Biopolym. Cell. 2006; 22(6):468-474.
Bioorganic Chemistry
Nucleosides with tricyclic aglycone. The ribonucleosides of condensed 1,2,4-triazine: synthesis and its antiherpetic activity
1Alexeeva I. V., 1Palchikovskaya L. G., 2Rybalko S. L., 1Usenko L. S., 1Kobko A. S., 2Popova L. A., 2Dyadun S. T., 1Shved A. D.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680
  2. Gromashevsky L.V. Institute of Epidemiology and Infection Diseases, AMS of Ukraine
    5, Amosova Str., Kyiv, Ukraine, 03038


The method of synthesis of tricyclic aglicones based on the condensed 1,2,4-triazine has been developed to perform their ribosylation by the simplified procedure (technique) of silylic condensation. The identity and structure of the resultant compounds were ascertained through chromatography, UV, PMR, and massspectrometry. High tautomeric status of 3-oxo-(3-thioxo)-triazinebenzothiazines (I and II bases) may promote formation of two regioisomeric nucleosides. The introduction of alkylmercapto-substituent into position 3 of triazine fragment of aglicone molecule stabilizes tautomeric form with proton in thiazine cycle, thus it allows achieving the regiospecificity of the process. Research on the toxicity and antiherpetic activity of the synthesized compounds (bases and nucleosides) was carried out in RK-13 tissue culture. It was demonstrated that 3-oxo-triazinebenzothiazine (base I) proved to be the least toxic and the most effective with respect to herpes virus (HSV-2), the selectivity index of which exceeded that of acyclovir (Virolex) significantly.
Keywords: abnomal nucleosides, tricyclic aglicones, herpes virus of the 2nd type (HSV-2), antivirus agents


[1] Yin PD, Das D, Mitsuya H. Overcoming HIV drug resistance through rational drug design based on molecular, biochemical, and structural profiles of HIV resistance. Cell Mol Life Sci. 2006;63(15):1706-24.
[2] Korth C, May BC, Cohen FE, Prusiner SB. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A. 2001;98(17):9836-41.
[3] Lin R-Y, Jones RJ, Mateucci M. Tricyclic 2'-Deoxycytidine Analogs: Syntheses and Incorporation into Oligodeoxynucleotides Which Have Enhanced Binding to Complementary RNA. J Am Chem. Soc. 1995.; 117(13): 3873-4.
[4] Zozulya VN, Blagoi YuP, Dubey IY, Fedoryak OD, Shcherbakova AS, Fedoryak DM. Stabilization of duplex and triplex complexes of oligothymidylate by covalently linked imidazophenazine glycoside. Biopolym Cell. 1998; 14(1):54-61.
[5] Thuong NT, Helene C. Sequence-specific recognition and modification of double-helical DNA by oligonucleotides. Angew Chem. 1993; 32(5): 666-90.
[6] Sandin P, Wilhelmsson LM, Lincoln P, Powers VE, Brown T, Albinsson B. Fluorescent properties of DNA base analogue tC upon incorporation into DNA--negligible influence of neighbouring bases on fluorescence quantum yield. Nucleic Acids Res. 2005;33(16):5019-25.
[7] Bobek M, Farka? J, Gut J. Nucleic acids components and their analogues. XCI. An improved synthesis of 6-azauracil and its 5-substituted derivatives. Collection of Czechoslovak Chemical Communications. 1967;32(3):1295–8.
[8] Chang PK. New 5-Substituted 6-Azauracils 1 . J Org Chem. 1961;26(4):1118–20.
[9] [Methods of investigating carbohydrates]. Ed. AYa Khorlin. M.: Mir, 1975. 445 p.
[10] Cristescu C, Badea V. Azauracil derivatives with potential cytostatic activity. VII. Thionation of 5-benzylthio-6-azauracil. Rev Roum Chim. 1969; 14: 135-140.
[11] Alexeeva IV, Palchikovskaya LI, Nosach LN, Usenko LS, Zhovnovataya VL, Dyachenko NS. The glycosilic analogues of 6-aza-cytidine: synthesis and antiviral activity. Biopolym Cell. 2004; 20(5):435-9.
[12] Barquero AA, Alch? LE, Coto CE. Antiviral activity of meliacine on the replication of a thymidine kinase-deficient mutant of Herpes simplex virus type 1 alone and in combination with acyclovir. Int J Antimicrob Agents. 1997;9(1):49-55.
[13] Preclinical studies of drugs. Guidelines. Kyiv, 2001;371-96.
[14] Roth B, Schloemer LA. 5-Arylthiopyrimidines. III. Cyclization of 4-Hydroxy Derivatives to 10H-Pyrimido[5,4-b][1,4]benzothiazines (1,3-Diazaphenothiazines) 1 . J Org Chem. 1963;28(10):2659–72.
[15] Lukevic EYa, Zabolotskaya AE. Silyl nucleoside synthesis method. Riga: Zinatne, 1985. 440 p.
[16] Ienaga K, Pfleiderer W. Nucleoside, XXV. Synthese und Eigenschaften von Alloxazin-nucleosiden. Chem Ber. 1977;110(10):3449–55.
[17] Wang Z, Rizzo CJ. Regioselective synthesis of beta-N1- and beta-N3-alloxazine nucleosides. Org Lett. 2000;2(2):227-30.
[18] Goryunova OV, Korbukh IA, Preobrazhenskaya MN, Chernyshev AI. Nucleosides of 5-methylmercapto-6H-pyrazolo (4,3-d) pyrimidinone-7. Bioorg Khim. 1979; 5 (9):1361-8
[19] Melnik SYa, Bakhmedova AA, Volodin YuYu, Preobrazhenskaya MN, Chernyshev AI, Esipov SE, Navashin SM. Synthesis of reumycin glycoside derivatives. Bioorg Khim. 1981; 7 (11):1723-30
[20] Bretner M, Baier A, Kopa?ska K, Najda A, Schoof A, Reinholz M, Lipniacki A, Piasek A, Kulikowski T, Borowski P. Synthesis and biological activity of 1H-benzotriazole and 1H-benzimidazole analogues--inhibitors of the NTpase/helicase of HCV and of some related Flaviviridae. Antivir Chem Chemother. 2005;16(5):315-26.
[21] Zagorodnya S, Nesterova N, Alexeeva I, Palchikovskaya L, Baranova G, Kobko A, Golovan A. Studying of anti Epstein-Barr virus activity of new triazine bearing tricyclic bases and their N-glycosidic derivatives. Abstrs of 19-th Int. Conf. on Antiviral Research (San Juan, Puerto Rico, May 7—11, 2006). San Juan, 2006:A69—A70.