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Current Organic Chemistry

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ISSN (Print): 1385-2728
ISSN (Online): 1875-5348

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Research Article

Convenient and Efficient Syntheses of Peptide Nucleic Acid Purine Monomers

Author(s): Ahmed S. Abdelbaky*, Ivan A. Prokhorov, Elena V. Gnuskova, Olga V. Esipova and Yulia G. Kirillova

Volume 23, Issue 19, 2019

Page: [2122 - 2130] Pages: 9

DOI: 10.2174/1385272823666191014161442

Price: $65

Abstract

Currently, peptide nucleic acids (PNAs) play an important role as therapeutic agents, molecular tools for diagnosis and detection of genetic diseases as well as in biosensor probes. This research aims to optimize the synthesis of aeg- and γ-(S)-Me PNA monomers based on L-Ala, intended for oligomerization according to the Boc protocol. The monomers were obtained through the condensation of the corresponding pseudopeptides with carboxymethyl purine nucleic bases. During the work, the optimization of benzyloxycarbonyl- N6-adenine-9-yl-acetic acid and benzyloxycarbonyl-N2-guanine-9-ylacetic acid was carried out. The synthesis of benzyloxycarbonyl-N6-adenine-9-yl-acetic acid was conducted in three stages based on adenine with an overall yield of 22%. At the same time, the conditions for effective recrystallization of the mixture after alkylation of benzyloxycarbonyl-N6-adenine with ethyl bromoacetic acid ether have been developed to isolate the desired N9-regioisomer. Also, the optimization of a known method for producing benzyloxycarbonyl-N2-guanine-9-ylacetic acid from 2-amino-6-chloropurine was carried out. The total yield of the five-stage scheme was 55%. Condensation of aeg- and γ-(S)-Me pseudopeptides with benzyloxycarbonyl-N6-adenine-9-yl-acetic acid and benzyloxycarbonyl-N2-guanine-9-yl-acetic acid was performed by the standard carbodiimide method, DCC/HOBt in DMF followed by the removal of C-terminal methyl protective group by alkaline hydrolysis. The structure of the new compounds obtained was confirmed by spectral analysis methods. This work provides simple and optimized methods for obtaining protected carboxymethyl purine bases and increasing the efficiency of the synthesis and synthesized purine PNA monomers in an acceptable yield.

Keywords: aeg-PNA, γ-PNA, carboxymethyl-nucleobases, adenine, guanine, benzyloxycarbonyl protective group, PNA monomers.

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[1]
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, 254(5037), 1497-1500.
[http://dx.doi.org/10.1126/science.1962210] [PMID: 1962210]
[2]
Tackett, A.J.; Corey, D.R.; Raney, K.D. Non-Watson-Crick interactions between PNA and DNA inhibit the ATPase activity of bacteriophage T4 Dda helicase. Nucleic Acids Res., 2002, 30(4), 950-957.
[http://dx.doi.org/10.1093/nar/30.4.950] [PMID: 11842106]
[3]
Corradini, R.; Sforza, S.; Tedeschi, T.; Totsingan, F.; Manicardi, A.; Marchelli, R. Peptide nucleic acids with a structurally biased backbone. Updated review and emerging challenges. Curr. Top. Med. Chem., 2011, 11(12), 1535-1554.
[http://dx.doi.org/10.2174/156802611795860979] [PMID: 21510833]
[4]
Sugiyama, T.; Kittaka, A. Chiral peptide nucleic acids with a substituent in the N-(2-aminoethy) glycine backbone. Molecules, 2012, 18(1), 287-310.
[http://dx.doi.org/10.3390/molecules18010287] [PMID: 23271467]
[5]
Varizhuk, A.M.; Dezhenkov, A.V.; Kirillova, Y.G. Chiral acyclic pna modifications: Synthesis and properties. Stud. Nat. Prod. Chem., 2016, 47, 261-305.
[http://dx.doi.org/10.1016/B978-0-444-63603-4.00008-5]
[6]
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, 128(31), 10258-10267.
[http://dx.doi.org/10.1021/ja0625576] [PMID: 16881656]
[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 (gammaGPNAs). J. Org. Chem., 2009, 74(4), 1509-1516.
[http://dx.doi.org/10.1021/jo802211n] [PMID: 19161276]
[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, 76(14), 5614-5627.
[http://dx.doi.org/10.1021/jo200482d] [PMID: 21619025]
[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, 10(10)e0140468
[http://dx.doi.org/10.1371/journal.pone.0140468] [PMID: 26469337]
[10]
Dueholm, K.L.; Egholm, M.; Behrens, C.; Christensen, L.; Hansen, H.F.; Vulpius, T.; Petersen, K.H.; Berg, R.H.; Nielsen, P.E.; Buchardt, O. Synthesis of peptide nucleic acid monomers containing the four natural nucleobases: thymine, cytosine, adenine, and guanine and their oligomerization. J. Org. Chem., 1994, 59(19), 5767-5773.
[http://dx.doi.org/10.1021/jo00098a042]
[11]
Uhlmann, E.; Peyman, A.; Breipohl, G.; Will, D.W. PNA: Synthetic polyamide nucleic acids with unusual binding properties. Angew. Chem. Int. Ed. Engl., 1998, 37(20), 2796-2823.
[http://dx.doi.org/10.1002/(SICI)1521-3773(19981102)37:20<2796:AID-ANIE2796>3.0.CO;2-K] [PMID: 29711102]
[12]
Dezhenkov, A.V.; Cheshkov, D.A.; Prokhorov, I.A.; Dezhenkova, L.G.; Shvets, V.I.; Kirillova, Y.G. Regioselective alkylation of guanine derivatives in the synthesis of peptide nucleic acid monomers. Russ. Chem. Bull., 2015, 64(5), 1100-1106.
[http://dx.doi.org/10.1007/s11172-015-0986-3]
[13]
Boyarskaya, N.P.; Kirillova, Y.G.; Stotland, E.A.; Prokhorov, D.I.; Zvonkova, E.N.; Shvets, V.I. Synthesis of two new thymine-containing negatively charged PNA monomers. Dokl. Chem., 2006, 408(1), 57-60.
[http://dx.doi.org/10.1134/S0012500806050016]
[14]
Dezhenkov, A.V.; Tankevich, M.V.; Nikolskaya, E.D.; Smirnov, I.P.; Pozmogova, G.E.; Shvets, V.I.; Kirillova, Y.G. Synthesis of anionic peptide nucleic acid oligomers including γ-carboxyethyl thymine monomers. Mend. Comm., 2015, 25(1), 47-48.
[http://dx.doi.org/10.1016/j.mencom.2015.01.017]
[15]
Lyanov, M.A.; Kirillova, Y.G.; Prokhorov, D.I.; Lyutik, A.I.; Esipova, O.V.; Shvets, V.I. Synthesis of two thymine-containing monomers PNA based on L-alanine and glycine. J. Fine Chem. Technol., 2010, 5(1), 104-108.
[16]
Meltzer, P.C.; Liang, A.Y.; Matsudaira, P. Peptide Nucleic Acids (PNAs): Synthesis of thymine, adenine, guanine, and cytosine nucleobase. J. Org. Chem., 1995, 60(13), 4305-4308.
[http://dx.doi.org/10.1021/jo00118a062]
[17]
Gourishankar, A.; Ganesh, K.N. (α,α-dimethyl)glycyl (dmg) PNAs: Achiral PNA analogs that form stronger hybrids with cDNA relative to isosequential RNA. Artif. DNA PNA XNA, 2012, 3(1), 5-13.
[http://dx.doi.org/10.4161/adna.19185] [PMID: 22679528]
[18]
Timár, Z.; Kovács, L.; Kovács, G.; Schmél, Z. Fmoc/acyl protecting groups in the synthesis of polyamide (peptide) nucleic acid monomers. J. Chem. Soc. Perkin Trans., 2000, 1, 19-26.
[http://dx.doi.org/10.1039/a907832k]
[19]
Boyarskaya, N.P.; Prokhorov, D.I.; Kirillova, Y.G.; Zvonkova, E.N.; Shvets, V.I. Synthesis of protected pseudopeptides from dicarboxylic amino acids by Mitsunobu condensation. Tetrahedron Lett., 2005, 46(43), 7359-7362.
[http://dx.doi.org/10.1016/j.tetlet.2005.08.121]
[20]
Watkins, B.E.; Rapoport, H. Synthesis of benzyl and benzyloxycarbonyl base-blocked 2′-deoxyribonucleosides. J. Org. Chem., 1982, 47(23), 4471-4477.
[http://dx.doi.org/10.1021/jo00144a014]
[21]
Pothukanuri, S.; Pianowski, Z.; Winssinger, N. Expanding the scope and orthogonality of PNA synthesis. Eur. J. Org. Chem., 2008, 2008(18), 3141-3148.
[http://dx.doi.org/10.1002/ejoc.200800141]
[22]
Will, D.W.; Breipohl, G.; Langner, D.; Knolle, J.; Uhlmann, E. The synthesis of polyamide nucleic acids using a novel monomethoxytrityl protecting-group strategy. Tetrahedron, 1995, 51(44), 12069-12082.
[http://dx.doi.org/10.1016/0040-4020(95)00766-2]
[23]
Thomson, S.A.; Josey, J.A.; Cadilla, R.; Gaul, M.D.; Hassman, C.F.; Luzzio, M.J.; Pipe, A.J.; Reed, K.L.; Ricca, D.J.; Wiethe, R.W.; Noble, S.A. Fmoc mediated synthesis of peptide nucleic acids. Tetrahedron, 1995, 51(22), 6179-6194.
[http://dx.doi.org/10.1016/0040-4020(95)00286-H]
[24]
Heuer-Jungemann, A.; Howarth, N.M.; Saudatu, C.; Rosair, G.M. Development of a convenient route for the preparation of the N2-Cbz-protected guaninyl synthon required for Boc-mediated PNA synthesis. Tetrahedron Lett., 2013, 54(46), 6275-6278.
[http://dx.doi.org/10.1016/j.tetlet.2013.09.034]
[25]
Fletcher, S.; Shahani, V.M.; Lough, A.J.; Gunning, P.T. Concise access to N9-mono-, N2-mono-and N2, N9-di-substituted guanines via efficient Mitsunobu reactions. Tetrahedron, 2010, 66(25), 4621-4632.
[http://dx.doi.org/10.1016/j.tet.2010.03.118]
[26]
Falkiewicz, B.; Kołodziejczyk, A.S.; Liberek, B.; Wiśniewski, K. Synthesis of achiral and chiral peptide nucleic acid (PNA) monomers using Mitsunobu reaction. Tetrahedron, 2001, 57(37), 7909-7917.
[http://dx.doi.org/10.1016/S0040-4020(01)00759-1]
[27]
Manna, A.; Rapireddy, S.; Sureshkumar, G.; Ly, D.H. Synthesis of optically pure γPNA monomers: A comparative study. Tetrahedron, 2015, 71(21), 3507-3514.
[http://dx.doi.org/10.1016/j.tet.2015.03.052] [PMID: 30792557]

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