Selective Delivery of a Quinone Methide Precursor by Peptide Nucleic Acids

Abstract

Quinone methides (QMs) are electrophilic intermediates that can be generated in vivo to alkylate DNA and function as anti-cancer drugs. Previously, DNA-QM conjugates have shown the ability to selectively deliver a QM to specific sequences of DNA. Peptide nucleic acids (PNAs) conjugates of QM are now being developed since PNA binds DNA with higher affinity than natural DNA. Synthesis of PNA oligomers and conjugation of the PNA to QM precursor are reported here. Synthesis of peptides was used to study the optimum conditions for preparation of the ultimate peptide-PNA conjugate. Both peptides and peptide-PNA have been synthesized after optimizing solid-phase techniques. Conditions for coupling a quinone methide precursor (QMP) and peptide-PNA conjugates were also evaluated. 8-Amino-3,6-dioxaoctanoic acid that links PNA and QMP is essential for coupling. MOPS buffer containing the peptide-PNA and an acetonitrile/dimethylformamide mixture containing QMP were combined for coupling. Finally, reactive QM derivative of peptide-PNA-QM was studied.