Search

In Drosophila, a group of zinc finger architectural proteins recruits the CP190 protein to the chromatin, an interaction that is essential for the functional activity of promoters and insulators. In this study, we describe a new architectural C2H2 protein called Madf and Zinc-Finger Protein 1 (Mzfp1) that interacts with CP190. Mzfp1 has an unusual structure that includes six C2H2 domains organized in a C-terminal cluster and two tandem MADF domains. Mzfp1 predominantly binds to housekeeping gene promoters located in both euchromatin and heterochromatin genome regions. In vivo mutagenesis studies showed that Mzfp1 is an essential protein, and both MADF domains and the CP190 interaction region are required for its functional activity. The C2H2 cluster is sufficient for the specific binding of Mzfp1 to regulatory elements, while the second MADF domain is required for Mzfp1 recruitment to heterochromatin. Mzfp1 binds to the proximal part of the Fub boundary that separates regulatory domains of the Ubx and abd-A genes in the Bithorax complex. Mzfp1 participates in Fub functions in cooperation with the architectural proteins Pita and Su(Hw). Thus, Mzfp1 is a new architectural C2H2 protein involved in the organization of active promoters and insulators in Drosophila., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

In higher eukaryotes, distance enhancer-promoter interactions are organized by topologically associated domains, tethering elements, and chromatin insulators/boundaries. While insulators/boundaries play a central role in chromosome organization, the mechanisms regulating their functions are largely unknown. In the studies reported here, we have taken advantage of the well-characterized Drosophila bithorax complex (BX-C) to study one potential mechanism for controlling boundary function. The regulatory domains of BX-C are flanked by boundaries, which block crosstalk with their neighboring domains and also support long-distance interactions between the regulatory domains and their target gene. As many lncRNAs have been found in BX-C, we asked whether readthrough transcription (RT) can impact boundary function. For this purpose, we took advantage of two BX-C boundary replacement platforms, Fab-7 attP50 and F2 attP , in which the Fab-7 and Fub boundaries, respectively, are deleted and replaced with an attP site. We introduced boundary elements, promoters, and polyadenylation signals arranged in different combinations and then assayed for boundary function. Our results show that RT can interfere with boundary activity. Since lncRNAs represent a significant fraction of Pol II transcripts in multicellular eukaryotes, it is therefore possible that RT may be a widely used mechanism to alter boundary function and regulation of gene expression.

In higher eukaryotes, the regulation of developmental gene expression is determined by enhancers, which are often located at a large distance from the promoters they regulate. Therefore, the architecture of chromosomes and the mechanisms that determine the functional interaction between enhancers and promoters are of decisive importance in the development of organisms. Mammals and the model animal Drosophila have homologous key architectural proteins and similar mechanisms in the organization of chromosome architecture. This review describes the current progress in understanding the mechanisms of the formation and regulation of long-range interactions between enhancers and promoters at three well-studied key regulatory loci in Drosophila.

Reactivity of transition metal complexes containing the redox-active gallylene (dpp-bian)Ga ligand (dpp-bian = 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene) toward isocyanide, isocyanate, isothiocyanate, and ketene substrates is described. The reaction of [(dpp-bian)GaCr(CO) 5 ] ( 1 ) with tBuNC results in a dative complex [(dpp-bian)Ga(CNtBu)Cr(CO) 5 ] ( 2 ), while compound [(dpp-bian)GaCr(CO) 5 ] 2 [Na(THF) 2 ] 2 ( 3 ) reacts with tBuNC to give the coordination polymer [(dpp-bian)GaCr(CO) 5 ][Na(CNtBu)(THF)] n ( 5 ). Treatment of [(dpp-bian)GaCr(CO) 5 ] 2 [Na(THF) 2 ] 2 with an excess of PhNCO results in trimerization of the latter and formation of complex [(dpp-bian)GaCr(CO) 5 ][Na(PhNCO) 3 (Et 2 O) (DME)] ( 4 ). [(dpp-bian)GaFeCp(CO) 2 ] ( 7 ) treated with Ph 2 CCO or PhNCS results in cycloaddition products [(dpp-bian)(Ph 2 CCO)GaFeCp(CO) 2 ] ( 8 ) and [(dpp-bian)(PhNCS)GaFeCp(CO) 2 ] ( 9 ). The formation of 2 and 9 was found to be reversible, which offers a means for facile regulation of transition metal center reactivity and cooperative substrate activation. New compounds were characterized by EPR ( 2 ), NMR ( 4 , 8 , and 9 ), and IR spectroscopy ( 2 , 4 , 5 , 8 , and 9 ). The molecular structures of 2 , 4 , 5 , 8 , and 9 were established by single-crystal X-ray diffraction analysis. Electronic structures of the compounds have been examined by DFT calculations.

The dialanes [(dpp-Bian)Al-Al(dpp-Bian)] ( 1 ) and [(dpp-dad)Al(THF)-(THF)Al(dpp-dad)] ( 2 ) (dpp-Bian = 1,2-[(2,6- i Pr 2 C 6 H 3 )NC] 2 C 12 H 6 , dpp-dad = [(2,6- i Pr 2 C 6 H 3 )NC(CH 3 )] 2 ) react with some isothiocyanates, isocyanates, and diphenylketene via [2 + 4] cycloaddition of the C═O or C═S bond across the C═C-N-Al fragment to afford complexes [L(X═C-Y)Al-Al(X═C-Y)L] with an intact Al-Al single bond ( 3 , L = dpp-Bian, X = PhN, Y = O; 4 , L = dpp-Bian, X = Ph 2 C, Y = O; 6 , L = dpp-dad, X = BnN, Y = S; 7 , L = dpp-dad, X = t BuN, Y = O; 8 , L = dpp-dad, X = i PrN, Y = S; and 9 , L = dpp-dad, X = CyN, Y = S). A mixed C═N and C═O mode cycloadduct, [(dpp-Bian)(TosN═C-O)Al-Al(TosN-C═O)(dpp-Bian)] 5 , was obtained in the reaction of 1 with tosylisocyanate. Heating the solution of 3 resulted in a thermal transformation and a change of the cycloaddition mode from C═O to C═N to give the product [(dpp-Bian)(PhN-C═O)Al(O)Al(PhN-C═O)(dpp-Bian)] 10 . The reduction of 7 and 8 with Na yielded the products [Na(THF) n ] 2 [(dpp-dad -H )(X═C-Y)Al] 2 ( 12 , X = i PrN, Y = S, n = 2 and 13 , X = t BuN, Y = O, n = 3) in which one of the methyl groups of the backbone of the initial dpp-dad ligand was dehydrogenated. When 2 was reacted with the bulky adamantyl isocyanate AdNCO, the C-C coupling of two substrates occurred to form 14 [(dpp-dad)Al(O═C-NAd) 2 Al(dpp-dad)] in which the coupled dianionic oxamide ligand bridged two Al atoms in a μ,η 4 -N,O/N,O mode. Moreover, in the presence of 2.0 equiv of Na metal, precursor 2 reacts with t BuNCS, p -TolylNCS, or Me 3 SiNCO, possibly through the reduced Al I intermediate, to yield the sulfur- or oxygen-bridged dimer [Na(solv) n ] 2 [(dpp-dad)Al(μ-E)] 2 ( 15 , E = S, solv = THF, n = 3 and 16 , E = O, solv = DME, n = 2) upon C═S or C═O bond cleavage. Dialane 1 reacts with dimethylsulfone to give a Lewis adduct [(dpp-Bian)(Me 2 SO 2 )Al] 2 ( 17 ), which releases dimethylsulfone upon heating. The diamagnetic compounds 3 - 10 and 12 - 17 were characterized by NMR and IR spectroscopy. The molecular structures of 3 - 17 were established by single-crystal X-ray diffraction analysis. Electronic structures of the compounds and possible isomers have been examined by DFT calculations.

The reaction of dialane [LAl-AlL] (1; L=dianion of 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene, dpp-bian) with carbon dioxide results in two different products depending on solvent. In toluene at temperatures of about 0 °C, the reaction gives cycloadduct [L(CO 2 )Al-Al(O 2 C)L] (2), whereas in diethyl ether, the reaction affords oxo-bridged carbamato derivative [L(CO 2 )(Et 2 O)Al(μ-O)AlL] (3). The DFT and QTAIM calculations provide reasonable explanations for the reversible formation of complex 2 in the course of two subsequent (2+4) cycloaddition reactions. Consecutive transition states with low activation barriers were revealed. Also, the DFT study demonstrated a crucial effect of diethyl ether coordination to aluminium on the reaction of dialane 1 with CO 2 . The optimized structures of key intermediates were obtained for the reactions in the presence of Et 2 O; calculated thermodynamic parameters unambiguously testify the irreversible formation of the product 3., (© 2021 Wiley-VCH GmbH.)

Using an original method, we have received Drosophila melanogaster with a deficiency including a complete sequence of quick-to-court gene. In this report, we describe the behavioural features of this new deletion mutant. There were no serious deviations from the normal mating behaviour in flies with the deletion, but the behaviour of deletion mutants still had some features. Of all the elements, only the frequency of licking significantly increased in mutants. The duration of mating elements did not change in flies with deletion, and the latent period decreased only for following the female and licking. We have found that mutant males produce more courtship song than control males when courting Oregon R females as estimated by the pulse song index. In our experiment, mutant females provoked much less pulse song production by Oregon R males than control females do. Moreover, Oregon R males initiate courtship song towards mutant females later than towards control females. In other words, the study of pulse song production showed that the deficiency in females leads to a decrease in the intensity of courtship of wild-type males, whereas the deficiency in males leads to more intensive care for wild-type females.

Reduction of ArBIG-bian (1, 1,2-bis[(2,6-dibenzhydryl-4-methylphenyl)imino]acenaphthene) with an excess of samarium in tetrahydrofuran (thf) and crystallization of the crude product from a thf/toluene mixture affords [(ArBIG-bian)Sm]·C7H8 (2a), which is free of the coordinating solvent. The use of 1,2-dimethoxyethane (dme) as the reaction medium resulted in the same product, [(ArBIG-bian)Sm]·C4H10O2 (2b), which differs from 2a only in the crystal lattice solvent. Reduction of 1 with an excess of ytterbium in dme gives compound [(ArBIG-bian)Yb(dme)]·2.5C7H8 (3), containing a coordinated dme molecule. All three products consist of dianionic ArBIG-bian ligands whose bulky 2,6-(Ph2CH)2-4-Me-C6H2 groups shield effectively the metal atoms. The newly prepared compounds 2a, 2b and 3 were characterized by 1H NMR and IR spectroscopy. The molecular structures of complexes 2a, 2b and 3 have been established by single crystal X-ray analysis. The intramolecular interactions were analysed on the basis of DFT calculations. The temperature dependence of the magnetic susceptibility of 2b and 3 in the region of 2-300 K was studied. The magnetic moments of complex 2b correspond to divalent samarium.

In mammals, a C2H2 zinc finger (C2H2) protein, CTCF, acts as the master regulator of chromosomal architecture and of the expression of Hox gene clusters. Like mammalian CTCF, the Drosophila homolog, dCTCF, localizes to boundaries in the bithorax complex (BX-C). Here, we have determined the minimal requirements for the assembly of a functional boundary by dCTCF and two other C2H2 zinc finger proteins, Pita and Su(Hw). Although binding sites for these proteins are essential for the insulator activity of BX-C boundaries, these binding sites alone are insufficient to create a functional boundary. dCTCF cannot effectively bind to a single recognition sequence in chromatin or generate a functional insulator without the help of additional proteins. In addition, for boundary elements in BX-C at least four binding sites for dCTCF or the presence of additional DNA binding factors is required to generate a functional insulator., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

We studied the inhibitory activity of methylene blue (MB) γ-carbolines (gC) conjugates (MB-gCs) against human erythrocyte acetylcholinesterase (AChE), equine serum butyrylcholinesterase (BChE), and a structurally related enzyme, porcine liver carboxylesterase (CaE). In addition, we determined the ability of MB-gCs to bind to the peripheral anionic site (PAS) of Electrophorus electricus AChE (EeAChE) and competitively displace propidium iodide from this site. Moreover, we examined the ability of MB-gCs to scavenge free radicals as well as their influence on mitochondrial potential and iron-induced lipid peroxidation. We found that MB-gCs effectively inhibited AChE and BChE with IC 50 values in the range 1.73-10.5 μM and exhibited low potencies against CaE (9.8-26% inhibition at 20 μM). Kinetic studies showed that MB-gCs were mixed-type reversible inhibitors of both cholinesterases. Molecular docking results showed that the MB-gCs could bind both to the catalytic active site and to the PAS of human AChE and BChE. Accordingly, MB-gCs effectively displaced propidium from the peripheral anionic site of EeAChE. In addition, MB-gCs were extremely active in both radical scavenging tests. Quantum mechanical DFT calculations suggested that free radical scavenging was likely mediated by the sulfur atom in the MB fragment. Furthermore, the MB-gCs, in like manner to MB, can restore mitochondrial membrane potential after depolarization with rotenone. Moreover, MB-gCs possess strong antioxidant properties, preventing iron-induced lipid peroxidation in mitochondria. Overall, the results indicate that MB-gCs are promising candidates for further optimization as multitarget therapeutic agents for neurodegenerative diseases.

Neuronal excitotoxicity which is induced by exposure to excessive extracellular glutamate is shown to be involved in neuronal cell death in acute brain injury and a number of neurological diseases. High concentration of glutamate induces calcium deregulation which results in mitochondrial calcium overload and mitochondrial depolarization that triggers the mechanism of cell death. Inhibition of mitochondrial calcium uptake could be potentially neuroprotective but complete inhibition of mitochondrial calcium uniporter could result in the loss of some physiological processes linked to Ca 2+ in mitochondria. Here, we found that a novel compound, TG-2112x, can inhibit only the lower concentrations mitochondrial calcium uptake (induced by 100 nM-5 μM) but not the uptake induced by higher concentrations of calcium (10 μM and higher). This effect was not associated with changes in mitochondrial membrane potential and cellular respiration. However, a pre-treatment of neurons with TG-2112x protected the neurons against calcium overload upon application of toxic concentrations of glutamate. Thus, sequestration of mitochondrial calcium uptake protected the neurons against glutamate-induced mitochondrial depolarization and cell death. In our hands, TG-2112x was also protective against ionomycin-induced cell death. Hence, low rate mitochondrial calcium uptake plays an underestimated role in mitochondrial function, and its inhibition could protect neurons against calcium overload and cell death in glutamate excitotoxicity.

The reaction of digallane (dpp-bian)Ga-Ga(dpp-bian) (2) (dpp-bian=1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene) with allyl chloride (AllCl) proceeded by a two-electron oxidative addition to afford paramagnetic complexes (dpp-bian)Ga(η 1 -All)Cl (3) and (dpp-bian)(Cl)Ga-Ga(Cl)(dpp-bian) (4). Treatment of complex 4 with pyridine induced an intramolecular redox process, which resulted in the diamagnetic complex (dpp-bian)Ga(Py)Cl (5). In reaction with allyl bromide, complex 2 gave metal- and ligand-centered addition products (dpp-bian)Ga(η 1 -All)Br (6) and (dpp-bian-All)(Br)Ga-Ga(Br)(dpp-bian-All) (7). The reaction of digallane 2 with Ph 3 SnNCO afforded (dpp-bian)Ga(SnPh 3 ) 2 (8) and (dpp-bian)(NCO)Ga-Ga(NCO)(dpp-bian) (9). Treatment of GaCl 3 with (dpp-bian)Na in diethyl ether resulted in the formation of (dpp-bian)GaCl 2 (10). Diorganylgallium derivatives (dpp-bian)GaR 2 (R=Ph, 11; tBu, 14; Me, 15; Bn, 16) and (dpp-bian)Ga(η 1 -All)R (R=nBu, 12; Cp, 13) were synthesized from complexes 3, 10, Bn 2 GaCl, or tBu 2 GaCl by salt metathesis. The salt elimination reaction between (dpp-bian)GaI 2 (17) and tBuLi was accompanied by reduction of both the metal and the dpp-bian ligand, which resulted in digallane 2 as the final product. Similarly, the reaction of complex 10 with MentMgCl (Ment=menthyl) proceeded with reduction of the dpp-bian ligand to give the diamagnetic complex [(dpp-bian)GaCl 2 ][Mg 2 Cl 3 (THF) 6 ] (18). Compounds 11, 12, 13, 15, and 16 were thermally robust, whereas compound 14 decomposed when heated at reflux in toluene to give complex (dpp-bian-tBu)GatBu 2 (19). Both complexes 7 and 19 contain R-substituted dpp-bian ligand: in the former compound the allyl group was attached to the imino-carbon atom, whereas in complex 19, the tBu group was situated on the naphthalene ring. Crystal structures of complexes 3, 8, 9, 10, 13, 14, 18, and 19 were determined by single-crystal X-ray analysis. The presence of dpp-bian radical anions in 3, 6, 8, and 10-16 was determined by ESR spectroscopy., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A comparative study performed in mice investigating the action of DF302, a novel fluoride-containing gamma-carboline derivative, in comparison to the structurally similar neuroprotective drug dimebon. Drug effects on learning and memory, emotionality, hippocampal neurogenesis and mitochondrial functions, as well as AMPA-mediated currents and the 5-HT6 receptor are reported. In the step-down avoidance and fear-conditioning paradigms, bolus administration of drugs at doses of 10 or 40 mg/kg showed that only the higher dose of DF302 improved long-term memory while dimebon was ineffective at either dosage. Short-term memory and fear extinction remained unaltered across treatment groups. During the 5-day predation stress paradigm, oral drug treatment over a period of 2 weeks at the higher dosage regimen decreased anxiety-like behaviour. Both compounds supressed inter-male aggression in CD1 mice, the most eminent being the effects of DF302 in its highest dose. DF302 at the higher dose decreased floating behaviour in a 2-day swim test and after 21-day ultrasound stress. The density of Ki67-positive cells, a marker of adult neurogenesis, was reduced in the dentate gyrus of stressed dimebon-treated and non-treated mice, but not in DF302-treated mice. Non-stressed mice that received DF302 had a higher density of Ki67-positive cells than controls unlike dimebon-treated mice. Similar to dimebon, DF302 effectively potentiated AMPA receptor-mediated currents, bound to the 5-HT6 receptor, inhibited mitochondrial permeability transition and displayed cytoprotective properties in cellular models of neurodegeneration. Thus, DF302 exerts multi-target effects on the key mechanisms of neurodegenerative pathologies and can be considered as an optimized novel analogue of the neuroprotective agent dimebon.

The reaction of Cl 2 GaH with a sodium salt of the dpp-Bian radical-anion (dpp-Bian •- )Na (dpp-Bian = 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene) affords paramagnetic gallane (dpp-Bian •- )Ga(Cl)H (1). Oxidation of (dpp-Bian 2- )Ga-Ga(dpp-Bian 2- ) (2) with N 2 O results in the dimeric oxide (dpp-Bian •- )Ga(μ 2 -O) 2 Ga(dpp-Bian •- ) (3). A treatment of the oxide 3 with phenylsilane affords paramagnetic gallium hydrides (dpp-Bian •- )GaH 2 (4) and (dpp-Bian •- )Ga{OSi(Ph)H 2 }H (5) depending on the reagent's stoichiometry. The reaction of digallane 2 with benzaldehyde produces pinacolate (dpp-Bian •- )Ga(O 2 C 2 H 2 Ph 2 ) (6). In the presence of PhSiH 3 , the reaction between digallane 2 and benzaldehyde (2: PhSiH 3 : PhC(H)O = 1:4:4) affords compound 4. The newly prepared complexes 1, 3-6 consist of a spin-labeled diimine ligand-dpp-Bian radical-anion. The presence of the ligand-localized unpaired electron allows the use of the ESR spectroscopy for characterization of the gallium hydrides reported. The molecular structures of compounds 1, 3-6 have been determined by the single-crystal X-ray analysis.

A new group of compounds, promising for the design of original multitarget therapeutic agents for treating neurodegenerative diseases, based on conjugates of aminoadamantane and carbazole derivatives was synthesized and investigated. Compounds of these series were found to interact with a group of targets that play an important role in the development of this type of diseases. First of all, these compounds selectively inhibit butyrylcholinesterase, block NMDA receptors containing NR2B subunits while maintaining the properties of MK-801 binding site blockers, exert microtubules stabilizing properties, and possess the ability to protect nerve cells from death at the calcium overload conditions. The leading compound C-2h has been shown the most promising effects on all analyzed parameters. Thus, these compounds can be regarded as promising candidates for the design of multi-target disease-modifying drugs for treatment of AD and/or similar neuropathologies.

The start of World War II (WWII) led to the deployment of combat troops in several continents. Destruction and many casualties among both the military and civilians became an inevitable consequence. A large amount of people injured were in need of life-saving treatment and a speedy return to duty. Intensive studies of the specific issues of diagnosis and treatment of thermal injury were conducted in the Soviet Union before the war. The first special units for patients with burn injuries were created, and the first specialists received their first clinical experience. The contributions of famous Soviet scientists in the development of the treatment of burns and frostbite in WWII are studied in this article. The structure of thermal injuries among military personnel and the results of their treatment are shown. Treatment, classification and quantity frostbite in the structure of sanitary losses during the WWII are studied in this article.

Expression efficiency is one of the major characteristics describing genes in various modern investigations. Expression efficiency of genes is regulated at various stages: transcription, translation, posttranslational protein modification and others. In this study, a special EloE (Elongation Efficiency) web application is described. The EloE sorts the organism's genes in a descend order on their theoretical rate of the elongation stage of translation based on the analysis of their nucleotide sequences. Obtained theoretical data have a significant correlation with available experimental data of gene expression in various organisms. In addition, the program identifies preferential codons in organism's genes and defines distribution of potential secondary structures energy in 5´ and 3´ regions of mRNA. The EloE can be useful in preliminary estimation of translation elongation efficiency for genes for which experimental data are not available yet. Some results can be used, for instance, in other programs modeling artificial genetic structures in genetically engineered experiments.

Alzheimer disease is a multifactorial pathology and the development of new multitarget neuroprotective drugs is promising and attractive. We synthesized a group of original compounds, which combine in one molecule γ-carboline fragment of dimebon and phenothiazine core of methylene blue (MB) linked by 1-oxo- and 2-hydroxypropylene spacers. Inhibitory activity of the conjugates toward acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and structurally close to them carboxylesterase (CaE), as well their binding to NMDA-receptors were evaluated in vitro and in silico. These newly synthesized compounds showed significantly higher inhibitory activity toward BChE with IC50 values in submicromolar and micromolar range and exhibited selective inhibitory action against BChE over AChE and CaE. Kinetic studies for the 9 most active compounds indicated that majority of them were mixed-type BChE inhibitors. The main specific protein-ligand interaction is π-π stacking of phenothiazine ring with indole group of Trp82. These compounds emerge as promising safe multitarget ligands for the further development of a therapeutic approach against aging-related neurodegenerative disorders such as Alzheimer and/or other pathological conditions.

A gallium(I) carbenoid derived from redox-active diimine 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene (dpp-bian) in complexes with molybdenum may serve either as a neutral [(dpp-bian)Ga:] or an anionic [(dpp-bian)Ga:](-) two-electron donor depending on the electronic state of the transition metal.

The synthesis of novel peptide conjugates of N-substituted-tetrahydro-γ-carbolines has been performed using the sequence of the Ugi multicomponent reaction and Cu(I)-catalyzed click chemistry. The effect of obtained γ-carboline-peptide conjugates on the rat liver mitochondria was evaluated. It was found that all compounds in the concentration of 30 µM did onot induce depolarization of mitochondria but possessed some inhibitory effect on the mitochondria permeability transition. The original N-substituted-tetrahydro-γ-carbolines containing an terminal alkyne group demonstrated a high prooxidant activity, whereas their conjugates with peptide fragments slightly inhibited both autooxidation and the t-BHP-induced lipid peroxidation.

Certain organophosphorus compounds (OPCs) inhibit various serine esterases (EOHs) via phosphorylation of their active site serines. We focused on 4 EOHs of particular toxicological interest: acetylcholinesterase (AChE: acute neurotoxicity; cognition enhancement), butyrylcholinesterase (BChE: inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors; cognition enhancement), carboxylesterase (CaE: inhibition of drug metabolism and/or stoichiometric scavenging of EOH inhibitors), and neuropathy target esterase (NTE: delayed neurotoxicity, OPIDN). The relative degree of inhibition of these EOHs constitutes the "esterase profile" of an OPC and serves as a major determinant of its net physiological effects. Thus, understanding and controlling the esterase profile of OPC activity and selectivity toward these 4 target enzymes is a significant undertaking. In the present study, we analyzed the inhibitor properties of 52 OPCs against the 4 EOHs, along with pairwise and multitarget selectivities between them, using 2 QSAR approaches: Hansch modeling and Molecular Field Topology Analysis (MFTA). The general formula of the OPCs was (RO)(2)P(O)X, where R = alkyl, X = - SCH(Hal)COOEt (Hal = Cl, Br), -SCHCl(2), -SCH(2)Br, -OCH(CF(3))R(1) (R(1) = C(6)H(5), CF(3), COOEt, COOMe). The Hansch model showed that increasing neuropathic potential correlated with rising R hydrophobicity; moreover, OPC binding to scavenger EOHs (BChE and CaE) had different effects on potential acute and delayed neurotoxicity. Predicted protective roles of BChE and CaE against acute toxicity were enhanced with increasing hydrophobicity, but projected protection against OPIDN was decreased. Next, Molecular Field Topology Analysis (MFTA) models were built, considering atomic descriptors, e.g., effective charge, van der Waals radius of environment, and group lipophilicity. Activity/selectivity maps confirmed predictions from Hansch models and revealed other structural factors affecting activity and selectivity. Virtual screening based on multitarget selectivity MFTA models was used to design libraries of OPCs with favorable esterase profiles for potential application as selective inhibitors of CaE without untoward side effects., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Dimebon belongs to a fast-growing group of "old" drugs that were suggested to be effective for therapy of pathological conditions different from their original targets. Following initial reports of successful Phase II clinical trials for mild-to-moderate Alzheimer's and Huntington's diseases, effects of Dimebon on various neurodegenerative conditions were investigated both in follow-up clinical trials and in various model systems. Although results of Phase III clinical trials carried out so far were disappointing, there is growing body of evidence that this drug can affect neuronal physiology in a way that would be beneficial at particular stages of development of certain types of neurodegeneration. To reveal what molecular and cellular pathological processes might be affected by Dimebon, we tested the ability of this drug to ameliorate pathology in model systems recapitulating particular pathogenic mechanisms involved in the development and progression of neurodegenerative diseases. Here we assessed the ability of Dimebon to modify several prominent features of tauopathies using transgenic tauP301S mice as a model. Chronic treatment with Dimebon was found to partially protect against the progressive decline in motor function and accumulation of tau-positive dystrophic neurons characteristic of tauP301S mice. Similar results were obtained with two further γ-carbolines structurally similar to Dimebon. Our data suggest that Dimebon and Dimebon-like compounds might be considered as drugs possessing disease-modifying activity for diseases with prominent tau pathology.

A modification of novel fluorinated organophosphorous compounds containing terminal alkyne group by different azidopeptides via Cu(I)-catalyzed click chemistry has been described. The inhibitor activity of trifluoromethyl-containing methylphosphonates and their peptide-conjugates towards acetylcholinesterase, butyrylcholinesterase, and carboxylesterase has been investigated. It was shown that the incorporation of peptide fragments significantly modulates the esterase profile of starting methylphosphonates., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Rapamycin contributes to the expansion of regulatory T cells (Tregs) in vitro. We investigated CD4(+)CD25(high)CD127(low) Treg level dynamics as well as the major parameters of cell immunity and sCD25 and highly sensitive C-reactive protein (hsCRP) concentrations in the blood of patients after coronary stenting (CS) with sirolimus (rapamycin)-eluting stents (SES; n = 43). The relation between initial Treg values and the severity of coronary atherosclerosis was observed. Treg and sCD25 levels were increased 1 month after CS versus baseline values and versus data in the control group (coronary angiography [CA], n = 20). A positive correlation between Treg and sCD25 levels was reported, whereas no relation was observed with the length of SES implanted. HsCRP level was increased during the first 7 days and returned to baseline values 1 month after CS/CA. Treg content is lower in patients with multivessel CAD. Elevated levels of Tregs and sCD25 after SES implantation might occur because of the immunomodulating effect of rapamycin., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

A flexible and polarizable methanol model has been developed on the basis of charge response kernel (CRK) theory. The present CRK methanol model well reproduces bulk liquid and interfacial properties, including density, enthalpy of vaporization, diffusion coefficient, surface tension, and radial distribution functions. The modeling of intramolecular potential incorporates the anharmonic coupling effects pertinent to the Fermi resonance of stretching and bending overtones, with its effective quantum correction. Therefore, the present methanol model can describe the vibrational spectroscopic features of infrared, Raman, and sum frequency generation spectra of C-H or C-D stretching region of methanol or deuterated methanol on the same footing. This model allows for further detailed analysis of C-H vibrations of alkyl moieties by molecular dynamics simulation.

Vibrational spectra of methyl C-H stretching region are notoriously complicated, and thus a theoretical method of systematic assignment is strongly called for in condensed phase. Here we develop a unified analysis method of the vibrational spectra, such as infrared (IR), polarized and depolarized Raman, and ssp polarized sum frequency generation (SFG), by flexible and polarizable molecular dynamics simulation. The molecular model for methanol has been developed by charge response kernel model to allow for analyzing the methyl C-H stretching vibrations. The complicated spectral structure by the Fermi resonance has been unraveled by empirically shifting potential parameters, which provides clear information on the coupling mechanism. The analysis confirmed that for the IR, polarized Raman, and SFG spectra, two-band structure at about 2830 and 2950 cm(-1) results from the Fermi resonance splitting of the methyl C-H symmetric stretching and bending overtones. In the IR spectrum, the latter, higher-frequency band is overlapped with prominent asymmetric C-H stretching bands. In the depolarized Raman spectrum, the high frequency band at about 2980 cm(-1) is assigned to the asymmetric C-H stretching mode. In the SFG spectrum, the two bands of the splitted symmetric C-H stretching mode have negative amplitudes of imaginary nonlinear susceptibility χ(2), while the higher-frequency band is partly cancelled by positive imaginary components of asymmetric C-H stretching modes.

The reaction of (dpp-BIAN)Mg(THF)3 (1) with anhydrous CrCl3 in THF at 80 degrees C affords the mixed chromium-magnesium complex (dpp-BIAN)Cr(mu-Cl)3Mg(THF)3 (2). The treatment of 2 with 1,4-dioxane causes the elimination of MgCl2 and the formation of dimeric [(dpp-BIAN)Cr(mu-Cl)(THF)]2 (3). The reaction of (dpp-BIAN)Na2 with CrCl3 gives the chlorine-free compound [Na(THF)6][(dpp-BIAN)2Cr] (4). Paramagnetic complexes 2, 3 and 4 have been characterized by IR and electronic absorption spectroscopy. The magnetic susceptibilities of 2 and 4 have been determined in solution using Evans method. The molecular structures of 2-4 have been established by single crystal X-ray analysis.

Acetylcholinesterase and butyrylcholinesterase inhibitors are potential cognition enhancers in Alzheimer disease. O,O-Dialkylphosphate inhibitors with 1-substituted 2,2,2-trifluoroethoxy leaving groups were synthesized by phosphonate-phosphate rearrangement. Substituents in the 1-position of the leaving group along with the O-alkyl groups modulated potency and selectivity against acetylcholinesterase, butyrylcholinesterase, and carboxylesterase.

The title compound, C(13)H(16)F(6)NO(5)PS, is of inter-est with respect to inhibition of serine hydro-lases. Its structure contains a 1.8797 (13) Å P-C bond and two inter-molecular N-H⋯O=P hydrogen bonds, resulting in centrosymmetric dimers. An intra-molecular N-H⋯O=P hydrogen bond is also present.

New simple expressions for average number of electrons in the valence orbital of a reacting ion and the charge susceptibility are obtained that allow one to calculate adiabatic free energy surfaces (AFES) and corresponding kinetic regime diagrams (KRD) for adiabatic processes of electron transfer from the ion, located in a polar liquid, to a metal within the framework of the exactly solvable (in the limit T-->0) model of the metal with the infinitely wide conduction band. This model represents one of limiting cases of the Anderson model that may be applied to s-p metals. Unlike previous studies of the adiabatic reactions in the model of the metal with the infinitely wide conduction band, the present work takes into account the electron-electron correlation effects in an exact manner. General results are illustrated with KRD which determine the regions of the physical parameters of the system corresponding to various types of electron transfer processes. AFES are calculated for some typical parameters sets. The exact AFES are compared with those calculated within the Hartree-Fock approximation. It is shown that the correlation effects are of importance and results not only in a considerable decrease of the activation free energy but also to qualitatively different shapes of AFES in some regions of the system parameters., ((c) 2004 American Institute of Physics)

Inhibition of acetylcholinesterase (AChE) versus inhibition and aging of neuropathy target esterase (NTE) by organophosphorus (OP) compounds in vivo can give rise to distinct neurological consequences: acute cholinergic toxicity versus OP compound-induced delayed neurotoxicity (OPIDN). Previous work has shown that the relative potency of an OP compound to react with NTE versus AChE in vitro may predict its capability to produce OPIDN. The present study was conducted to evaluate further the validity of such predictions and to enhance them with quantitative structure-activity relationships (QSAR) using a homologous series of alkyl phenylphosphonates (RO)C6H5P(O)ON = CCICH3 (PhP; R = alkyl). Neuropathic potential of PhP was assessed by measuring ki(NTE)ki(AChE) ratios in vitro and comparing these with ED50 ratios in vivo. Selectivity for NTE increased with rising R-group hydrophobicity. The ki(NTE)/ki(AChE) ratios were 0.42 (methyl), 3.6 (ethyl), 15 (isopropyl), 36 (propyl), 69 (isobutyl), 105 (butyl), and 124 (pentyl). Ratios > 1 suggest the potential to produce OPIDN at doses lower than the LD50. Inhibition of NTE and AChE in hen brain in vivo was studied 24 h after i.m. injection of hens with increasing doses of methyl and butyl derivatives. Analysis of dose-response curves yielded ED50(AChE)/ED50(NTE) ratio of 0.86 for methyl PhP and 22.1 for butyl PhP. These results predict that the butyl derivative should be more neuropathic than the methyl analogue. Excellent correspondence between in vivo and in vitro predictions of neuropathic potential indicate that valid predictive QSAR models may be based on the in vitro approach. Adoption of this system would result in reducing experimental animal use, lowering costs, accelerating data production, and enabling standardization of a biochemically based risk assessment of the neuropathic potential of OP compounds.