Bis-3-chloropiperidines containing bridging lysine linkers: Influence of side chain structure on DNA alkylating activity

Abstract

A series of bis-3-chloropiperidines containing lysine linkers was synthesised as DNA alkylating model compounds by using a bidirectional synthetic strategy. These novel piperidine mustard based agents have been evaluated for their alkylating properties towards nucleic acids and were shown to alkylate and cleave DNA with strong preference for guanine residues. Our studies reveal that the introduction of aromatic groups in the side chain of the lysine linker has an impact on DNA alkylating activity. Analysis by ESI mass spectrometry enabled the verification of the reactive aziridinium ion formation. Overall, the results confirm our recently proposed reaction mechanism of bis-3-chloropiperidines.

Keywords: Alkylating agents; Aziridinium ion; Bis-3-chloropiperidines; DNA cleavage; Nitrogen mustards.