Ultrafast Photodynamics of Glucose

We have investigated the photodynamics of β-d-glucose employing our field-induced surface-hopping (FISH) method, which allows us to simulate the coupled electron–nuclear dynamics, explicitly including nonadiabatic effects and light-induced excitation. Our results reveal that from the initially populated S₁ and S₂ states, glucose returns nonradiatively to the ground state within about 200 fs. This takes place mainly via conical intersections (CIs), whose geometries in most cases involve the elongation of a single O–H bond, whereas in some instances, ring-opening due to dissociation of a C–O bond is observed. Experimentally, excitation to a distinct excited electronic state is improbable due to the presence of a dense manifold of states bearing similar oscillator strengths. Our FISH simulations, explicitly including a UV laser pulse of 6.43 eV photon energy, reveal that after initial excitation, the population is almost equally spread over several close-lying electronic states. This is followed by a fast nonradiative decay on the time scale of 100–200 fs, with the final return to the ground state proceeding via the S₁ state through the same types of CIs as observed in the field-free simulations

Photodynamics of Free and Solvated Tyrosine

We present a theoretical simulation of the ultrafast nonadiabatic photodynamics of tyrosine in the gas phase and in water. For this purpose, we combine our TDDFT/MM nonadiabatic dynamics (Wohlgemuth et al. <i>J. Chem. Phys.</i> <b>2011</b>, <i>135</i>, 054105) with the field-induced surface hopping method (Mitrić et al. <i>Phys. Rev. A</i> <b>2009</b>, <i>79</i>, 053416) allowing us to explicitly include the nonadiabatic effects as well as femtosecond laser excitation into the simulation. Our results reveal an ultrafast deactivation of the initially excited bright ππ* state by internal conversion to a dark <i>n</i>π* state. We observe deactivation channels along the O–H stretching coordinate as well as involving the N–H bond cleavage of the amino group followed by proton transfer to the phenol ring, which is in agreement with previous static energy path calculations. However, since in the gas phase the canonical form of tyrosine is the most stable one, the proton transfer proceeds in two steps, starting from the carboxyl group that first passes its proton to the amino group, from where it finally moves to the phenol ring. Furthermore, we also investigate the influence of water on the relaxation processes. For the system of tyrosine with three explicit water molecules solvating the amino group, embedded in a classical water sphere, we also observe a relaxation channel involving proton transfer to the phenol ring. However, in aqueous environment, a water molecule near the protonated amino group of tyrosine acts as a mediator for the proton transfer, underlining the importance of the solvent in nonradiative relaxation processes of amino acids

Dynamics of Isolated 1,8-Naphthalimide and <i>N</i>‑Methyl-1,8-naphthalimide: An Experimental and Computational Study

In this work we investigate the excited-state structure and dynamics of the two molecules 1,8-naphthalimide (NI) and <i>N</i>-methyl-1,8-naphthalimide (Me-NI) in the gas phase by picosecond time- and frequency-resolved multiphoton ionization spectroscopy. The energies of several electronically excited singlet and triplet states and the S₁ vibrational wavenumbers were calculated. Nonadiabatic dynamics simulations support the analysis of the radiationless deactivation processes. The origin of the S₁ ← S₀ (ππ*) transition was found at 30 082 cm^–1 for NI and at 29 920 cm^–1 for Me-NI. Furthermore, a couple of low-lying vibrational bands were resolved in the spectra of both molecules. In the time-resolved scans a biexponential decay was apparent for both Me-NI and NI. The fast time constant is in the range of 10–20 ps, whereas the second one is in the nanosecond range. In accordance with the dynamics simulations, intersystem crossing to the fourth triplet state S₁ (ππ*) → T₄ (nπ*) is the main deactivation process for Me-NI due to a large spin–orbit coupling between these states. Only for significant vibrational excitation internal conversion via a conical intersection becomes a relevant deactivation pathway

Time-Resolved Study of 1,8-Naphthalic Anhydride and 1,4,5,8-Naphthalene-tetracarboxylic Dianhydride

We investigate the excited electronic states of 1,8-naphthalic anhydride (NDCA) and 1,4,5,8-naphthalene-tetracarboxylic dianhydride (NTCDA) by time- and frequency-resolved electronic spectroscopy in the gas phase using picosecond lasers and by femtosecond time-resolved transient absorption in cyclohexane. The experiments are accompanied by calculations that yield the energy of the excited singlet and triplet states as well as by surface hopping dynamics simulations and calculations of spin–orbit couplings that give insight into the photochemistry. The origin of the A ¹A₁ ← X ¹A₁ (ππ*) transition in isolated NDCA was found at 30 260 cm^–1, and several low-lying vibrational bands were observed. The lifetime drops sharply from 1.2 ns at the origin to around 30 ps at an excess energy of 800 cm^–1. Both internal conversion (IC) and intersystem crossing (ISC) are possible deactivation pathways as found in coupled electron–nuclear dynamics simulations. In cyclohexane solution, two time constants were observed. Deactivation of the initially excited state by ISC seems to dominate as supported by computations. For NTCDA we observed a gas phase lifetime of 16 ps upon excitation at 351 nm

Tuning Structural and Optical Properties of Thiolate-Protected Silver Clusters by Formation of a Silver Core with Confined Electrons

We present a systematic theoretical investigation of the structural and optical properties of thiolate-protected silver clusters with the goal to design species exhibiting strong absorption and fluorescence in the UV–vis spectral range. We show that the optical properties can be tuned by creating systems with different counts of confined electrons within the cluster core. We consider liganded silver complexes with <i>n</i> silver atoms (Ag_<i>n</i>) and <i>x</i> ligands (L_<i>x</i>) in anionic complexes [Ag_<i>n</i>L_<i>x</i>]⁻ with L = SCH₃. Variation of the composition ratio gives rise to systems with (i) zero confined electrons for <i>x</i> = <i>n</i> + 1, (ii) two confined electrons for <i>x</i> = <i>n</i> – 1, and (iii) four confined electrons for <i>x</i> = <i>n</i> – 3. We show that the number of confined electrons within the cluster core and the geometric structure of the latter are responsible for the spectral patterns, giving rise to intense absorption transitions and fluorescence in the visible or even infrared range. Our results open a perspective for the rational design of stable ligand-protected silver cluster chromophores that might find numerous applications in the field of biosensing

Additional file 1: Table S1. of Sporadic late-onset nemaline myopathy: clinico-pathological characteristics and review of 76 cases

Genetic variants identified in patients with SLONM using NGS and a panel of 283 genes. (DOC 72 kb

Discovery of a Series of 3‑Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors

We report the discovery of a novel series of 3-cinnoline carboxamides as highly potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitors. Optimization of this series focusing on potency and physicochemical properties (especially permeability) led to the identification of compound <b>21</b>, a highly potent ATM inhibitor (ATM cell IC₅₀ 0.0028 μM) with excellent kinase selectivity and favorable physicochemical and pharmacokinetics properties. <i>In vivo</i>, <b>21</b> in combination with irinotecan showed tumor regression in the SW620 colorectal tumor xenograft model, superior inhibition to irinotecan alone. Compound <b>21</b> was selected for preclinical evaluation alongside AZD0156

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3‑Kinase (PI3K)‑γ Inhibitors

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as <b>15</b>, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound <b>15</b> was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3‑Kinase (PI3K)‑γ Inhibitors

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as <b>15</b>, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound <b>15</b> was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally