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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 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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