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SYNTHESIS OF P EPTIDE N UCLEIC A CID (PNA) OLIGOMERS AND THEIR CONJUGATES

SYNTHESIS OF P EPTIDE N UCLEIC A CID (PNA) OLIGOMERS AND THEIR CONJUGATES . Györgyi Kovács 1* , Zoltán Timár 1* , Zoltán Kupihár 1* , Zoltán Kele 1 , Péter Forgó 2 , Lajos Kovács 1*. University of Szeged, 1 Institute of Medicinal Chemistry, *Laboratory Of Nucleic Acid,

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SYNTHESIS OF P EPTIDE N UCLEIC A CID (PNA) OLIGOMERS AND THEIR CONJUGATES

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  1. SYNTHESIS OF PEPTIDE NUCLEIC ACID (PNA) OLIGOMERS AND THEIR CONJUGATES Györgyi Kovács1* , Zoltán Timár 1* , Zoltán Kupihár 1* , Zoltán Kele 1, Péter Forgó 2, Lajos Kovács 1* University of Szeged, 1 Institute of Medicinal Chemistry, *Laboratory Of Nucleic Acid, 2 Department Of Organic Chemistry, 6720 Szeged, Dóm tér 8 Introduction Antisense and antigene effect  molecular biology and medicinal chemistry Advantage in vivo stability and strong hybridization disadvantage poor cellular uptake and low activity Possible solutionsPNA-peptide and PNA-oligonucleotide conjugates Schematic representation of PNA oligomers Synthesis of our own PNA monomers using Fmoc/acyl protecting groups, as they are compatibleboth with peptide and oligonucleotide synthesis protocols (conjugate). Aims Synthesis of PNA oligomers, PNA-peptide and PNA-oligonucleotide conjugates from our monomers Results Problems with the oligomer synthesis and the proposed solutions optimization of the coupling step (efficiency of coupling agents in solution phase): I. (HBTU/HOBt/DIPEA/Lutidine) < (HATU/ DIPEA/ Lutidine) < BET/ DIPEA < CMP/ DIPEA 76 %90 %98-99 % > 99 % Selection of the solid phase II. compatible with peptide and oligonucleotide synthesis, acyl and PNA removal in one step with aq. NH3 but: oligoethylene-glycol chains disturb the analysis TentaGel II.1. The mass spectra of PNAs, prepared on Tentagel, showed [M+70]+ions (not complete removal of Ibu) and valuessmaller than M+ II.2. to check the efficiency of the coupling and acyl protecting group removal (the most critical steps) Wang CPG II.3. Synthesis of the PNA-oligonucleotide conjugates III. removal of the acyl protecting group aq. NH3 order of stability: Ibu > An> 4-tBuBz H-Gly-(gIbu)5-Lys-OH 50 °C, ON PNA synthesis monomer : HATU: DIPEA: lutidine 3: 2.7:3.3:3.3 20minutes; DMF PNA-oligonucleotide conjugate Peptide-PNA conjugate PNA-linker2-5'-oligonucleotide- 3' H-Cys-ArgArgMetLysTrpLysLys-OH + H-Cys(Npys)-gIbuaAnaAnc4tBuBzaAntc4tBuBzaAntgIbugIbutc4tBuBzgIbut -Lys-OH 5'-oligonucleotide-3'-linker-PNA Financial support: OTKA T 022551 FKFP 0597/1999 linker Dr. Gyula Sági et al.

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