internal conversion in the singlet manifolds. Intersystem crossing, instead, takes place on a longer time scale of ∼1 ps. The dynamics simulations further reveal that the spin transitions occur via two distinct pathways with different contribution for the three systems, which are determined by electronic factors and the torsion of the nitro group. This study, therefore, indicates that the existence of sub-picosecond intersystem crossing in other nitroaromatic molecules should be questioned.

6.
J Am Chem Soc ; 141(46): 18437-18443, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31714077

RESUMO

Functionalization at the α-position of carbonyl compounds has classically relied on enolate chemistry. As a result, the generation of a new C-X bond, where X is more electronegative than carbon requires an oxidation event. Herein we show that, by rendering the α-position of amides electrophilic through a mild and chemoselective umpolung transformation, a broad range of widely available oxygen, nitrogen, sulfur, and halogen nucleophiles can be used to generate α-functionalized amides. More than 60 examples are presented to establish the generality of this process, and calculations of the mechanistic aspects underline a fragmentation pathway that accounts for the broadness of this methodology.

7.
J Chem Theory Comput ; 15(11): 5925-5964, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31509407

RESUMO

In this Article we describe the OpenMolcas environment and invite the computational chemistry community to collaborate. The open-source project already includes a large number of new developments realized during the transition from the commercial MOLCAS product to the open-source platform. The paper initially describes the technical details of the new software development platform. This is followed by brief presentations of many new methods, implementations, and features of the OpenMolcas program suite. These developments include novel wave function methods such as stochastic complete active space self-consistent field, density matrix renormalization group (DMRG) methods, and hybrid multiconfigurational wave function and density functional theory models. Some of these implementations include an array of additional options and functionalities. The paper proceeds and describes developments related to explorations of potential energy surfaces. Here we present methods for the optimization of conical intersections, the simulation of adiabatic and nonadiabatic molecular dynamics, and interfaces to tools for semiclassical and quantum mechanical nuclear dynamics. Furthermore, the Article describes features unique to simulations of spectroscopic and magnetic phenomena such as the exact semiclassical description of the interaction between light and matter, various X-ray processes, magnetic circular dichroism, and properties. Finally, the paper describes a number of built-in and add-on features to support the OpenMolcas platform with postcalculation analysis and visualization, a multiscale simulation option using frozen-density embedding theory, and new electronic and muonic basis sets.

8.
Nutrients ; 11(9)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31500172

RESUMO

A healthy dietary pattern and high quality nutrient intake reduce atherosclerotic cardiovascular disease risk. Red wine grape pomace (RWGP)-a rich natural source of dietary fiber and antioxidants-appears to be a potential functional food ingredient. The impact of a dietary supplementation with RWGP flour was evaluated in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice, a model of lethal ischemic heart disease. SR-B1 KO/ApoER61h/h mice were fed with atherogenic (high fat, cholesterol, and cholic acid, HFC) diet supplemented with: (a) 20% chow (HFC-Control), (b) 20% RWGP flour (HFC-RWGP), or (c) 10% chow/10% oat fiber (HFC-Fiber); and survival time was evaluated. In addition, SR-B1 KO/ApoER61h/h mice were fed for 7 or 14 days with HFC-Control or HFC-RWGP diets and plasma lipid levels, inflammation, oxidative damage, and antioxidant activity were measured. Atherosclerosis and myocardial damage were assessed by histology and magnetic resonance imaging, respectively. Supplementation with RWGP reduced premature death, changed TNF-α and IL-10 levels, and increased plasma antioxidant activity. Moreover, decreased atheromatous aortic and brachiocephalic plaque sizes and attenuated myocardial infarction and dysfunction were also observed. These results suggest that RWGP flour intake may be used as a non-pharmacological therapeutic approach, contributing to decreased progression of atherosclerosis, reduced coronary heart disease, and improved cardiovascular outcomes.


Assuntos
Antioxidantes/administração & dosagem , Aorta/metabolismo , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Suplementos Nutricionais , Frutas/química , Isquemia Miocárdica/prevenção & controle , Miocárdio/metabolismo , Estresse Oxidativo , Extratos Vegetais/administração & dosagem , Vitis/química , Ração Animal , Animais , Antioxidantes/isolamento & purificação , Antioxidantes/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores/sangue , Dieta Aterogênica , Modelos Animais de Doenças , Feminino , Mediadores da Inflamação/sangue , Interleucina-10/sangue , Lipídeos/sangue , Masculino , Camundongos Knockout para ApoE , Isquemia Miocárdica/sangue , Isquemia Miocárdica/genética , Isquemia Miocárdica/patologia , Miocárdio/patologia , Extratos Vegetais/sangue , Extratos Vegetais/isolamento & purificação , Placa Aterosclerótica , Receptores Depuradores Classe B/deficiência , Receptores Depuradores Classe B/genética , Fator de Necrose Tumoral alfa/sangue
9.
J Phys Chem A ; 123(38): 8321-8332, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31479265

RESUMO

We report an efficient iterative procedure that exploits surface-hopping trajectory methods and quantum dynamics to achieve two complementary purposes: to identify the minimum dimensionality of a molecular Hamiltonian in terms of electronic and nuclear degrees of freedom to study radiationless relaxation mechanisms as well as to provide a reference quantum dynamical calculation that allows assessing of the validity of surface-hopping parameters. This double goal is achieved by a feedback loop between surface hopping and MCTDH calculations based on potential energy surfaces parametrized with a linear vibronic coupling method. Initially, a surface hopping calculation in full dimensionality with a chosen set of parameters is performed, and it is repeated, gradually reducing its dimensionality until divergence with the initial calculation is observed or the system is small enough to be treated quantum dynamically. A comparison between the quantum dynamics and surface hopping simulations dictates the validity of the surface hopping parameters. Using these new parameters, the reduction loop is started again, until convergence. As an example, this strategy is applied to simulate the ultrafast intersystem crossing dynamics of [PtBr6]2- in solution. The 15-dimensional space initially including 200 electronic states is reduced to a 9-dimensional problem with 76 electronic states, without a considerable loss of accuracy.

10.
Phys Chem Chem Phys ; 21(32): 17971-17977, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31384846

RESUMO

The electron-hole injection from a family of spiropyran photoswitches into A/T-duplex DNA has been investigated at the molecular level for the first time. Multiscale computations coupled with automatized quantitative wavefunction analysis reveal a pronounced directionality and regioselectivity towards the template strand of the duplex DNA. Our findings suggest that this directional and regioselective photoinduced electron-hole transfer could thus be exploited to tailor the charge transport processes in DNA in specific applications.


Assuntos
Benzopiranos/química , DNA/química , Indóis/química , Substâncias Intercalantes/química , Nitrocompostos/química , Transporte de Elétrons , Luz , Modelos Moleculares , Conformação de Ácido Nucleico , Oxirredução , Processos Fotoquímicos , Prótons , Termodinâmica
11.
Org Biomol Chem ; 17(34): 7891-7899, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31397456

RESUMO

Insight into the catalytic mechanism of Lactobacillus leichmannii nucleoside 2'-deoxyribosyltransferase (LlNDT) has been gained by calculating a quantum mechanics-molecular mechanics (QM/MM) free-energy landscape of the reaction within the enzyme active site. Our results support an oxocarbenium species as the reaction intermediate and thus an SN1 reaction mechanism in this family of bacterial enzymes. Our mechanistic proposal is validated by comparing experimental kinetic data on the impact of the single amino acid replacements Tyr7, Glu98 and Met125 with Ala, Asp and Ala/norLeu, respectively, and accounts for the specificity shown by this enzyme on a non-natural substrate. This work broadens our understanding of enzymatic C-N bond cleavage and C-N bond formation.


Assuntos
Pentosiltransferases/química , Domínio Catalítico , Cinética , Lactobacillus leichmannii/enzimologia , Modelos Químicos , Simulação de Dinâmica Molecular , Estudo de Prova de Conceito , Conformação Proteica , Teoria Quântica , Termodinâmica
12.
J Chem Theory Comput ; 15(9): 5031-5045, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31339716

RESUMO

The reliability of different parameters in the surface hopping method is assessed for a vibronic coupling model of a challenging transition metal complex, where a large number of electronic states of different multiplicities are met within a small energy range. In particular, the effect of two decoherence correction schemes and of various strategies for momentum rescaling and treating frustrating hops during the dynamics is investigated and compared against an accurate quantum dynamics simulation. The results show that surface hopping is generally able to reproduce the reference but also that small differences in the protocol used can strongly affect the results. We find a clear preference for momentum rescaling along only one degree of freedom, using either the nonadiabatic coupling or the gradient difference vector, and trace this effect back to an enhanced number of frustrated hops. Furthermore, reflection of the momentum after frustrated hops is shown to work better than to ignore the process completely. The study also highlights the importance of the decoherence correction, but neither of the two methods employed, energy based decoherence or augmented fewest switches surface hopping, performs completely satisfactory and we trace this effect back to a lack of size-consistency. Finally, the effect of different methods for analyzing the populations is highlighted. More generally, the study emphasizes the importance of the often neglected parameters in surface hopping and shows that there is still a need for simple, robust, and generally applicable correction schemes.

13.
J Chem Theory Comput ; 15(6): 3730-3742, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31038951

RESUMO

Excited-state MS-CASPT2 and ADC(2) quantum chemical calculations and nonadiabatic dynamics simulations show that 2-selenouracil is able to both efficiently populate and depopulate reactive triplet states in an ultrashort time scale. Thus, the heavier homologue of 2-thiouracil unites the ultrafast, high-yield intersystem crossing of 2-thiouracil with the short excited-state lifetime and photostability of the parent nucleobase uracil-two properties that have been traditionally thought to be diametrically opposed. Remarkably, while the S2 → S1 → T2 → T1 deactivation dynamics of 2-selenouracil is analogous to that of 2-thiouracil, the calculations show that the triplet lifetime of 2-selenouracil should decrease by up to 3 orders of magnitude in comparison to that 2-thiouracil, possibly down to the few-picosecond time scale. The main reasons for this decrease are the lack of a second T1 minimum, the enhanced spin-orbit coupling, and the reduction of the energy barrier to access the T1/ S0 crossing-in particular in aqueous solution-compared to 2-thiouracil. Such unusual photophysical properties, together with its significant red-shifted absorption spectrum, could make 2-selenouracil a useful specialized photosensitizer for photodynamical therapy.


Assuntos
Uracila/análogos & derivados , Simulação de Dinâmica Molecular , Estrutura Molecular , Teoria Quântica , Termodinâmica , Uracila/química
14.
Nat Commun ; 10(1): 2327, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31127092

RESUMO

The direct synthesis of ketones via carbon-carbon bond formation represents one of the most important challenges in organic synthesis. Hydroacylation of alkenes offers perhaps the most efficient and atom-economical approach for the preparation of ketones employing carbonyl compounds and alkenes as feedstocks. State-of-the-art hydroacylation is typically achieved by a transition metal-catalysed coupling of an aldehyde and an alkene but is plagued by competing decarbonylation, requiring the installation of directing groups in the aldehyde reactant. Herein, we present a method for the hydroacylation of alkenes employing amides in a metal-free regime, proceeding by a new mechanism and offering orthogonal reactivity to the conventional, metal-catalysed alternatives.

15.
J Chem Theory Comput ; 15(6): 3470-3480, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31050425

RESUMO

The ability of different electronic structure methods to correctly describe intersystem crossing dynamics is evaluated, using thioformaldehyde as a test case. Mischievously, all methods considered-ranging from the multireference methods MRCISD, MS-CASPT2, or SA-CASSCF, to the single-reference methods ADC(2), CC2, and TDDFT in different flavors-provide the same state ordering and energies of the low-lying singlet and triplet electronic excited states within an acceptable error of 0.2-0.3 eV. However, the outcome of the nonadiabatic simulations after excitation to the lowest S1 (1 nπ*) state are dramatically different. While MS-CASPT2, ADC(2), BP86, and PBE do not transfer population to the triplet states within 500 fs-consistent with experimental evidence-SA-CASSCF, B3LYP, and BHHLYP predict intersystem crossing yields between 3% and 21% within the same time. The different excited state dynamics can be rationalized by inspecting potential energy profiles along the C-S bond stretch mode and single-triplet energy gaps. It is found that already at a C-S bond length of 1.9 Å, all the single-reference methods struggle to describe the correct asymptotic behavior of the potentials. Moreover, some methods, including SA-CASSCF, obtain incorrect 1 nπ*-3 ππ* energy gaps, leading to compensation of errors (ADC(2), BP86, PBE), or wrong dynamics (SA-CASSCF, B3LYP, BHHLYP). Only the accurate MRCISD and MS-CASPT2 methods are able to describe the C-S bond correctly and thus able to deliver the correct potential energy surfaces and dynamics for the right reason. A correlation with the amount of Hartree-Fock exchange in the density functional and the ease to access the 3 ππ* state from the 1 nπ* are able to explain the different behavior observed for GGA and hybrid functionals. It is thus illustrated that even in the case of a simple molecule, like CH2S, the sole assessment of vertical excitation energies as reliability predictors for nonadiabatic dynamics is inadequate. The reason is that ISC does not occur at the FC geometry, but rather at distorted geometries where the singlet-triplet gaps become small. Hence, a characterization of the potential energy surfaces beyond the Franck-Condon region is mandatory.

17.
Phys Chem Chem Phys ; 21(9): 4871-4878, 2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30778485

RESUMO

The deactivation dynamics of 1,1-difluoroethylene after light excitation is studied within the surface hopping formalism in the presence of 3s and 3p Rydberg states using multi-state second order perturbation theory (MS-CASPT2). Due to the proximity of the Rydberg π-3s state with the ππ* state, the states are mixed favoring ultrafast exchange of population via a conical intersection that closely resembles the equilibrium structure. After excitation, it is found that the π-3s state acts as a doorway state, trapping the population and delaying internal conversion to the ππ* state, from which deactivation to the closed-shell ground state takes place. Besides the conical intersection between the π-3s and ππ* states, five additional conical intersections between the ππ* state and the ground state are found, indicating that after the system is excited, it stretches the C[double bond, length as m-dash]C bond before it twists and pyramidalizes at any of the carbon atoms, in the spirit of a hula-twist mechanism.

18.
Phys Chem Chem Phys ; 21(17): 8614-8618, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30801589

RESUMO

The binding mechanism of the protonated open form of three spiropyran derivatives into a 12-mer (poly-dAT)2 has been unveiled by means of computational methods. It is found that the electrostatic term in the probe:DNA binding energy, modulates the binding mode, providing new guidelines for the design of spiropyran photoswitches with specific binding modes to DNA.

19.
J Eukaryot Microbiol ; 66(4): 654-669, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30620421

RESUMO

Autophagy is an adaptive response for cell survival in which cytoplasmic components and organelles are degraded in bulk under normal and stress conditions. Trichomonas vaginalis is a parasite highly adaptable to stress conditions such as iron (IR) and glucose restriction (GR). Autophagy can be traced by detecting a key autophagy protein (Atg8) anchored to the autophagosome membrane by a lipid moiety. Our goal was to perform a morphological and cellular study of autophagy in T. vaginalis under GR, IR, and Rapamycin (Rapa) treatment using TvAtg8 as a putative autophagy marker. We cloned tvatg8a and tvatg8b and expressed and purified rTvAtg8a and rTvAtg8b to produce specific polyclonal antibodies. Autophagy vesicles were detected by indirect immunofluorescence assays and confirmed by ultrastructural analysis. The biogenesis of autophagosomes was detected, showing intact cytosolic cargo. TvAtg8 was detected as puncta signal with the anti-rTvAtg8b antibody that recognized soluble and lipid-associated TvAtg8b by Western blot assays in lysates from stress-inducing conditions. The TvAtg8b signal co-localized with the CytoID and lysotracker labeling (autolysosomes) that accumulated after E-64d treatment in GR parasites. Our data suggest that autophagy induced by starvation in T. vaginalis results in the formation of autophagosomes for which TvAtg8b could be a putative autophagy marker.

20.
Phys Chem Chem Phys ; 21(26): 14261-14269, 2019 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-30565616

RESUMO

The analysis of the absorption spectrum and density of states of a cluster of phenol solvated with 15 water molecules indicates that the reorganization of the water molecules, facilitating the formation of solvated electrons, is a plausible mechanism in the photodissociation of phenol. Using quantitative wavefunction analysis, we demonstrate that while charge-transfer states involving electron transfer from phenol to water are mainly dark, a considerable number of them exists below the maximum of the ππ* absorption band and could be populated by internal conversion. These low-lying charge-transfer states do not show extended O-H distances, but are found for large electron-hole separations at which several water molecules can solvate and stabilize the transferred electron. Thus, charge-transfer states in solvated phenol can be stabilized by two factors: (i) elongation of the O-H bond, as was extensively discussed in the past, and (ii) reorganization of solvent molecules, as it is shown here.

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