The Forty-Sixth Euro Congress on Drug Synthesis and Analysis: Snapshot

The 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017) was arranged within the celebration of the 65th Anniversary of the Faculty of Pharmacy at Comenius University in Bratislava, Slovakia from 5-8 September 2017 to get together specialists in medicinal chemistry, organic synthesis, pharmaceutical analysis, screening of bioactive compounds, pharmacology and drug formulations; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topic of the conference, Drug Synthesis and Analysis, meant that the symposium welcomed all pharmacists and/or researchers (chemists, analysts, biologists) and students interested in scientific work dealing with investigations of biologically active compounds as potential drugs. The authors of this manuscript were plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting

Optimization of Phasor Measurement Unit Placement Using Several Proposed Case Factors for Power Network Monitoring

Recent developments in electrical power systems are concerned not only with static power flow control but also with their control during dynamic processes. Smart Grids came into being when it was noticed that the traditional electrical power system structure was lacking in reliability, power flow control, and consistency in the monitoring of phasor quantities. The Phasor Measurement Unit (PMU) is one of the main critical factors for Smart Grid (SG) operation. It has the ability to provide real-time synchronized measurement of phasor quantities with the help of a Global Positioning System (GPS). However, when considering the installation costs of a PMU device, it is far too expensive to equip on every busbar in all grid stations. Therefore, this paper proposes a new approach for the Optimum Placement of the PMU problem (OPP problem) to minimize the installed number of PMUs and maximize the measurement redundancy of the network. Exclusion of the unwanted nodes technique is used in the proposed approach, in which only the most desirable buses consisting of generator bus and load bus are selected, without considering Pure Transit Nodes (PTNs) in the optimum PMU placement sets. The focal point of the proposed work considers, most importantly, the case factor of the exclusion technique of PTNs from the optimum PMU locations, as prior approaches concerning almost every algorithm have taken PTNs as their optimal PMU placement sets. Furthermore, other case factors of the proposed approach, namely, PMU channel limits, radial bus, and single PMU outage, are also considered for the OPP problem. The proposed work is tested on standard Institute of Electrical and Electronics Engineering (IEEE)-case studies from MATPOWER on the MATLAB software. To show the success of the proposed work, the outputs are compared with the existing techniques

New molecular targets in Hodgkin and Reed-Sternberg cells

Recent discoveries shed light on molecular mechanisms responsible for classical Hodgkin lymphoma (HL) development and progression, along with features of Hodgkin – Reed and Sternberg cells (HRS). Here, we summarize current knowledge on characteristic molecular alterations in HL, as well as existing targeted therapies and potential novel treatments for this disease. We discuss the importance of cluster of differentiation molecule 30 (CD30) and the programmed cell death-1 protein (PD-1) and ligands (PD-L1/2), and other molecules involved in immune modulation in HL. We highlight emerging evidence indicating that the altered function of SWI/SNF-type chromatin remodeling complexes, PRC2, and other epigenetic modifiers, contribute to variations in chromatin status, which are typical for HL. We postulate that despite of the existence of plentiful molecular data, the understanding of HL development remains incomplete. We therefore propose research directions involving analysis of reverse signaling in the PD-1/PD-L1 mechanism, chromatin remodeling, and epigenetics-related alterations, in order to identify HL features at the molecular level. Such attempts may lead to the identification of new molecular targets, and thus will likely substantially contribute to the future development of more effective targeted therapies

Nové karbamáty benzenu pro AChE/BChE inhibici: synthéza a ligand/struktura-orientovaná SAR studie

A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl- and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl- compared to acetylcholinesterase; however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structure-activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the host-target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology.Byla navržena, syntetizována a komplexně charakterizována řada nových derivátů na bázi benzenu. Všechny testované sloučeniny byly hodnoceny na schopnost in vitro potenciálně inhibovat enzymy acetyl- a butyrylcholinesterázy. Byl také stanoven index selektivity jednotlivých molekul k cholinesterázám. Obecně byla inhibiční účinnost silnější proti butyryl ve srovnání s acetylcholinesterázou; nicméně některé ze sloučenin vykazovaly slibnou inhibici obou enzymů. Ve skutečnosti dvě sloučeniny (benzylethyl (l-oxo-l-fenylpropan-2-yl) karbamát a benzyl (l- (3-chlorfenyl) -l-oxopropan-2-yl) (methyl) karbamát) měly velmi vysoký index selectivity. U druhé látky pak byla indikována nejnižší hodnota IC50 inhibiční koncentrace, což docela dobře odpovídá galanthaminu. Kromě toho byly provedeny srovnávací studie nezávislé na receptoru a závislé na struktuře strukturní aktivity, aby se vysvětlily pozorované variace v inhibici potenciálu zkoumané řady karbamátů. Hlavním cílem studie založené na ligandu bylo analyzovat molekulární povrch, aby bylo možné nahlédnout do elektronických nebo sterických faktorů, které řídí schopnost inhibovat enzymatické aktivity. Prostorové rozdělení potenciálně důležitých stérických a elektrostatických faktorů bylo stanoveno pomocí postupu mapování farmakoforem řízeného pravděpodobností, který je založen na iterační metodě eliminace proměnných. Kromě toho byly pro všechny účinné látky vytvořeny planární a prostorové mapy interakcí mezi hostitelem a cílem a porovnány s molekulami léčiva pomocí dokovací metodiky

Regulation of IL-2 expression by transcription factor BACH2 in umbilical cord blood CD4+ T cells

On activation, umbilical cord blood (UCB) CD4+ T cells demonstrate reduced expression of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), where as maintaining equivalent interleukin-2 (IL-2) levels, as compared with adult peripheral blood (PB) CD4þ T cells. Nuclear factor of activated T cells (NFAT1) protein, a transcription factor known to regulate the expression of IL-2, TNF-α and IFN-γ, is reduced in resting and activated UCB CD4+ T cells. In contrast, expression of Broad-complex-Tramtrack-Bric-a-Brac and Cap n collar homology 1 bZip transcription factor 2 (BACH2) was shown by gene array analyses to be increased in UCB CD4+ T cells and was validated by qRT-PCR. Using chromatin immunoprecipitation, BACH2 was shown binding to the human IL-2 proximal promoter. Knockdown experiments of BACH2 by transient transfection of UCB CD4+ T cells with BACH2 siRNA resulted in significant reductions in stimulated IL-2 production. Decreased IL-2 gene transcription in UCB CD4+ T cells transfected with BACH2 siRNA was confirmed by a human IL-2 luciferase assay. In summary, BACH2 maintains IL-2 expression in UCB CD4þ T cells at levels equivalent to adult PB CD4+ T cells despite reduced NFAT1 protein expression. Thus, BACH2 expression is necessary to maintain IL-2 production when NFAT1 protein is reduced, potentially impacting UCB graft CD4+ T-cell allogeneic responses