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

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.