Published in

American Chemical Society, Journal of the American Chemical Society, 16(136), p. 5860-5863, 2014

DOI: 10.1021/ja5014344

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Reprogramming the Mechanism of Action of Chlorambucil by Coupling to a G-Quadruplex Ligand

Journal article published in 2014 by Marco Di Antonio ORCID, Keith I. E. McLuckie, Shankar Balasubramanian
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

The nitrogen mustard Chlorambucil (Chl) generates covalent adducts with double-helical DNA and inhibits cell proliferation. Among these adducts inter-strand crosslinks (ICLs) are the most toxic, as they stall replication by generating DNA double strand breaks (DSBs). Intra-strand crosslinks generated by Chl are repaired by a dedicated Nucleotide Excision Repair (NER) enzyme. We synthesized a novel crosslinking agent that combines Chl with the G-quadruplex (G4) ligand PDS (PDS-Chl). We demonstrated that PDS-Chl alkylates G4 structures at low μM doses, without reactivity towards double- or single-stranded DNA. Since intra-molecular G4s arise from a single DNA strand, we reasoned that preferential alkylation of such structures might prevent the generation of ICLs, whilst favoring intra-strand crosslinks. We observed that PDS-Chl selectively impairs growth in cells genetically deficient in NER, but did not show any sensitivity to the repair gene BRCA2, involved in double-stranded break repair. Our findings suggest that G4 targeting of this clinically important alkylating agent alters the overall mechanism of action. These insights may inspire new opportunities for intervention in diseases specifically characterised by genetic impairment of NER, such as skin and testicular cancers.