Density Functional Molecular Computations on Protonated Serotonin in the Gas Phase and Various Solvent Media

5-Hydroxytryptamine (serotonin) was geometry optimized at the B3YP/6-31G(d) level of theory to determine the energetically most favourable conformations of the aromatic hydroxyl group and the protonated ethylamine side chain. The hydroxyl group was found to be most stable at anti for all conformations, and the two lowest energy gas phase conformers found were: chi(2) = g(+), chi(3) = g(-) and chi(2) = g(-), chi(3) = g(+). The protonated amino group was found equally stable at g+, g- and anti. The transition structures linking each gas phase minimum were also computed. Minima found were subjected to solvation calculations in chloroform, DMSO, ethanol and water, which shifted their relative stabilities. (C) 2002 Elsevier Science B.V. All rights reserved

Density Functional Molecular Study on the Full Conformational Space of the S-4-(2-Hydroxypropoxy)carbazol Fragment of Carvedilol (1-(9H−Carbazol-4-yloxy)-3- [2-(2-methoxyphenoxy)ethylamino]-2-propanol) in Vacuum and in Different Solvent Media

Density functional theory (DFT) conformational analysis was carried out on the potential energy hypersurface (PEHS) of the carbazole-containing molecular fragment, S-4-(2-hydroxypropoxy)-carbazol, of the chiral cardiovascular drug molecule carvedilol, (1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxy-phenoxy)ethylamino]-2-propanol) . The PEHS was computed in vacuum, chloroform, ethanol, DMSO, and water at the B3LYP/6-31G(d) level of theory. The carbazole ring system was confirmed to be planar, and the resultant PEHS in vacuum contained 19 converged minima, of which the global minima possessed a conformation with chi(1), chi(2), and chi(3) in the anti position and chi(10) in the g position. Conformer stability for the S-4-(2-hydroxypropoxy)carbazol PEHS was influenced by intramolecular hydrogen bonding. Tomasi PCM reaction-field calculations revealed that the lowest SCF energies, relative conformer energies, and solvation free energies (DeltaG (solvation)) for the S-4-(2-hydroxypropoxy)carbazol PEHS were in protic solvents, ethanol and water, because of the larger hydrogen bond donor values of these solvents, which aid in stabilization of the dipole moment created by the carbazole ring system and the oxygen and nitrogen atoms. However, solvent effects contributed most significantly to the stabilization of S-4-(2-hydroxypropoxy)carbazol conformers that contained no internal hydrogen bonding, whereas solvent effects were not as important for conformers that contained intramolecular hydrogen bonding

Restricting excessive cardiac action potential and QT prolongation: a vital role for IKs in human ventricular muscle

Background - Although pharmacological block of the slow, delayed rectifier potassium current (I-Ks) by chromanol 293B, L-735,821, or HMR-1556 produces little effect on action potential duration (APD) in isolated rabbit and dog ventricular myocytes, the effect of IKs block on normal human ventricular muscle APD is not known. Therefore, studies were conducted to elucidate the role of IKs in normal human ventricular muscle and in preparations in which both repolarization reserve was attenuated and sympathetic activation was increased by exogenous dofetilide and adrenaline. Methods and Results - Preparations were obtained from undiseased organ donors. Action potentials were measured in ventricular trabeculae and papillary muscles using conventional microelectrode techniques; membrane currents were measured in ventricular myocytes using voltage-clamp techniques. Chromanol 293B (10 mu mol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 mu mol/L) produced a < 12-ms change in APD while pacing at cycle lengths ranging from 300 to 5000 ms, whereas the I-Kr blockers sotalol and E-4031 markedly lengthened APD. In voltage-clamp experiments, L- 735,821 and chromanol 293B each blocked IKs in the presence of E-4031 to block IKr. The E-4031-sensitive current (I-Kr) at the end of a 150-ms-long test pulse to 30 mV was 32.9 +/- 6.7 pA (n = 8); the L-735,821-sensitive current (I-Ks) magnitude was 17.8 +/- 2.94 pA (n = 10). During a longer 500-ms test pulse, IKr was not substantially changed (33.6 +/- 6.1 pA; n = 8), and I-Ks was significantly increased (49.6 +/- 7.24 pA; n = 10). On application of an "action potential-like" test pulse, I-Kr increased as voltage became more negative, whereas I-Ks remained small throughout all phases of the action potential - like test pulse. In experiments in which APD was first lengthened by 50 nmol/L dofetilide and sympathetic activation was increased by 1 mu mol/L adrenaline, 1 mu mol/L HMR-1556 significantly increased APD by 14.7 +/- 3.2% (P < 0.05; n = 3). Conclusions - Pharmacological IKs block in the absence of sympathetic stimulation plays little role in increasing normal human ventricular muscle APD. However, when human ventricular muscle repolarization reserve is attenuated, IKs plays an increasingly important role in limiting action potential prolongation

Vitamin E models. Conformational analysis and stereochemistry of tetralin, chroman, thiochroman and selenochroman

Tetralin, chroman as well as its' S and Se containing congeners were subjected to ab initio (RHF/3-21G and RHF/6-31G(d)) and DFT (B3LYP/6-31G(d)) computation. Molecular geometries and the activation energies for ring inversions were determined with full geometry optimizations. (C) 2002 Elsevier Science B.V. All rights reserved

Vitamin E models. Shortened sidechain models of alpha, beta, gamma and delta tocopherol and tocotrienol - a density functional study

Model compounds of alpha-, beta-, gamma-, and delta-tocopherol and Tocotrienol, as well as their sulphur and selenium congeners, were subjected to density functional analysis. The mono methyl substitution either stabilized or destabilized the ring structures to a small extent as assessed in terms of isodesmic reactions. In general, multiple methyl substitutions destabilized the ring. Dimethyl para-substitution results in electronic stabilization and steric repulsion being nearly additive. This was not the case for oriho-dimethyl derivatives, whereby steric repulsions dominate; the meta-substituted models reflect the same trend to a lesser degree. Structurally, the phenolic hydroxyl orientation was approximately planar, with the hydroxyl proton oriented away from the adjacent Me group whenever the structure permitted such an orientation. (C) 2003 Published by Elsevier B.V

Vitamin E models. Can the anti-oxidant and pro-oxidant dichotomy of α-tocopherol be related to ionic ring closing and radical ring opening redox reactions?

The free radical scavenging mechanism, leading to a quinodal structure via an oxidative ring opening is exothermic. However, the ionic oxidative ring opening is endothermic. Consequently, the ionic reductive ring closing must be exothermic. This leads to the suggestion that Vitamin E may be recovered, unchanged, thus effectively acts as a catalyst for the following reaction 2HOO + H3O(+) + NADH --> 2HOOH + H2O + NAD((+)), DeltaE approximate to 120 kcal mol(-1). As Vitamin E is biologically recycled, a single alpha-tocopherol molecule may convert numerous HOO radical to H2O2 which is accumulated if not removed at the same rate, enzymatically, with the participation of catalase (Fe) or glutathione peroxidase, GP,(Se). This accumulation of peroxide, which may be referred to as a 'peroxide traffic jam', may well be the reason of the prooxidant effect of Vitamin E. (C) 2002 Published by Elsevier Science B.V

Molecular Phenotypes of Unifocal, Multifocal, and Diffuse Invasive Breast Carcinomas

We analyzed the subgross distribution of the invasive component in 875 consecutive cases of breast carcinomas using large-format histology sections and compared the immunophenotype (estrogen and progesterone receptor expression, HER2 overexpression and expression of basal-like markers, CK5/6, CK14, and epidermal growth factor receptor) in unifocal, multifocal, and diffuse tumors. Histology grade and lymph node status were also analyzed. Unifocal invasive carcinomas comprised 58.6% (513/875), multifocal invasive carcinomas 36.5% (319/875), and diffuse invasive carcinomas 4.9% (43/875) of the cases. The proportion of lymph node-positive cases was significantly higher in multifocal and diffuse carcinomas compared to unifocal cancers, but no other statistically significant differences could be verified between these tumor categories. Histological multifocality and diffuse distribution of the invasive tumor component seem to be negative morphologic prognostic parameters in breast carcinomas, independent of the molecular phenotype

An ab initio and DFT conformational analysis of unsubstituted and omega-substituted ethyl-benzene: (Ph-CH2-CH2-Z; Z = -H, -F, -NH3+, -CH3)

A series of compounds of Ph-CH2-CH2-Z, with substituents Z = -H, -F, -NH3+-, and -CH3, were subjected to conformational analysis. Conformational potential energy surfaces were generated and their minima were geometrically optimized at three levels of theory. The relative stabilities of the minima correlated with the electron withdrawing nature of the substituents (Z). (C) 2002 Elsevier Science B.V. All rights reserved

Rigidified Derivative of the Non-macrocyclic Ligand H₄OCTAPA for Stable Lanthanide(III) Complexation

Financiado para publicación en acceso aberto: Universidade da Coruña/CISUG[Abstract] The stability constants of lanthanide complexes with the potentially octadentate ligand CHXOCTAPA4–, which contains a rigid 1,2-diaminocyclohexane scaffold functionalized with two acetate and two picolinate pendant arms, reveal the formation of stable complexes [log KLaL = 17.82(1) and log KYbL = 19.65(1)]. Luminescence studies on the Eu3+ and Tb3+ analogues evidenced rather high emission quantum yields of 3.4 and 11%, respectively. The emission lifetimes recorded in H2O and D2O solutions indicate the presence of a water molecule coordinated to the metal ion. 1H nuclear magnetic relaxation dispersion profiles and 17O NMR chemical shift and relaxation measurements point to a rather low water exchange rate of the coordinated water molecule (kex298 = 1.58 × 106 s–1) and relatively high relaxivities of 5.6 and 4.5 mM–1 s–1 at 20 MHz and 25 and 37 °C, respectively. Density functional theory calculations and analysis of the paramagnetic shifts induced by Yb3+ indicate that the complexes adopt an unprecedented cis geometry with the two picolinate groups situated on the same side of the coordination sphere. Dissociation kinetics experiments were conducted by investigating the exchange reactions of LuL occurring with Cu2+. The results confirmed the beneficial effect of the rigid cyclohexyl group on the inertness of the Lu3+ complex. Complex dissociation occurs following proton- and metal-assisted pathways. The latter is relatively efficient at neutral pH, thanks to the formation of a heterodinuclear hydroxo complex.F.L.-M., D.E.-G., and C.P.-I. thank Ministerio de Ciencia e Innovación (Grant PID2019-104626GB-I00) and Xunta de Galicia (ED431B 2020/52) for generous financial support. The authors thank the financial support for the Hungarian National Research, Development and Innovation Office (NKFIH K-128201, 134694 and FK-134551 projects). G.T. and C.P.-I. gratefully acknowledge the bilateral Hungarian–Spanish Science and Technology Cooperation Program (2019-2.1.11-TET-2019-00084 supported by NKFIH). B.V. was supported by the Doctoral School of Chemistry at the University of Debrecen, Debrecen, Hungary. This publication and the scientific research were supported by the Gedeon Richter’s Talentum Foundation established by Gedeon Richter Plc (Gedeon Richter Ph.D. Fellowship). The research was prepared with the professional support of the Doctoral Student Scholarship Program of the Cooperative Doctoral Program of the Ministry of Innovation and Technology financed from the National Research, Development and Innovation Fund (NKFIH). The research was supported by the ÚNKP-21-4 new national excellence program of the Ministry of Human Capacities (F.K.K.) and the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (F.K.K.). The authors are indebted to Centro de Supercomputación de Galicia (CESGA) for providing the computer facilities. C.P.-I. thanks Prof. M. Mazzanti for noticing that the emission quantum yields reported previously for OCTAPA4– complexes were incorrect. Funding for open access provided by Universidade da Coruña/CISUGXunta de Galicia; ED431B 2020/52Hungary. National Research, Development and Innovation Office; NKFIH K-128201Hungary. National Research, Development and Innovation Office; NKFIH K-134694Hungary. National Research, Development and Innovation Office; NKFIH FK-134551Hungary. National Research, Development and Innovation Office; 2019-2.1.11-TET-2019-00084Hungary. Ministry of Human Capacities; ÚNKP-21-

Activation of feedforward wiring in adult hippocampal neurons by the basic-helix-loop-helix transcription factor Ascl4

Although evidence indicates that the adult brain retains a considerable capacity for circuit formation, adult wiring has not been broadly considered and remains poorly understood. In this study, we investigate wiring activation in adult neurons. We show that the basic-helix-loop-helix transcription factor Ascl4 can induce wiring in different types of hippocampal neurons of adult mice. The new axons are mainly feedforward and reconfigure synaptic weights in the circuit. Mice with the Ascl4-induced circuits do not display signs of pathology and solve spatial problems equally well as controls. Our results demonstrate reprogrammed connectivity by a single transcriptional factor and provide insights into the regulation of brain wiring in adults