Fine Chemical Technologies

Advanced search


Full Text:


The synthesis of a dimer consisting of γ-thymine chiral monomer based on L-Ala and thymine aeg-PNA monomer (synthesized from deuterated glycine), in which the methylene protons of the pseudopeptide residue were exchanged with deuterium atoms, was described. The deuterated monomer was introduced into acylation reaction by means of a mixed anhydride procedure with γ-PNA chiral monomer trifluoroacetate based on L-Ala. The latter was obtained from the fully protected thymine monomer by the reaction with trifluoroacetic acid. The structure and purity of the target monomer were confirmed by NMR-spectroscopy, and the elemental composition was estimated by quantitative elemental analysis. The double quantum filtered COSY-NMR-spectroscopy (DQF-COSY) method was used to determine the methylene signals of the dimer chiral fragment. With the use of the spectrum analysis, the chemical shifts and calculated spin-spin coupling constants of the protons from the dimer chiral part were found. Given that Karplus equation associates the value of the dihedral angle between the vicinal protons with their spin-spin coupling constant, it was concluded that the chiral fragment is in the right-helix conformation for all the dimer rotamers.

About the Authors

A. V. Dezhenkov
Moscow Technological University (Institute of Fine Chemical Technologies)
Russian Federation
Moscow, 119571 Moscow, Russia

D. A. Cheshkov
Research Institute of Chemistry and Technology of Organoelement Compounds
Russian Federation
Moscow,105118 Russia

I. A. Prokhorov
Moscow Technological University (Institute of Fine Chemical Technologies)
Russian Federation
Moscow, 119571 Moscow, Russia

A. I. Lutik
Moscow Technological University (Institute of Fine Chemical Technologies)
Russian Federation
Moscow, 119571 Moscow, Russia

Yu. G. Kirillova
Moscow Technological University (Institute of Fine Chemical Technologies), Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency
Russian Federation

Moscow, 119571 Moscow, Russia

Moscow, 119435 Russia


1. Milligan J.F., Matteucci M.D., Martin J.C. Current concepts in antisense drug design // J. Med. Chem. 1993. V. 36. P. 1923–1937.

2. Nielsen P.E., Egholm M., Berg R.H., Buchardt O. Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide // Science. 1991. V. 254. P. 1497–1500.

3. Kumar V.A., Ganesh K.N. Conformationally сonstrained PNA фnalogues: Structural evolution toward DNA/RNA binding selectivity. // Acc. Chem. Res. 2005. V. 38. P. 404–412.

4. Dragulescu-Andrasi A., Rapireddy S., Frezza B.M., Gayathri C., Gil R.R., Ly D.H. A simple γ-backbone modification preorganizes peptide nucleic acid into a helical structure // J. Am. Chem. Soc. 2006. V. 128. P. 10258–10267.

5. Mitra R., Ganesh K.N. Aminomethylene peptide nucleic acid (am-PNA): Synthesis, regio-/stereospecific DNA binding, and differential cell uptake of (α/γ,R/S)amPNA analogues // J. Org. Chem. 2012. V. 77. P. 5696−5704.

6. Tedeschi T., Sforza S., Corradini R., Marchelli R. Synthesis of new chiral PNAs bearing a dipeptide-mimic monomer with two lysine-derived stereogenic centres // Tetrahedron Lett. 2005. V. 46 P. 8395–8399.

7. Sahu B., Chenna V., Lathrop K.L., Thomas S.M., Zon G., Livak K.J., Ly D.H. Synthesis of conformationally preorganized and cell-permeable guanidine-based γ-peptide nucleic acids (γGPNAs) // J. Org. Chem. 2009. V. 74. P. 1509–1516.

8. Sahu B., Sacui I., Rapireddy S., Zanotti K.J., Bahal R., Armitage B.A., Ly D.H. Synthesis and characterization of conformationally preorganized, (R)-diethylene glycol-containing γ-peptide nucleic acids with superior hybridization properties and water solubility // J. Org. Chem. 2011. V. 76. P. 5614–5627.

9. Kirillova Y., Boyarskaya N., Dezhenkov A., Tankevich M., Prokhorov I., Varizhuk A., Eremin S., Esipov D., Smirnov I., Pozmogova G. Polyanionic carboxyethyl peptide nucleic acids (ce-PNAs): Synthesis and DNA binding // PLoS One. 2015. V. 10. e0140468.

10. De Costa N.T.S., Heemstra J.M. Evaluating the effect of ionic strength on duplex stability for PNA having negatively or positively charged side chains // PLoS One. 2013. V. 8. P. 1−8.

11. de Koning M.C., Petersen L., Weterings J.J., Overhand M., van der Marel G.A., Filippov D.V. Synthesis of thiol-modified peptide nucleic acids designed for post-assembly conjugation reactions // Tetrahedron. 2006. V. 62. P. 3248–3258.

12. Dose C., Seitz O. Convergent synthesis of peptide nucleic acids by native chemical ligation // Org. Lett. 2005. V. 7. P. 4365–4368.

13. Zhou P., Dragulescu-Andrasi A., Bhattacharya B., O'Keefe H., Vatta P., Hyldig-Nielsen J.J., Ly D.H. Synthesis of cell-permeable peptide nucleic acids and characterization of their hybridization and uptake properties // Bioorg. Med. Chem. Lett. 2006. V. 16. P. 4931–4935.

14. Vieville J.M.P., Barluenga S., Winssinger N., Delsuc M-A. Duplex formation and secondary structure of γ-PNA observed by NMR and CD // Biophys. Chem. 2016. V. 210. P. 9–13.

15. Falkiewicz B., Kołodziejczyk A.S., Liberek B., Wiśniewski K. Synthesis of achiral and chiral peptide nucleic acid (PNA) monomers using Mitsunobu reaction // Tetrahedron. 2001. V. 57. P. 7909–7917.

16. Lyanov M.A., Kirillova Yu.G., Prokhorov D.I., Lyutik A.I., Esipova O.V., Shvets V.I. Synthesis of two PNA thymine monomers based on L-alanine and glycine // Vestnik MITHT (Fine Chem. Technol.). 2010. V. 5. № 1. P. 104–108. (in Russ.).

17. Chen S.M., Mohan V., Kiely J.S., Griffith M.C., Griffey R H. Molecular dynamics and NMR studies of single-stranded PNAs // Tetrahedron Lett. 1994. V. 35. P. 5105–5108.

18. He W., Crawford M.J., Rapireddy S., Madrid M., Gil R.R., Ly D.H., Achim C. The structure of a γ-modified peptide nucleic acid duplex // Mol. BioSyst. 2010. V. 6. P. 1619–1629.

19. Yeh J.I., Shivachev B., Rapireddy S., Crawford M.J., Gil R.R., Du S., Madrid M., Ly D.H. Crystal structure of chiral γPNA with complementary DNA strand: Insights into the stability and specificity of recognition and conformational preorganization // J. Am. Chem. Soc. 2010. V. 132. P.10717–10727.

For citation:

Dezhenkov A.V., Cheshkov D.A., Prokhorov I.A., Lutik A.I., Kirillova Yu.G. γ-PNA PREORGANIZATION: SYNTHESIS OF MODEL DIMER AND ITS STRUCTURE STUDY BY 2D NMR SPECTROSCOPY. Fine Chemical Technologies. 2017;12(2):62-71. (In Russ.)

Views: 144

ISSN 2410-6593 (Print)
ISSN 2686-7575 (Online)