Biopolym. Cell. 2009; 25(6):491-499.
Bioorganic Chemistry
New 1,2,4-triazine bearing compounds: molecular modelling, synthesis and biotesting
1Palchykovska L. G., 1Alexeeva I. V., 1Platonov M. O., 1Kostenko O. M., 1Usenko L. S., 1Negrutska V. V., 1Shved A. D.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680

Abstract

Aim. The addition of the new biologically active compounds to the series of the 1,2,4-triazino[5,6-b] [1,4]benzothiazine (1,2,4-TBT) derivatives and reveal among them the RNA synthesis inhibitors. Methods. The methods of structure optimization the 3-oxo-1,2,4-TBT by fragment-oriented substitution, the molecular doking of the new structures in a virtual target, the rational chemical synthesis of the theoretically prognoses compounds and their testing in the model transcription in vitro. Results. The series of 1,2,4-TBT derivatives with substituents in the benzene and triazine cycles of the base molecule were synthesized. Testing of the synthesized compounds in in vitro transcription system directed by T7 RNA polymerase revealed the structure- and concentration-dependent inhibition of the RNA synthesis by some of compounds. The experimental and virtual screening data for all investigated compounds have a good correlation. It was found that most effective derivative is the 3-oxo-8-butyl-1,2,4-TBT which completely inhibited transcription at the concentration of 6 mg/ml. Conclusions. Analysis of the testing data allows us to assume that the inhibition of the RNA synthesis is caused by binding of the 3-oxo-8-butyl-1,2,4-TBT both as to free RNA polymerase molecules, as to those consisting in transcriptional complex with DNA.
Keywords: 1,2,4-triazino[5,6-b][1,4]benzothiazines, design, virtual screening, synthesis, model transcription system

References

[1] DNA and RNA binders. From small molecules to drugs. Eds M. Demeunynck, C. Bailly, W. D. Wilson Weinheim: WileyVCH, 2003 Vol. 1:278–315.
[2] Hendry L. B., Mahesh V. B., Bransome Jr. E. D., Ewing D. E. Small molecule intercalation with double stranded DNA: Implications for normal gene regulation and for predicting the biological efficacy and genotoxicity of drugs and other chemicals Mutat. Res 2007 623:53–71.
[3] Alexeeva . V., Palchikovskaya L. G., Rybalko S. L., Usenko L. S., Kobko O. S., Popova L. A., Dyadun S. T., Shved A. D. Nucleosides with tricyclic aglycone. The ribonucleosides of condensed 1,2,4-triazine: synthesis and its antiher.etic activity Biopolym. Cell 2006 22, N 6:468–474.
[4] Alexeeva . V., Palchikovska L. G., Usenko L. S., Kostina V. G. Tricyclic 1,2,4-triazine bearing heterosystem: directed synthesis of new bioactive compounds Biopolym. Cell 2008 24, N 5:406–411.
[5] Nagamatsu T., Yamasaki H., Hirota T., Yamato M., Kido Y., Shibata M., Yoneda F. Syntheses of 3-substituted 1-methyl6-phenylpyrimido[5,4-e]-1,2,4-triazine-5,7(1H, 6H)-diones (6-phenyl analogs of toxoflavin) and their 4-oxides, and evaluation of antimicrobial activity of toxoflavins and their analogs Chem. Pharm. Bull. (Tokyo) 1993 41, N 2:362–368.
[6] Shorshnev S. V., Yesipov S. Ye., Chernyshev A. I., Pozharskii A. F., Nanavyan I. M., Kuz'menko V. V. Different basic hydrolysis of fervenuline and isofervenuline. Chem. Heterocycl. Compounds. 1987; N 11:1555–1559.
[7] Piestrzeniewich M., Studzian K., Wilmanska D., Plucienniczak G., Gniazdowski M. Effect of DNA-interacting drugs on page T7 RNA polymerase. Acta Biochim. Pol. 1998; 45(1):127–132.
[8] McMartin C., Bohacek R. S. QXP: powerful, rapid computer algorithms for structure-based drug design. Comput. Aided Mol. Des. 1997; 11(4):333–344.
[9] Temiakov D., Patlan V., Anikin M., Callister W. T., Yokoyama S., Vassylyev D. G. Structural basis for substrate selection by T7 RNA polymerase Cell 2004 116, N 3:381–391.
[10] Warren G. L., Andrews C. W., Capelli A. M., Clarke B., LaLonde J., Lambert M. H., Lindvall M., Nevins N., Semus S. F., Senger S., Tedesco G., Wall I. D., Woolven J. M., Peishoff E., Head M. S. A critical assessment of docking programs and scoring functions J. Med. Chem 2006 49, N 20 P. 5912–5931.
[11] Alexeeva I. V., Palchikovs'ka L. G., Usenko L. S., Kostina V. G. 5-Aminosubstituted triazine nucleosides and their furanidylic analogues: synthesis and primary screening on tumor cell models. Biopolym. Cell 2005 21, N 2:174–179.
[12] Thomas L., Gupta A., Gupta V. Synthesis of 2-amino-5-cloro3(trifluoromethyl)benzenethiol and conversion into 4H-1,4benzothiazines and their sulfones. J. Fluorine Chem 2003 122, N 2:207–213.
[13] Palchykovska L. G., Alexeeva I. V., Kostina V. G., Platonov M. O., Negrutska V. V., Deriabin O. M., Tarasov O. A., Shved A. D. New amides of phenazine-1-carboxylic acid: antimicrobial activity and structure-activity relationship. Ukr Biokhim Zh. 2008; 80(3):140–147.
[14] Levine M., Tjian R. Transcription regulation and animal diversity Nature 2003 424, N 6945:147–151.