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NOVEL PEPTIDE NUCLEIC ACID MONOMERS FROM TRIPLEX-FORMING BASES

Zoltán Timár a , Péter Forgó b , Zoltán Kele a , Lajos Kovács a, * University of Szeged, a Department of Medicinal Chemistry and b Department of Organic Chemistry, 6720 Szeged, Dóm tér 8, Hungary. * E-mail: kovacs@ovrisc.mdche.u-szeged.hu.

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NOVEL PEPTIDE NUCLEIC ACID MONOMERS FROM TRIPLEX-FORMING BASES

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  1. Zoltán Timára, Péter Forgób, Zoltán Kelea, Lajos Kovácsa, * University of Szeged, aDepartment of Medicinal Chemistry and bDepartment of Organic Chemistry, 6720 Szeged, Dóm tér 8, Hungary. *E-mail: kovacs@ovrisc.mdche.u-szeged.hu NOVEL PEPTIDE NUCLEIC ACID MONOMERSFROM TRIPLEX-FORMING BASES Introduction Oligonucleotide-directed triple-helix formation is one of the most powerful methods for the sequence-specific recognition of double-helical DNA. According to our previous theoretical calculations,1 the artificial nucleobases containing 2-aminopyridine (N) and 2-aminoquinoline (Q) moieties, respectively, deem to be good candidates as universal triple helix-forming agents both for the A:T and T:A base pairs by Hoogsteen-type H-bonding. So far compounds capable to selectively bind to both strands of DNA have not been prepared. On the other hand, peptide nucleic acids (PNA) are very promising nucleic acid mimics.2 We wish to report herein our efforts directed toward the chemical synthesis of PNA monomers containing the above triplex-forming heterocycles. Geometry of the natural triplex-forming nucleobases (C:G|C+, C:G|G, T:A|T and T:A|A. Colon: Watson-Crick, vertical bar: Hoogsteen-type binding) Geometry of the designed triplex-forming nucleobases (T:A|N and Q|A:T) Isomorphism of the natural and designed triplex-forming nucleobases Results The 2-aminopyridine (N) unit was prepared starting from ethyl 3-pyridylacetate using the procedure by Wachi et al.3 but the yields were rather low therefore an alternative approach was sought. Thus, the same starting material was subjected to Minisci reaction with formamide4 and subsequent Hofmann degradation is in progress. N The 2-aminoquinoline (Q) unit was prepared from 3-methyl-4-nitrobenzoic acid through the 3-carbaldehyde followed by a Horner-Wadsworth-Emmons chain elongation. The reduction and cyclisation of the 3-(2-cyanovinyl) derivative to the desired quinoline was accomplished using tin(II) salts or, preferably, sodium dithionite. The latter method made the purification of the product more convenient. The acids protected with anisoyl and 4-tert-butylbenzoyl groups will be coupled to Fmoc-protected tert-butyl N-(2-aminoethyl)glicinate and their use in the synthesis of the corresponding PNA oligomers is in progress. Q References 1. R. Fenyõ, Z. Timár, I. Pálinkó and B. Penke (2000): J. Mol. Struct. (Theochem), 496, 101-105. 2. P. E. Nielsen (1999): Peptide nucleic acid. A molecule with two identities. Acc. Chem. Res.32, 624-630. 3.K. Wachi and A. Terada (1980): Chem. Pharm. Bull., 28, 465-472. 4. J. A. Joule, K. Mills and G. F. Smith (1995): Heterocyclic chemistry. 3rd ed. Chapman and Hall, London. p. 26.

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