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2008 Vol VI #1

Synthesis of reagents based on 7-substituted 3-thiazolylcoumarins for covalent labeling of oligonucleotides

Ia.B. Kuziv1, V.V. Ishchenko2, V.P. Khilya2, I.Ya. Dubey1

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

2 Department of Chemistry, Taras Shevchenko National University
64 Volodymyrska Str., Kyiv, 01033, Ukraine

Summary: The synthesis of carboxyl derivatives of fluorescent probes based on 7-substituted 3-thiazolylcoumarins for the attachment of the dyes to oligonucleotides and other biomolecules is described. They include 7-hydroxy-, 7-methoxy and 7-acetoxy derivatives of 3-thiazolyl- and 3-(phenylthiazolyl)coumarin. The key intermediates in the synthesis were 7-hydroxy derivatives of corresponding coumarins containing protected carboxyalkyl group. Their synthesis was performed by condensing 2,4-dihydroxybenzaldehyde with two 2-(cyanomethyl)thiazoles containing ester function on an alkyl linker. Thiazole derivatives were in turn obtained by the condensation of cyanothioacetamide with corresponding a-haloketones. 7-Methoxy and 7-acetoxy coumarin derivatives and reagents with free carboxylic group were obtained by the combination of acylation, methylation and acidic hydrolysis reactions.

coumarins, fluorescent probes, covalent labeling, oligonucleotides conjugates.

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Synthesis of fluorescent dyes on the basis of 3-hydroxyquinolin-4-ones and 3-hydroxynaphthyridin-4-ones

M.D. Bilokin1, D.A. Yushchenko1,2, O.V. Pivovarenko1, V.G. Pivovarenko1

1 Department of Chemistry, Taras Shevchenko National University
64 Volodymyrska Str., Kyiv, 01033, Ukraine

2 Photophysique des Interactions Biomoleculaires, UMR 7175-LC1 du CNRS, Institute Gilbert Laustriat, Faculte de Pharmacie,Universite Louis Pasteur, 67401, Illkirch, France

Abstract: The efficiency of several synthetic routes leading to the derivatives 3-hydroxyquinolin- and 3-hydroxynaphthyridin-4-ones was studied. The optimal conditions to the preparation of mentioned classes of dyes with special structure were analyzed and retrieved. A new series of mentioned compounds was synthesized with the purpose of their chemical and fluorescent properties study. A new approach to the synthesis of 4-dialkylamino-2-aryl derivatives of quinolones and naphthyridones was proposed.

Keywords: 3-hydroxyquinolones, 3-hydroxynaphthyridones, photostability, excited state intramolecular proton transfer, fluorescent probes, fluorescent sensors, nucleophilic substitution.

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Qualitative analysis of peptide and protein composition of human fetal tissue cytosolic fractions

D.V. Cherkashina, O.Yu. Semenchenko, O.Yu. Petrenko

Institute for Problems of Cryobiology and Cryomedicine, NAS of Ukraine
23 Pereyaslavska Str., Kharkiv, 61015, Ukraine

Summary: An actual problem of current stem and progenitor cell biology and regenerative medicine is a search of biologically active substances in tissues enriched by stem/progenitor cells. Area of our interest is the fetal tissues mainly of mesenchymal and mesodermal origin that demonstrated a wide spectrum of biological activity. In this study low molecular weight peptides and proteins of human fetal tissue cytosol (FTC) obtained by two-steps high-speed ultracentrifugation of tissue homogenate were analyzed using gel-chromatography and gel-electrophoresis.
Gel-chromatography was performed using polyvinyl gels TSK-Gel Toyopearl HW-40, HW-60 Fine (Toyosoda, Japan) and tris-HCl buffer (25 mM, pH 7.5) contained 1 M urea and 100 mM NaCl as an eluent. Obtained fractions were estimated spectrophotometrically, at wave-length 254 and 280 nm. Horizontal ultrathin gel-electrophoresis was performed using polyacrylamide gel with pore gradient 4-22.5 %. Sodium dodecyl sulfate was used as a main detergent.
During gel-chromatography 6 pronounced peaks were obtained. One of them was a protein fraction, the rest 5 turned out to be peptides with molecular weights 2990, 2410, 1570, 1150, 900 Da approximately. Protein fraction was about 34000 Da.
After gel-electrophoresis of total FTC 13 protein fractions were discovered. Two of them fit the standards such as chemotrypsinogen A and albumin. For protein fraction obtained during chromatographic separation 15 lines were shown, 3 of them fit the standards, additional one was identified as cytochrome c. Protein molecular weight ranged between 9000 and 110000 Da.

Keywords: fetal tissues, gel-chromatography, horizontal ultrathin gel-electrophoresis.

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This article is sponsored by Otava, Ltd.

Search for specific protein kinase 2 inhibitors and vasoactive compounds among 5-amino-1,3-oxazoles derivatives

O.V. Shablykin1, O.P. Kucharenko2, I.N. Iakovenko1, S.M. Yarmoluk2, V.S. Brovarets1

1 Institute of Bioorganic and Petroleum Chemistry, NAS of Ukraine
1 Murmanska Str., Kyiv, 02660, Ukraine

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

Summary: Under treatment of 2-acylamino-3,3-dichloroacrylonitriles with glycine, β-alanine, γ-amino acid and ornitine the new N-substituted aminooxazoles were obtained. The new chemical compounds were screened for the possible influence on the tonus of isolated rabbit carotid arteries as well as for inhibitory activity against some human protein kinases. Some compounds revealed vessels relaxation activity on the phenylephrine-preconstricted rabbit carotids. Due to the maximal vasodilatation activity of compound 4, the mechanism of its influence on vessels was further investigated. It was shown that 4 did not change the level of vessel constriction caused due to prior +-depolarization of smooth myocyte biomembranes at increasing + concentration in solution. This was opposite to that observed with vasodilatate caused due to prior vessel constriction with phenylephrine. Nevertheless the relaxation effect of 4 on phenylephrine-constricted vessels was observed even on the background of high + constriction. The vasodilatator properties of 4e and closely related compounds among investigated 5-amino-1,3-oxazole derivatives, highly correlated with its specific inhibitor activity against human protein kinase 2. Protein kinase CK2 participates in the regulation of intracellular transduction signalling involving phosphoinositide triphosphates (PIP3) and Ca2+ release. The possible role of CK2 inhibition in the vasodilatation effect of 4e is discussed.

Keywords: amino acid, 5-amino-1,3-oxazole, blood vessels, vasodilatators, protein kinase CK2.

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UV-, IR-spectroscopy researches on interaction of 3-(5-methyl-1,2,4-triazolo[4,3-a]quinoline) propane acid with biometals

D.S. Kovalenko1, O.V. Luganska1, L.O. Omelyanchick1, O.A. Brazhko1, O.M. Nargna2

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

2 Ukrainian State Research Institute of Plastic Masses
97 Illich Av., Donetsk, 83059, Ukraine

Summary:The method of UV-spectroscopy explores an interaction between metal cations and 3-(5-methyl-1,2,4-triazolo[4,3-a]quinoline) a propane acid that evidence non-associative character of the interaction. Adsorbtion spectra of the bonds resulted from this interaction showed the desobeying to the law of additivity. This suggest covalent bond formation between metal and ligand.

Keywords: 1,2,4-triazolo[4,3-a]quinolines, complexes, UV-spectroscopy.

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Aminoalkylnaphthalimides as antiviral and interferon inducing agents. Synthesis and properties

O.S. Karpenko1, I.V. Dorovskikh1,2, S.A. Lyakhov1,2, S.A. Andronati1,2, N.M. Zholobak3, N.Ya. Spivak3, J.V. Nekhoroshkova4, L.M. Shafran4

1 O.V. Bogatsky Physicochemical Institute, NAS of Ukraine
86 Lustdorska doroga, Odesa, 65080, Ukraine

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

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

4 Ukrainian Scientific and Research Institute of Medicine on Transport
92 anatna Str., Odesa, 65039, Ukraine

Summary: Viral infections and epidemies are currently among the most severe factors of human mortality. HIV, hepatitis (A, B, C), acute respiratory infections including influenza and SARS are only the most mentioned examples. Given the rate of viral mutability and high risk of the new virus species appearing, developing of the effective antivirals is extremely actual. Ribavirin, arbidol, amizon, CMA (as cycloferon or neovir) and amixine (tilorone) may be referred as such drugs. The last one seems as the most perspective as capable of interferon inducing activity, indirect antiviral action, immunomodulation, and some other activities. No side effects are observed under therapeutics doses. These drugs DNA and RNA intercalation ability was speculated as a start point of their action. Multiple mechanisms of antiviral activity (see the title) permitted us to postulate amixine as a polymodal antiviral drug. Thus, if intercalation really plays the main role in the amixine activities, any intercalator containing positively charged side chain should demonstrate similar antiviral and interferon inducing activity. Naphthalimides unsubstituted in the ring are attractive candidates because of proved intercalation ability and low cytotoxicity.
Synthesis of the compounds was performed using naphthalic anhydride condensation with N,N-di(mono)-substituted α,ω-diamines in the solvent free media under heating up to 115 °C during 2-3 h. Structures of the synthesized compounds were proved by the FAB mass-spectrometry and 1H-NMR (300 MHz). Their affinity to CTDNA was evaluated using ethidium bromide competition test under pH=5.5 and appeared in a range of 1106-5106 M-1. Cytotoxicity of the synthesized compounds was tested using L929 cell line under standard conditions. Most of the compounds appeared less toxic as tilorone. Interferon inducing activity was tested using EPT cell line after 24 h incubation after drug inoculation in the culture. All tested compounds demonstrated high level of interferon induction and appeared to be more active as tilorone under the same protocol. All compounds also demonstrated the high levels of the antiviral protection in the decamicromol range of concentrations when inoculated simultaneously with virus and much less when inoculated 24 h before viral infection start. So it may be concluded that the mechanisms of these antiviral actions are plural. Thus, capable of DNA intercalation ring unsubstituted N-(ω-aminoalkyl)naphthalimides are moderately cytotoxic acive antivirals and interferon inducers, as we have speculated previously for DNA intercalators.

Keywords: dialkylaminoalkylnaphthalimides, antiviral drugs, interferon inducers, DNA intercalators, citotoxicity.

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2-(5-Aryl-2-furyl)quinolin-4-carboxylic acids and their antimicrobial activity

Yu.I. Horak1, V.S. Matiychuk1, M.D. Obushak1, R.V. Kutsyk2, R.Z. Lytvyn1, L.M. Kurovets2

1 Ivan Franko National University of Lviv
6 Kyryla and Mefodiya Str., Lviv, 79005, Ukraine

2 Ivano-Frankivsk State Medical University
2 Halytska Str., Ivano-Frankivsk, 76018, Ukraine

Summary: 2-(5-Aryl-2-furyl)-4-quinolincarboxylic acids were obtained in the reaction of 5-aryl-2-acetylfurans with isatin derivatives under the conditions of Pfitzinger reaction and resulted in excellent yield. Their antimicrobial activity has been tested in vitro. Some compounds were found to be effective against antibiotic-resistant bacteria.

Keywords: arylfurans, 5-aryl-2-acetylfurans, isatin, quinoline-4-carboxylic acid derivatives, Pfitzinger reaction, antimicrobial activity.

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This article is sponsored by Otava, Ltd.

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

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

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

Summary: Chemical synthesis of (1,1-dioxido-3-oxoisothiazolidin-2-yl)-benzenesulfonyl chlorides was developed. A row of (1,1-dioxido-3-oxoisothiazolidin-2-yl)-benzenesulfonyl chlorides was converted into a lot of novel (1,1-dioxido-3-oxoisothiazolidin-2-yl)-benzenesulfonamides.

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

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Efficient synthesis of 3-amino-5,6-diphenyl-1,2,4-triazine

D.M. Musatov, D.V. Kurilov, A.K. Rakishev

N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences
47 Leninsky prosp., Moscow, 119991, Russian Federation

Summary: Efficient optimized method for the synthesis of 3-amino-5,6-diphenyl-1,2,4-triazine was developed.

Keywords: 3-amino-5,6-diphenyl-1,2,4-triazine, dibenzoyl, aminoguanidine bicaronate.

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