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2007 Vol V #1


Synthesis of 6-substituted 3-phenyl[1,2,4]triazolo
[3,4-b][1,3,4] thiadiazoles as perspective compounds for drug design

V.S. Matiychuk, N.T. Pokhodylo, I.I. Krupa, M.D. Obushak

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

Summary: New 3-phenyl[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazole derivatives containing pharmacophores have been synthesized in good yield by the reaction of 4-amino-5-phenyl-4H-1,2,4-triazole-3-thiol with a series of carboxylic acids in phosphorus oxychloride. 6-R-3-Phenyl-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazole was obtained (R = 2-Cl-4,5-F2C6H2; 4-CF3C6H4; 4-NCC6H4; 2,4-Cl2C6H3OCH2; (C6H5)2CHCH2; 5-nitro-furan-2-yl; pyridin-4-yl; 3-(pyrrolidine-1-sulfonyl)-phenyl; 3-(morpholine-4-sulfonyl)-phenyl; 4-phenoxyphenyl); 3-phenyl-6-[2-phenyl-1-(3-phenyl[1,2,4]triazolo[3,4-b]
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole were prepared starting from 4-amino-5-phenyl-4H-1,2,4-triazole-3-thiol and the benzylmalonic acid.

Keywords: [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole, 1,2,4-triazole derivatives, 1,3,4-thiadiazole derivatives, 4-amino-5-phenyl-4H-[1,2,4]triazole-3-thiol, heterocyclization.


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Optimization of synthesis stages of a novel complex inducer for type I interferons

Yu.M. Penchuk, A.V. Karpov, S.V. Verevka1

National University of Food Technologies
68 Volodymyrska Str., Kyiv, 01033, Ukraine

1Palladin Institute of Biochemistry, NAS of Ukraine
9 Leontovicha Str., Kyiv, 01601, Ukraine

Abstract: Optimal conditions have been determined and the most effective components have been chosen neccesary for design of a novel interferon type I inducer of multiple use based on the RNA Ė tilorone complex immobilized on insoluble granular matrices.

Keywords: immobilization, interferon, inducer, spheron, RNA, tilorone.

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Metal complexes of 1,4,7-triazacyclononane and their oligonucleotide conjugates as chemical nucleases

I.Ya. Dubey, L.V. Dubey, E.V. Piletska1, S.A. Piletsky1

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

1Cranfield Health, Cranfield University
Silsoe, Bedfordshire, MK45 4DT, UK

Summary: The efficiency of nucleic acids cleavage by complexes of 1,4,7-triazacyclononane (TACN) with various transition metals under physiological conditions was studied. It was found that copper (II), europium (III) and terbium (III) macrocyclic complexes cleaved ApA diribonucleotide with significant activity, but complexes of the other studied metal ions (Co2+, Fe3+, Mn2+, V3+ and Zn2+) did not show nucleolytic activity. TACN coomplexes with all studied metals except zinc demonstrated nuclease activity on double-stranded pBR322 plasmid DNA. The efficient DNA cleavage was promoted by lanthanide complexes that probably work via hydrolytic rather than oxidative mechanism, whereas complexes of Red-Ox active metals (especially iron, copper and vanadium) could catalyze DNA oxidative scission. Vanadium complex was found to be one of the most active DNA cleavers. Model T15 deoxyoligonucleotide-TACN conjugate was obtained by post-synthetic coupling of N-carboxyalkyl derivative of bis(N-trifluoroacetyl)-protected azamacrocycle with 5'-aminoalkyl-functionalized oligonucleotide. Europium complex of T15-linked TACN demonstrated the ability to cleave a complementary polyadenylic acid.

Keywords: chemical nucleases, metallocomplexes, triazacyclononane, nucleic acids cleavage, oligonucleotide conjugates.

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Synthesis of 14C-gidazepam and his potential metabolites

N.Ya. Golovenko, V.I. Pavlovskiy, O.V. Mazepa, V.B. Larionov, E.V. Prepodobnaya

O.V. Bogatsky Physico-Chemical Institute, NAS of Ukraine
86 Lustdorfska Doroga, Odesa, 65080, Ukraine

Summary: Gidazepam has been obtained at the interaction of 7-brom-1-(hydrozinocarbonylmethyl)-5-phenyl-1,2-3H-1,4-benzdiazepin-2-ones with hydrazinehydrate, and dealkyl derivative of gidazepam has been obtained in the reaction of 2-amino-5-brombenzophenones with hydrochloride chloranhydride glycine. Heterocyclic oxygenated metabolite in position 3 of N-dealkyl derivative of gidazepam was obtained in the interaction of 7-brom-5-phenyl-3-hydroxy-1,2-dihydro-3H-1,4-benzdiazepine-2-ones with sodium hydroxide. Gidazepam, containing radioactive label (14C) in hydrazine fragment, was synthesized by the alkylation of 7-brom-5-phenyl-1,2-dihydro-3H-1,4-benzdiazepine-2-ones in the reaction of methylic ether with monobromacetic acid to follow addition hydrazine hydrates. Specific activity of the ordered material was 0.07 Cu/mol. In synthesis 14C-gidazepam and his N-dealkyles metabolite have been used 14C-glycine. The substances have radioactive label (14C) in positions 2 and 3 of the molecules, their specific radioactive purity is 0.003 Cu/mol, radiochemical purity was 88 %.

Keywords: gidazepam, dealkylgidazepam, 3-hydroxydealkylgidazepam, 14C-analogues.

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Calculation of the Fe(II) porphin spin states by the density functional theory

B.F. Minaev, V.A. Minaeva1, O.M. Vasenko1

—herkasy State Technological University
460 Shevchenko blvd., —herkasy, 18006, Ukraine

1Bohdan Khmelnytskyi —herkasy National University
81 Shevchenko blvd., —herkasy, 18031, Ukraine

Summary: The Fe(II) porphin molecule is calculated by the quantum-chemical method of density functional theory (DFT) with the UB3LYP/6-311G level and complete geometry optimization in the lowest singlet, triplet, and quintet states. Energies of the 1A1g, 3A2g states of the D4h symmetry are optimized and found to increse the quintet 5¬2g state energy of the D2h symmetry. This is the first time example when the DFT method predicts the quintet to be the lowest state in Fe(II) porphin. Geometry and electronic parameters of all three spin states are compared together with the hyperfine structure of all multiplets, which can be used in EPR and ENDOR spectra analysis

Keywords: Fe(II) porphin, spin states, quantum-chemical method of density functional theory, hyperfine structure.

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This article is sponsored by Otava, Ltd.

Polymethine dyes Ė derivatives of the 7-N,N-dialkylaminocoumarines

Ya.O. Prostota, Ya.O. Kachkovsky1, A.V. Kropachev1, M.Yu. Losytskyy, S.S. Tarnavskyy, S.M. Yarmoluk

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

1Institute of Organic Chemistry, NAS of Ukraine
5 Murmanska Str., Kyiv, 03660, Ukraine

Summary: A series of new polymethine dyes ó derivatives of the 7-N,N-diethylaminocoumarine substituted by polymethine chromophore at position 3 and its analogue with the fully fixed aminogroup (coumarine 343) were obtained. Absorption and emission spectra of these dyes were investigated. All these compounds were examined as possible fluorescent probes for nucleic acids and proteins detection. Dyes and 6‚ are the most appropriate for the non-specific detection of proteins in the presence of SDS (sodium dodecylsulphate). Nevertheless, the main disadvantage of this type of dyes is their low chemical stability in buffered solutions, as well as in the presence of biological molecules.

Keywords: polymethine dyes, coumarines, absorption, fluorescent probe.

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Synthesis of β-polyfluorÓalkyl containing γ-aminoacids and the preliminary study of the biological activity

E.N. Shaitanova, I.I. Gerus, L.A. Metelitsa, L.L. Charochkina

Institute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine
1 Murmanska Str., Kyiv, 02094, Ukraine

Summary: New and effective method to the synthesis of polyfluoroalkyl containing analogues of GABA (β-hydroxy-β-tri- and difluoromethyl GABAs) and β-CF3-carnitine, unknown till now, was developed based on the reaction of 1,2-addition to enones 1a,b. Both the racemic and two enantio pure forms were obtained; synthesized analogues were examined for biological activity. Most of all the synthesized compounds demonstrated immunomodulation activity.

Keywords: fluorinated amino acids, GABA, chiral resolution with PEA, phagocytic activity, immunity.


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This article is sponsored by Otava, Ltd.

The new method of distribution integrals evaluations for high throughput virtual screening

O.Ya. Yakovenko, A.A. Oliferenko1, A.G. Golub, V.G. Bdzhola, S.M. Yarmoluk

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

1Department of Chemistry, Moscow State University, Moscow, Russia

Summary: A new method of estimating the binding affinity of small organic compounds bound to biological targets is developed. The method incorporates the explicit evaluation of entropy loss for both internal and rotation-translation degrees of freedom. A small set of CK2 inhibitors with resolved crystal structures of their complexes with protein kinase CK2 was successfully fitted to experimentally derived binding constants Ki. The method is computationally efficient and accurate enough to be used in the field of high throughput receptor-oriented virtual screening.

Keywords: distribution functions, internal freedom degreases, virtual screening, affinity prediction.

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