Synthesis and biologic evaluation of thienopyrimidinones inhibition activity against protein kinase CK2

I.M. Kotey, A.O. Balanda, V.G. Bdzhola, S.S. Lukashov, O.P. Kukharenko, V.M. Kharchenko, S.M. Yarmoluk

Institute of Molecular Biology and Genetics, NAS of Ukraine
150 Zabolotny Str., Kyiv, 03143, Ukraine

Summary: Inhibition activity against protein kinase CK2 of thieno[2,3-d]pyrimidinone derivatives was discovered. In vitro testing of 86 compounds allowed finding of 15 compounds with IC₅₀ less than 20 mM. The most active compound is 4-{[5-(4-ethylphenyl)-4-oxothieno[2,3-d]pyrimidine-3-(4H)-yl]methyl} benzoic acid (IC₅₀=2.5 µM). The structure-actvity relationship of thieno[2,3-d]pyrimidinones was investigated and the binding modes of their interaction with protein kinase CK2 were proposed.

Keywords: CK2 inhibitors, thieno[2,3-d]pyrimidinones, flexible docking

Covalent conjugates of isoflavone formononetine and its synthetitc analogues with imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines and imidazo[1,2-a]thiazoles

N.V. Kovalenko, V.G. Pivovarenko

Taras Shevchenko National University
64 Volodymyrska Str., Kyiv, 01033, Ukraine

Abstract: By the interaction of 2-bromomethyl derivatives of imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine and imidazo[1,2-a]thiazole with natural 7-hydroxyisoflavone formononetin and with its synthetic analogues the corresponding 7-(imidazo[1,2-a]hetaryl-2-methoxy)-3-aryl-4H-4-chromenones were synthesized.

Keywords: 4H-4-chromenones, isoflavones, formononetin, imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine and imidazo[1,2-a]thiazole.

Studies of mono- and trimethine cyanine dyes as specific fluorescent probes for fibrillar β-lactoglobulin detection

K.D. Volkova¹, V.B. Kovalska¹, A.O. Balanda1, Yu.L. Slominskii², O.I. Tolmachev², V. Subramaniam³ and S.M. Yarmoluk¹

¹Institute of Molecular Biology and Genetics, NAS of Ukraine
150 Zabolotnogo Str., Kyiv, 03143, Ukraine

²Institute of Organic Chemistry, NAS of Ukraine
5 Murmanska Str., Kyiv, 02660, Ukraine

³MESA+ Institute for Nanotechnology, Biophysical Engineering Group, University of Twente, The Netherlands

Summary: We ascertained the ability to detect fibrillar β-lactoglobulin (BLG) of a series of mono- and trimethinecyanines containing on benzothiazole heterocycles. Fluorescent properties of these dyes were studied in the unbound state and in the presence of monomeric and fibrillar BLG. The correlation between the chemical nature of the dye molecules and the ability of dyes to bind aggregated proteins was established. We found that cyanines with amino substituents in heterocycle in contrast to the corresponding unsubstituted dyes have a binding preference to fibrillar BLG and give noticeable fluorescence response in the presence of the aggregated protein. Also it was shown, that incorporation of substituents into polymethine chain of trimethinecyanines leads to the increasing of the dye/fibrillar BLG complex fluorescence intensity. The trimethinecyanines L-5, SH-21252 and monomethinecyanine Т-414 specifically increase emission (up to 24 times) in the presence of fibrillar BLG and could be proposed as probes for fluorescent detection of aggregated proteins.

Keywords: cyanine dyes, amyloid proteins, fluorescent detection.

Synthesis of crowncarbenoid derivatives

N.I. Korotkikh¹, K.A. Marichev², A.V. Kiselyov¹, O.P. Shvaika²

¹L.M. Litvinenko Institute of Physical Organic and Coal Chemistry, NAS of Ukraine
70 R. Luxemburg Str., Donetsk, 83114, Ukraine

²Donetsk National University
24 Universytetska Str., Donetsk, 83055, Ukraine

Summary: Macrocyclic derivatives of crown-carbenoid compounds of the imidazole and benzimidazole series were synthesized on the base of the respective monooxa- and dioxaalkylenchlorides and azoles. Among them there are macrocyclic salts, bisazolones, bisazolthiones, bisazolselenones and a macrocyclic bisazoline with pharmacophor structures.

Keywords: crown-salts, crown-bisazolchalcogenones, crown-bisazoline, imidazoles, benzimidazoles

Synthesis of (1,1-dioxido-3-oxoisothiazolidin-2-yl)benzenamides

А.R. Synyugin, M.O. Chekanov, S.S. Lukashov, S.M. Yarmoluk

Institute of Molecular Biology and Genetics, NAS of Ukraine
150 Zabolotnogo Str., Kyiv, 03143, Ukraine

Summary: Early it was shown some pharmacological value of substituted isothiazolin-3-one-1,1-dioxides. In our preliminary work the synthesis of isothiazolidin-3-one-1,1-dioxides was described. With the aim of widening of the range of isothiazolidinone-1,1-dioxide derivatives synthetic scheme of (oxoisothiazolidin-3-one-1,1-dioxide-2-yl) benzamides preparation was developed.

Keywords: вenzamides, 3-isothiazolidinone-1,1-dioxides, (3-oxoisothiazolidinone-1,1-dioxide-2-yl)benzoyl chlorides, methyl 3-(chlorsulfonyl)propanoate, [(2-carboxyethyl)sulfonyl]aminobenzoic acids, (3-oxoisothiazolidinone-1,1-dioxide-2-yl) benzamides

The pharmacokinetic of 7-bromo-5-(2’-chloro)phenil-3-enantoiloxy-1,2-dihydro-3Н-1,4-benzodiazepin-2-one in the organism of experimental animals by different methods of delivery

I.А. Kravchenko¹, G.I. Sivko¹, I.N. Radaeva¹, А.А. Krysko², G.V. Samoylenko², Е.A. Semenishina², V.I. Pavlovsky²

¹I.I. Mechnikov Odesa National University
2 Dvoryanska Str., Odesa, 65026, Ukraine

²О.V. Bogatsky Physico-Chemical Institute, NAS of Ukraine
86 Lustdorfska doroga, Odesa, 65080, Ukraine

Summary: We have studied the pharmacokinetic of distribution of enantic ester of 3-hydroxyphenazepam and the product of its biotransformation — 7-bromo-3-hydroxy-5-(2’-chloro)phenil-1,2-dihydro-3Н-1,4-benzdiazepin-2-one in the organism of experimental animal by oral and intravenous methods of delivery. We showed significant accumulation and low excretion of this ester from brain, and its high affinity to brain tissue. All these determined the prolong pharmacology effect of this substance.

Keywords: pharmacokinetic, excretion, enantic ester of 3-hydroxyphenazepam, oral delivery, HPLC.

Diphenyloxazole substituted 3-hydroxychromones — perspective luminophores for ratiometric studies

D.A. Svechkarev, G.V. Karpushina, A.O. Doroshenko

V.N. Karazin Kharkiv National University
4 Svobody sq., Kharkiv, 61077, Ukraine

Summary: A new heterocyclic derivatives of 3-hydroxychromone with the 2,5-diphenyloxazole moiety in position 2 were synthesized. It was shown that the composition of these two fragments lead to one of the most effective fluorescent compounds in the 3-hydroxychromone family, preserving anomalous spectral properties caused by a proton phototransfer reaction.
Based on computation results, both title compounds were shown to be systems with a reverse charge transfer preserving their ability to form a phototautomer in the excited state. It was stated that an annelated benzene ring leads to decrease of the charge transfer intensity during the excitation, which causes lower solvatofluorochromism as well as lower sensitivity of the ratiometric response on the solvent polarity changes.
Spectral and fluorescent properties, as well as solvatofluorochromism and influence of the solvent polarity on the excited state intramolecular proton phototransfer process were investigated for the synthesized compounds in a series of 9 different solvents. Both derivatives are characterized by the absorption and fluorescence maxima close to the ones for the unsubstituted 3-hydroxyflavone, sometimes with slightly higher quantum yields of fluorescence. Both absorption and tautomer emission maxima are almost insensitive to the solvent polarity, while the position of the normal form fluorescence exhibits a significant bathochromic shift with the increase of the solvent polarity. A possibility was shown to use the title compounds as ratiometric probes of the medium polarity.

Keywords: 3-hydroxychromone, fluorescence, solvatofluorochromism, solvent polarity, ratiometric probe

Studies of complex formation in «iron phthalocyanine — aliphatic amine» system

V.Ya. Chernii

V.I. Vernadsky Institute of General & Inorganic Chemistry, NAS of Ukraine
32/34 Palladin ave., Kyiv, 03680, Ukraine

Summary: Complex formation in systems iron phthalocyanine — aliphatic amines was studied and stability constants for these complexes were calculated. It was shown that stability constant depends on the steric factor, when basicity of amine slightly affect on the complex formation. Stability constant values for the complexes increase in the row t-BuNH₂, i-PrNH₂, Pip=Mf, n-C₅Н₁₁NH₂. The correlation between lgK values as well as metal-to-ligand charge transfer (MLCT) position in absorption spectra and steric characteristics of axial ligand was ascertained. Complex formation was not observed in the systems of iron phthalocyanine with diethyl or dipropyl amine.

Keywords: benzenesulfonamides, isothiazolidine-3-one-1,1-dioxides, 2-phenylisothiazolidine-3-one-1,1-dioxides, methyl 3-(chlorosulfonyl)propanoate, 2-methoxycarbonyletanesulfonyl chlorides.

Synthesis and antiradical activity 6(8)-functionally substituted S-(2-methylquinolin-4-yl)-N-acetylcysteines

I.B. Labenskaya¹, L.A. Omelyanchik¹, A.A. Brazhko¹, M.P. Zavgorodny¹, V.I. Gencheva¹, O.V. Luganska¹, O.M. Narizhna²

¹Zaporizhzhya National University
66 Zhukovskogo Str., Zaporizhzhya, 69600, Ukraine

²Ukrainian State Science-Research Institute Plastic Mass
97 Illichya ave., Donetsk, 83059, Ukraine

Summary: Synthesis is a new 6(8)-functionally substituted S-(2-methylquinoline-4-yl)-N-acetylcysteine as the potential bioregulators. Their antiradical activity is analyses on model autooxidation adrenalin in adrenokhrom. Study dependence of biological action on structure of the given compounds.

Keywords: 6(8)-functionally substituted S-(2-methylquinoline-4-yl)-N-acetylcysteine, N-acylderivative, antiradical activity, dependence «structure—action».

Spin-dependent binding of dioxygen to heme and charge-transfer mechanism of spin-orbit coupling enhancement

B.F. Minaev, V.A. Minaeva

Bohdan Khmelnitskyi National University
81 Bvd. Shevchenko, Cherkasy, 18031, Ukraine

Summary: Spin-orbit coupling (SOC) between the starting triplet ³A''(2) state from the entrance channel of the heme-O₂ binding reaction and the final singlet ¹A'(1) open-shell state, which are dominated by the Fe³⁺-O₂^- radical-pair structures, is studied. Simulated potential energy surface cross sections along the reaction coordinate for these and other multiplets, calculated by density functional theory (DFT) agree with the recent DFT studies known from the literature. The heme-model includes Fe(II)-porphyrin complex with imidazol, or ammonia molecule, at the fith coordination position, which simulates the hystidine as an aminoacide residue of myoglobin. The SOC is induced mainly at the oxygen moiety by an orbital angular momentum change in the π_g-shell during the triplet-singlet transition. This SOC model explains pretty well the efficient spin inversion during the heme-O₂ binding.

Keywords: hemoglobin, myoglobin, cytochrome oxidase, spin-orbit coupling, triplet-singlet spin inversion, radical-pair structures, charge-transfer states, binding of diatomic ligands to heme.

Synthesis, antiviral and interferon inducing activities of the carboxy-derivatives of the planar polycyclic compounds

A.S. Karpenko¹, I.V. Dorovskykh^1,2, M.O. Shibinskaya¹, G.V. Maltsev¹, H.A. Lyakhova¹, Ju.O. Gusyeva¹, N.M. Zholobak³, N.Ya. Spivak³, S.A. Lyakhov^1,2, S.A. Andronati^1,2

¹О.V. Bogatsky Physico-Chemical Institute, NAS of Ukraine
86 Lustdorfska doroga, Odesa, 65080, Ukraine

²I.I. Mechnikov Odesa National University
2 Dvoryanska Str., Odesa, 65026, Ukraine

³Danylo Zabolotny Institute of Microbiology and Virology, NAS of Ukraine
152 Zabolotnogo Str., Kyiv, 03143, Ukraine

Summary: Amixine and Carboxymethylacridone (CMA) are representatives of the structurally broad class of the planar polycyclic compounds, most of which are active antivirals and IFN-inductors. CMA stands out of this class due to the presence of negative charge in the physiological conditions contrary to the positively charged other inducers, what, possibly, caused a speculation about uniqueness of this drug. We have synthesized and tested as antiviral and interferon inductors sodium salts of some planar polycyclic acids, notably: (1,3-dioxobenzo[de]isoquinolin-2-yl)-(3), benzoimidazo[1,2c]quinazolin-6-yl-(8), indoloqui-noxalin-6-yl-(10), (7-ethoxy-9-oxofluoren-2-yloxy)-(12), (7-carboxymethoxy-9-oxofluoren-2-yloxy)-(13) acetic acids, 3-(1,3-dioxobenzo[de]isoquinolin-2-yl)-(4) 3-benzoimidazo[1,2c]quinazolin-6-yl-(9) propionic acid, 4-(1,3-dioxobenzo[de]isoquinolin-2-yl)-butyric acid (5), 6-(1,3-dioxobenzo[de]isoquinolin-2-yl)-hexanoic acid (6), 3-(1,3-dioxobenzo[de]isoquinolin-2-yl)-benzoic acid (7), naphthofuran carboxylic acid (11). Cytotoxicity, IFN-inducing and antiviral properties were tested in the cell-culture assays. All tested compounds demonstrate low cytotoxicity ranking in the order: 3(>36)<CMA(34)≅7(>30.5)<5(16.4)≅6(15)<4(3.1)<12
(>2.6)<11(2.4)<8(>1.5)<9(>1.4)=13(>1.4)<10(>1.3). All synthesized compounds with the exception of 3 demonstrate significant interferon induction in the micromolar concentration range, ranking in the order (IFN titer/concentration, µM): 12(1:32/0.9)>CMA(1:32/1.2)>8(1:32/2.3)=9(1:32/2.3)>10(1:28/1)>
6(1:24/0.9)>7(1:16/0.9)>4(1:12/0.5)>5(1:10/1) >13(1:8/0.5)>>11(1:8/25.6). So, CMA isn’t the only one, but one from the set of planar anionic interferon inductors.

Keywords: synthesis, antiviral drugs, anionic interferon inducers, cytotoxicity.