Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 6, Pages 1241-1250Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.01.050
Keywords
Bis-3-chloropiperidines; Alkylating agents; Nitrogen mustards; Aziridinium ion; DNA cleavage
Funding
- MIUR, Progetti di Ricerca di Interesse Nazionale [2010W2KM5L_006]
- German National Academic Foundation (Studienstiftung des deutschen Volkes)
- International Giessen Graduate Centre for the Life Sciences (GGL)
- German Academic Exchange Service (DAAD)
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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. (C) 2015 Elsevier Ltd. All rights reserved.
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