Optimization of synthetic route to PNA-T-OH monomers

Yıl 2018, Cilt: 5 Sayı: 2, 457 - 468, 01.01.2018

Onur Alpturk Z. Sevcan Yeşilbaş Gözde Sarıoğlu Aslı Karaçaylı Aytül Saylam Salih Özçubukcu

https://doi.org/10.18596/jotcsa.380410

Öz

Peptide nucleic acids are synthetic molecules
crafted to mimic natural nucleic acids, and thus, they are widely utilized in
many chemical, and, biomedical applications. Although there exist many
approaches to synthesize monomers to date, there is still room to improve these
methodologies. With this motivation, we compared some widely utilized synthetic
routes to obtain N-Boc-PNA-T-OH, and N-Fmoc-PNA-T-OH. Our results indicate
that N-Boc-ethylenediamine is the
most pivotal intermediate in the chemistry of PNA, and synthetic route commencing
with this material affords these two PNA monomers in relatively high yield, and
purity, while being very reproducible. 

Anahtar Kelimeler

Peptide nucleic acid, monomer synthesis, optimization

Kaynakça

• Referans1. Nielsen PE, Egholm M, Berg RH, Buchardt O. Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide. Science 1991; 254:1497–1500.
• Referans2. Jensen KK, Ӧrum H, Nielsen PE, Nordén B. Kinetics for hybridization of peptide nucleic acids (PNA) with DNA and RNA studied with the BIAcore technique. Biochemistry 1997; 36(16):5072–5077.
• Referans3. Ray A, Nordén B. Peptide nucleic acid (PNA): its medical and biotechnical applications and promise for the future. FASEB J. 2000; 14(9):1041–1060.
• Referans4. Brandt O, Feldner J, Stephan A, Schröder M, Schnölzer M, Arlinghaus HF, Hoheisel JD, Jacob A. PNA microarrays for hybridization of unlabelled DNA samples. Nucleic Acids Res. 2003; 31(19):e119. Referans5. Tian K, He Z, Wang Y, Chen S-J, Gu L-Q. Designing a Polycationic Probe for Simultaneous Enrichment and Detection of MicroRNAs in a Nanopore. ACS Nano 2013; 7(5):3962–3969.
• Referans6. Stender H, Williams B, Coull J. PNA fluorescent in situ hybridization (FISH) for rapid microbiology and cytogenic analysis. Methods Mol. Biol. 2014; 1050:167-178.
• Referans7. Manna A, Rapireddy S, Sureshkumar G, Ly DH. Synthesis of optically pure γPNA monomers: a comparative study. Tetrahedron 2015; 71(21):3507-3514.
• Referans8. Falkiewicz B, Kozyra A, Kolodziejczyk AS, Liberek B, Wisniewski K. New procedure of the Mitsunobu reaction as the key step in peptide nucleic acid (PNA) monomers synthesis. Nucleic Acids Symp. Ser. 1999; 42:9-10.
• Referans9. Bonnard V, Azoulay S, Di Giorgio A, Patino N. “Polyamide Amino Acids”: a new class of RNA Ligands. Chem. Commun. 2009; 17:2302–2304.
• Referans10. Aldrian-Herrada G, Rabié A, Wintersteiger R, Brudiou J. Solid-phase synthesis of peptide nucleic acid (PNA) monomers and their oligomerization using disulphide anchoring linkers. J. Pept. Sci. 1998; 4(4):266-281.
• Referans11. Feagin TA, Shah NI, Heemstra JM. Convenient and Scalable Synthesis of Fmoc-Protected Peptide Nucleic Acid Backbone. J. Nucleic Acids 2012; 354549.
• Referans12. Debaene F, Da Silva JA, Pianowski Z, Duran FJ, Winssinger N. Expanding the scope of PNA-encoded libraries: divergent synthesis of libraries targeting cysteine, serine and metalloproteases as well as tyrosine phosphatases. Tetrahedron 2007; 63(28):6577–6586.
• Referans13. Altenbrunn F, Seitz O. O-Allyl protection in the Fmoc based synthesis of difficult PNA. Org. Biomol. Chem. 2008; 6(14):2493–2498.
• Referans14. Coban G, Kose FA, Kirmizibayrak PB, Pabuccuoglu V. Synthesis, biological activity screening and molecular modeling study of acylaminoacetamide derivatives. Med. Chem. Res. 2015; 24(10):3710-3729.
• Referans15. Falkiewicz B, Kolodziejczyk AS, Liberek B, Wiśniewski K. Synthesis of achiral and chiral peptide nucleic acid (PNA) monomer using Mitsunobu reaction. Tetrahedron, 2001; 57(37):7909-7917.
• Referans16. Fox BM, Beck HP, Roveto PM, Kayser F, Cheng Q, Dou H, Williamson T, Treanor J, Liu H, Jin L, Xu G, Ma J, Wang S, Olson SH. A Selective Prostaglandin E2 Receptor Subtype 2 (EP2) Antagonist Increases the Macrophage-Mediated Clearance of Amyloid-Beta Plaques. J. Med. Chem. 2015; 58(13):5256–5273.
• Referans17. Patino N, Di Giorgio C, Dan-Covalciuc C, Peytou V, Terreux R, Cabrol-Bass D, Bailly C, Condom R. Modelling, synthesis and biological evaluation of an ethidium–arginine conjugate linked to a ribonuclease mimic directed against TAR RNA of HIV-1. Eur. J. Med. Chem. 2002; 37:573–584.
• Referans18. Albrecht M, Zauner J, Eisele T, Weis P. The Synthesis of Catechol and 8-Hydroxyquinoline Derivatives with Short Peptide-Type Side Chains: Metal Complex Ligands with Additional Receptor Properties. Synthesis 2003; 7:1105-1111.
• Referans19. Fader LD, Boyd M, Tsantrizos YS. Backbone Modifications of Aromatic Peptide Nucleic Acid (APNA) Monomers and Their Hybridization Properties with DNA and RNA. J. Org. Chem. 2001; 66(10):3372-3379.
• Referans20. Sahu B, Sacui I, Rapireddy S, Zanotti KJ, Bahal R, Armitage BA, Ly DH. 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.
• Referans21. Pensato S, Saviano M, Bianchi N, Borgatti M, Fabbri E. c-Hydroxymethyl PNAs: Synthesis, interaction with DNA and inhibition of protein/DNA interactions. Bioorg. Chem. 2010; 38(5):196–201.
• Referans22. Slaitas A, Yeheskiely E. A Novel N-(Pyrrolidinyl-2-methyl) glycine-Based PNA with a Strong Preference for RNA over DNA. Eur. J. Org. Chem. 2002; 14:2391-2399.
• Referans23. Egholm M, Buchardt O, Nielsen PE, Berg RH. Peptide Nucleic Acids (PNA) Oligonucleotide Analogues with an Achiral Peptide Backbone. J. Am. Chem. Soc. 1992; 114(5):1895-1897.
• Referans24. Dueholm KL, Egholm M, Behrens C, Christensen L, Hansen HF, Vulpius T, Petersen KH, Berg RH, Nielsen PE, 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.
• Referans25. Thomson SA, Josey JA, Cadilla R, Gaul MD, Hassman CF, Luzzio MJ, Pipe AJ, Reed KL, Ricca DJ, Wiethe RW, Noble SA. Fmoc mediated synthesis of Peptide Nucleic Acids. Tetrahedron 1995; 51(22):6179-6194.
• Referans26. Feagin TA, Shah NI, Heemstra JM. Convenient and Scalable Synthesis of Fmoc-Protected Peptide Nucleic Acid Backbone. J. Nucleic Acids 2012; 354549.
• Referans27. Wisniewski K, Joswig S, Falkiewicz B, Kolodziejczyk A. A New Method of the Synthesis of Gly-Aaa Type Reduced Peptide Bond. Pol. J. Chem. 1997; 71(10):1506-1509.
• Referans28. The use of N-Boc-ethylenediamine in high excess is reported to halt di-alkylation (see ref19).
• Referans29. In both cases, the product could only be salvaged from solid support through excessive washing with ethyl acetate.
• Referans30. To synthesize backbone 8 without any chromatographic purification, see: Viirre RD, Hudson RHE. A Convenient and Scalable Synthesis of Ethyl N-[(2-Boc-amino)ethyl]glycinate and Its Hydrochloride. Key Intermediates for Peptide Nucleic Acid Synthesis. J. Org. Chem. 2003; 68(4):1630-1632.
• Referans31. For instance, see: Li P, Zhan C, Zhang S, Ding X, Guo F, He S, Yao J. Alkali metal cations control over nucleophilic substitutions on aromatic fused pyrimidine-2,4-[1H,3H]-diones: towards new PNA monomers. Tetrahedron 2012; 68(43):8908-8915.
• Referans32. For instance, see: Ellipilli, S.; Palvai, S.; Ganesh, K. N. Fluorinated Peptide Nucleic Acids with Fluoroacetyl Side Chain Bearing 5 (F/CF3) Uracil: Synthesis and Cell Uptake Studies. J. Org. Chem. 2016; 81:6364−6373.