Xenobiotic-induced activation of human aryl hydrocarbon receptor target genes in Drosophila is mediated by the epigenetic chromatin modifiers

Aryl hydrocarbon receptor (AHR) is the key transcription factor that controls animal development and various adaptive processes. The AHR\u27s target genes are involved in biodegradation of endogenous and exogenous toxins, regulation of immune response, organogenesis, and neurogenesis. Ligand binding is important for the activation of the AHR signaling pathway. Invertebrate AHR homologs are activated by endogenous ligands whereas vertebrate AHR can be activated by both endogenous and exogenous ligands (xenobiotics). Several studies using mammalian cultured cells have demonstrated that transcription of the AHR target genes can be activated by exogenous AHR ligands, but little is known about the effects of AHR in a living organism. Here, we examined the effects of human AHR and its ligands using transgenic Drosophila lines with an inducible human AhR gene. We found that exogenous AHR ligands can increase as well as decrease the transcription levels of the AHR target genes, including genes that control proliferation, motility, polarization, and programmed cell death. This suggests that AHR activation may affect the expression of gene networks that could be critical for cancer progression and metastasis. Importantly, we found that AHR target genes are also controlled by the enzymes that modify chromatin structure, in particular components of the epigenetic Polycomb Repressive complexes 1 and 2. Since exogenous AHR ligands (alternatively - xenobiotics) and small molecule inhibitors of epigenetic modifiers are often used as pharmaceutical anticancer drugs, our findings may have significant implications in designing new combinations of therapeutic treatments for oncological diseases. © Akishina et al

Химическая модификация различных соединений азотсодержащими гетероциклами

Heterocyclic compounds have an extremely important practical application, since many heterocycles are the basis of the most valuable medicinal substances, both natural (vitamins, enzymes, alkaloids, etc.) and synthetic biologically active compounds. The work mainly considers the most relevant directions for various purposes drugs search by modifying known bioactive natural, organoelement and framework compounds with 1,2-azole, oxazole, oxadiazole, thiazole, triazole, pyridine, pyrimidine heterocycles over the past 10 years. Chemical modification makes it possible to increase the water solubility of the compounds, which is important when choosing the pathways for the most rational drug introduction into the body, to reduce the toxicity of the corresponding substances, to increase the breadth of the therapeutic action, and also to give new valuable medicinal properties, thus significantly expanding their application in medicine and agriculture.Соединения гетероциклического ряда имеют исключительно важное практическое значение, так как многие гетероциклы лежат в основе молекул ценнейших лекарственных веществ как природных (витамины, ферменты, алкалоиды и др.), так и синтетических биологически активных соединений. В работе в основном рассмотрены наиболее актуальные за последние 10 лет направления поиска лекарственных средств различного назначения путем модификации известных биоактивных природных, элементоорганических и каркасных соединений 1,2-азольным, оксазольным, оксадиазольным, тиазольным, триазольным, пиридиновым, пиримидиновым гетероциклами. Химическая модификация позволяет повысить водорастворимость соединений, что является важным при выборе путей наиболее рационального введения препарата в организм, уменьшить токсичность соответствующих веществ, увеличить широту терапевтического действия, а также придать веществам новые ценные лечебные свойства, что таким образом в значительной мере расширить их применение в медицине и сельском хозяйстве

Challenges in QCD matter physics --The scientific programme of the Compressed Baryonic Matter experiment at FAIR

Substantial experimental and theoretical efforts worldwide are devoted to explore the phase diagram of strongly interacting matter. At LHC and top RHIC energies, QCD matter is studied at very high temperatures and nearly vanishing net-baryon densities. There is evidence that a Quark-Gluon-Plasma (QGP) was created at experiments at RHIC and LHC. The transition from the QGP back to the hadron gas is found to be a smooth cross over. For larger net-baryon densities and lower temperatures, it is expected that the QCD phase diagram exhibits a rich structure, such as a first-order phase transition between hadronic and partonic matter which terminates in a critical point, or exotic phases like quarkyonic matter. The discovery of these landmarks would be a breakthrough in our understanding of the strong interaction and is therefore in the focus of various high-energy heavy-ion research programs. The Compressed Baryonic Matter (CBM) experiment at FAIR will play a unique role in the exploration of the QCD phase diagram in the region of high net-baryon densities, because it is designed to run at unprecedented interaction rates. High-rate operation is the key prerequisite for high-precision measurements of multi-differential observables and of rare diagnostic probes which are sensitive to the dense phase of the nuclear fireball. The goal of the CBM experiment at SIS100 (sNN= 2.7--4.9 GeV) is to discover fundamental properties of QCD matter: the phase structure at large baryon-chemical potentials (μB> 500 MeV), effects of chiral symmetry, and the equation of state at high density as it is expected to occur in the core of neutron stars. In this article, we review the motivation for and the physics programme of CBM, including activities before the start of data taking in 2024, in the context of the worldwide efforts to explore high-density QCD matter

Синтез функционально замещенных сложных эфиров никотиновой и изоникотиновой кислот

Nicotinic (3-pyridinecarboxylic) acid is one of the most important vitamins as well as substance with versatile physiological activity, since it plays significant role in the human organism. Nicotinic acid (niacin, vitamin PP, vitamin B3) is widely used in medicine as drug which has a vasodilating effect, prevents the accumulation of cholesterol and normalizes the heart function. Isonicotinic (4-pyridinecarboxylic) acid is used for the production of valuable anti-tuberculosis drugs, antidepressants, etc. However, nicotinic and isonicotinic acids have various side effects: skin hyperemia, pruritus, formation of stomach peptic ulcers, liver dysfunction and hyperglycemia. To reduce the severity of side effects, their slightly soluble salts, esters or amides are obtained. The synthesis of nicotinic and isonicotinic acid esters with vanillin benzaldehydes, cholesterol, 8-hydroxyquinoline, quinine and (4,5-dichloroisothiazol-3-yl)methanol is described. Esters were obtained by acylation of hydroxybenzaldehydes and alcohols with nicotinic and isonicotinic acid hydrochlorides in the presence of triethylamine in anhydrous methylene chloride. The IR- UV- and NMR spectra of the compounds obtained are presented.Никотиновая кислота играет существенную роль в жизнедеятельности организма человека; широко применяется в медицине, а препараты на ее основе оказывают сосудорасширяющее действие, предотвращают накопление холестерина, нормализуют работу сердца. Изоникотиновую (4-пиридинкарбоновую) кислоту используют в качестве сырья для получения весьма ценных противотуберкулезных препаратов, в производстве антидепрессантов и др. Однако применение никотиновой и изоникотиновой кислот ограничивают побочные эффекты: гиперемия кожи, зуд, возможны образование пептических язв желудка, дисфункция печени, гипергликемия. Для снижения выраженности побочного действия кислот синтезируются их малорастворимые соли, эфиры, амиды. Описан синтез сложных эфиров никотиновой и изоникотиновой кислот с бензальдегидами ванилинового ряда, а также холестерином, 8-гидроксихинолином, хинином и (4,5-дихлоризотиазол-3-ил)метанолом. Сложные эфиры получали ацилированием серии гидроксибензальдегидов и спиртов гидрохлоридами хлорангидридов никотиновой и изоникотиновой кислот в присутствии триэтиламина в безводном хлористом метилене. Приведены ИК- УФ- и ЯМР-спектры полученных соединений

Синтез изоксазольных и изотиазольных производных куркумина

Curcumin is a chemical compound with antioxidant properties as well as strong anti-inflammatory, antiviral, analgesic, antimicrobial and antitumor effect, contained in the tuberous rhizomes of the turmeric plant (Curcuma longa). Curcumin derivatives are being intensively studied as potential drugs – antitumor drugs for the treatment of certain forms of cancer. The presence of reactive functional groups makes curcumin a convenient starting compound for the further chemical modification. The esters of curcumin and 5-phenylisoxazole-3-carboxylic acid, 5-(p-tolyl)isoxazole-3-carboxylic acid, 4,5- dichloroisothiazole-3-carboxylic acid and adduct of 5-(p-tolyl)isoxazol-3-carbaldehyde with curcumin were synthesized. Esters were obtained by acylation of curcumin with heterocycle-containing carboxylic acid chloride in diethyl ether in the presence of triethylamine. The IR and NMR spectra of the obtained compounds are described.Куркумин – химическое соединение, содержащееся в клубневидных корневищах растения куркума и обладающее антиоксидантными свойствами, а также оказывающее сильное противовоспалительное, противовирусное, болеутоляющее, антимикробное и противоопухолевое действия. Производные куркумина интенсивно исследуются в качестве потенциальных лекарственных средств – противоопухолевых препаратов для терапии некоторых форм онкологических заболеваний. Благодаря присутствию в его молекуле реакционноспособных функциональных групп может служить удобным и легкодоступным исходным соединением для последующей химической модификации. Описан синтез сложных эфиров куркумина и 5-фенилизоксазол-3-карбоновой, 5-(р-толил)изоксазол-3-карбоновой, 4,5-дихлоризотиазол-3-карбоновой кислот и аддукта 5-(р-толил)изоксазол-3-карбальдегида с куркумином. Сложные эфиры получали ацилированием куркумина хлорангидридами гетероциклосодержащих карбоновых кислот в среде диэтилового эфира в присутствии триэтиламина. Приведены ИК- и ЯМР-спектры полученных соединений

Синтез новых производных ремантадина и адамантан-1-карбоновой кислоты с 1,2-азольными фрагментами

Various adamantane derivatives were obtained by the condensation of rimantadine with substituted hydroxy-benzaldehydes, esters and ethers based on them, as well as 1,2-azole-3-carbaldehydes, followed by reduction. Further acylation of derivatives with active amino and hydroxy groups yielded compounds containing two 1,2-azole fragments in one molecule.Конденсацией ремантадина с различными замещенными гидроксибензальдегидами, сложными и простыми эфирами на их основе, а также 1,2-азол-3-карбальдегидами с образованием азометинов и последующим восстановлением последних получены вариативные адамантановые производные. Дальнейшим ацилированием производных с активными амино- и гидроксигруппами получены соединения, содержащие в одной молекуле два 1,2-азольных фрагмента

Challenges in QCD matter physics - The Compressed Baryonic Matter experiment at FAIR

Substantial experimental and theoretical efforts worldwide are devoted to explore the phase diagram of strongly interacting matter. At LHC and top RHIC energies, QCD matter is studied at very high temperatures and nearly vanishing net-baryon densities. There is evidence that a Quark-Gluon-Plasma (QGP) was created at experiments at RHIC and LHC. The transition from the QGP back to the hadron gas is found to be a smooth cross over. For larger net-baryon densities and lower temperatures, it is expected that the QCD phase diagram exhibits a rich structure, such as a first-order phase transition between hadronic and partonic matter which terminates in a critical point, or exotic phases like quarkyonic matter. The discovery of these landmarks would be a breakthrough in our understanding of the strong interaction and is therefore in the focus of various high-energy heavy-ion research programs. The Compressed Baryonic Matter (CBM) experiment at FAIR will play a unique role in the exploration of the QCD phase diagram in the region of high net-baryon densities, because it is designed to run at unprecedented interaction rates. High-rate operation is the key prerequisite for high-precision measurements of multi-differential observables and of rare diagnostic probes which are sensitive to the dense phase of the nuclear fireball. The goal of the CBM experiment at SIS100 (sqrt(s_NN) = 2.7 - 4.9 GeV) is to discover fundamental properties of QCD matter: the phase structure at large baryon-chemical potentials (mu_B > 500 MeV), effects of chiral symmetry, and the equation-of-state at high density as it is expected to occur in the core of neutron stars. In this article, we review the motivation for and the physics programme of CBM, including activities before the start of data taking in 2022, in the context of the worldwide efforts to explore high-density QCD matter.Comment: 15 pages, 11 figures. Published in European Physical Journal

Feasibility studies of the time-like proton electromagnetic form factor measurements with PANDA at FAIR

The possibility of measuring the proton electromagnetic form factors in the time-like region at FAIR with the \PANDA detector is discussed. Detailed simulations on signal efficiency for the annihilation of $\bar p +p$ into a lepton pair as well as for the most important background channels have been performed. It is shown that precision measurements of the differential cross section of the reaction $\bar p +p \to e^++ e^-$ can be obtained in a wide angular and kinematical range. The individual determination of the moduli of the electric and magnetic proton form factors will be possible up to a value of momentum transfer squared of $q^2\simeq 14$ (GeV/c)$^2$. The total $\bar p +p\to e^++e^-$ cross section will be measured up to $q^2\simeq 28$ (GeV/c)$^2$. The results obtained from simulated events are compared to the existing data. Sensitivity to the two photons exchange mechanism is also investigated.Comment: 12 pages, 4 tables, 8 figures Revised, added details on simulations, 4 tables, 9 figure

Синтез производных акридина, бисакридина и хинолина с 1,2-азольными, пиридиновыми и ферроценовыми фрагментами анионитами

Natural and synthetic derivatives of acridine and pyrimidoquinoline series are of considerable interest for study as antiviral, antitumor, antibacterial, antiparasitic agents; they are also useful in the treatment of Alzheimer’s disease. The combination of acridine and pyrimidoquinoline cycles with other pharmacophore groups can lead to a synergistic effect of their properties, the appearance of new types of biological activity, as well as a reducing of the severity of side effects. The synthesis of new derivatives of 8,9,10,12-tetrahydrobenzo[a]acridin-11(7H)-one and 10,12-dihydrobenzo[f] pyrimido [4,5-b] quinoline-9,11 (7H, 8H)-dione containing isoxazole, isothiazole heterocycles, ferrocene fragment, as well as nicotinic and isonicotinic acid residues covalently attached via ester groups to different positions of the aromatic nucleus, is described. A three-component cascade condensation of aromatic amines, aldehydes and cyclic β —dicarbonyl compounds was carried out by refluxing in butanol. The heat effects of the cyclization reaction have been determined using the DFT / B3LYP1 / MIDI method. The cytotoxic activity of the synthesized compounds was assessed on four different cancer cell lines (RKO, COLO320, LS174T, SW480).Природные и синтетические производные акридинового и пиримидохинолинового ряда представляют значительный интерес для исследования. Их используют в качестве противовирусных, противоопухолевых, антибактериальных, противопаразитарных агентов, они также применимы при лечении болезни Альцгеймера. Комбинация акридинового и пиримидохинолинового циклов с другими фармакофорными группами может привести к эффекту синергизма их свойств, появлению новых, неустановленных для данных структурных фрагментов видов биологической активности, а также снижению выраженности побочных эффектов. Описан синтез новых производных 8,9,10,12-тетрагидробензо[а]акридин-11(7H )-она и 10,12-дигидробензо [f] пиримидо[4,5-b  ]хинолин-9,11(7H,8H)-диона, содержащих изоксазольный, изотиазольный гетероциклы, ферроценовый фрагмент, а также остатки никотиновой и изоникотиновой кислот, ковалентно присоединенных с помощью сложноэфирных групп к различным положениям ароматического ядра. Трехкомпонентную каскадную конденсацию ароматических аминов, альдегидов и циклических β  -дикарбонильных соединений проводили кипячением в бутаноле. Путем квантово-химических расчетов с использованием метода DFT/B3LYP1/MIDI определены тепловые эффекты реакции циклизации. Проведена оценка цитотоксической активности синтезированных соединений на четырех различных линиях раковых клеток (RKO, COLO320, LS174T, SW480)