Synthesis and properties of ester-linked peptide nucleic acid prodrug conjugates

Nadia Bendifallah; Edward Kristensen; Otto Dahl; Uffe Koppelhus; Peter E. Nielsen

doi:10.1021/bc025621r

Synthesis and properties of ester-linked peptide nucleic acid prodrug conjugates

Nadia Bendifallah, Edward Kristensen, Otto Dahl, Uffe Koppelhus, Peter E. Nielsen

Transcription, RNA, and Gene Medicine Program

12 Citations (Scopus)

Abstract

A Boc-protected amino acid containing an ester function, 2-([N-Boc-glycyl]oxymethyl)benzoic acid, has been synthesized and incorporated into peptide nucleic acid (PNA) oligomers. In model experiments it is found that the ester is fairly stable in aqueous solution at pH 7.4 and 37 degrees C (t(1/2) = 6 h), whereas it is rapidly cleaved in mouse serum and in kidney and liver homogenates (t(1/2) = 0.1-0.5 min). Furthermore, ester-linked fatty acid PNA conjugates targeted to an aberrant splice site in luciferase mRNA were prepared and shown to be twice as potent for inducing active luciferase as the corresponding conjugate not containing the linker. Thus, a PNA prodrug approach may be useful for both ex vivo as well as in vivo applications.

Original language	English
Journal	Bioconjugate Chemistry
Volume	14
Issue number	3
Pages (from-to)	588-92
Number of pages	5
ISSN	1043-1802
DOIs	https://doi.org/10.1021/bc025621r
Publication status	Published - 22 May 2003

Keywords

Animals
Esters
Female
HeLa Cells
Humans
Mice
Peptide Nucleic Acids/chemical synthesis
Prodrugs/chemical synthesis
Transfection/methods

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10.1021/bc025621r

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title = "Synthesis and properties of ester-linked peptide nucleic acid prodrug conjugates",

abstract = "A Boc-protected amino acid containing an ester function, 2-([N-Boc-glycyl]oxymethyl)benzoic acid, has been synthesized and incorporated into peptide nucleic acid (PNA) oligomers. In model experiments it is found that the ester is fairly stable in aqueous solution at pH 7.4 and 37 degrees C (t(1/2) = 6 h), whereas it is rapidly cleaved in mouse serum and in kidney and liver homogenates (t(1/2) = 0.1-0.5 min). Furthermore, ester-linked fatty acid PNA conjugates targeted to an aberrant splice site in luciferase mRNA were prepared and shown to be twice as potent for inducing active luciferase as the corresponding conjugate not containing the linker. Thus, a PNA prodrug approach may be useful for both ex vivo as well as in vivo applications.",

keywords = "Animals, Esters, Female, HeLa Cells, Humans, Mice, Peptide Nucleic Acids/chemical synthesis, Prodrugs/chemical synthesis, Transfection/methods",

author = "Nadia Bendifallah and Edward Kristensen and Otto Dahl and Uffe Koppelhus and Nielsen, {Peter E.}",

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TY - JOUR

T1 - Synthesis and properties of ester-linked peptide nucleic acid prodrug conjugates

AU - Bendifallah, Nadia

AU - Kristensen, Edward

AU - Dahl, Otto

AU - Koppelhus, Uffe

AU - Nielsen, Peter E.

PY - 2003/5/22

Y1 - 2003/5/22

N2 - A Boc-protected amino acid containing an ester function, 2-([N-Boc-glycyl]oxymethyl)benzoic acid, has been synthesized and incorporated into peptide nucleic acid (PNA) oligomers. In model experiments it is found that the ester is fairly stable in aqueous solution at pH 7.4 and 37 degrees C (t(1/2) = 6 h), whereas it is rapidly cleaved in mouse serum and in kidney and liver homogenates (t(1/2) = 0.1-0.5 min). Furthermore, ester-linked fatty acid PNA conjugates targeted to an aberrant splice site in luciferase mRNA were prepared and shown to be twice as potent for inducing active luciferase as the corresponding conjugate not containing the linker. Thus, a PNA prodrug approach may be useful for both ex vivo as well as in vivo applications.

AB - A Boc-protected amino acid containing an ester function, 2-([N-Boc-glycyl]oxymethyl)benzoic acid, has been synthesized and incorporated into peptide nucleic acid (PNA) oligomers. In model experiments it is found that the ester is fairly stable in aqueous solution at pH 7.4 and 37 degrees C (t(1/2) = 6 h), whereas it is rapidly cleaved in mouse serum and in kidney and liver homogenates (t(1/2) = 0.1-0.5 min). Furthermore, ester-linked fatty acid PNA conjugates targeted to an aberrant splice site in luciferase mRNA were prepared and shown to be twice as potent for inducing active luciferase as the corresponding conjugate not containing the linker. Thus, a PNA prodrug approach may be useful for both ex vivo as well as in vivo applications.

KW - Animals

KW - Esters

KW - Female

KW - HeLa Cells

KW - Humans

KW - Mice

KW - Peptide Nucleic Acids/chemical synthesis

KW - Prodrugs/chemical synthesis

KW - Transfection/methods

U2 - 10.1021/bc025621r

DO - 10.1021/bc025621r

M3 - Journal article

C2 - 12757383

SN - 1043-1802

VL - 14

SP - 588

EP - 592

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

IS - 3

ER -

Synthesis and properties of ester-linked peptide nucleic acid prodrug conjugates

Abstract

Keywords

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