title: 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.
authors.affiliation: Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany; Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Zuravka
authors.affiliation: Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Roesmann
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Sosic
authors.affiliation: Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring 58, 35392 Giessen, Germany. Electronic address: richard.goettlich@uni-giessen.de.
authors.forename: Richard
authors.initials: R
authors.lastname: Göttlich
authors.affiliation: Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy. Electronic address: barbara.gatto@unipd.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gatto
mesh_terms: D000478:Alkylation / Q000187:drug effects; D004247:DNA / Q000737:chemistry* / Q000187:drug effects*; D053837:DNA Cleavage; D008239:Lysine / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010957:Plasmids
chemical_list: D010880:Piperidines; D004247:DNA; D008239:Lysine
keywords: Alkylating agents; Aziridinium ion; Bis-3-chloropiperidines; DNA cleavage; Nitrogen mustards