Reprogramming the Mechanism of Action of Chlorambucil by Coupling to a GQuadruplex Ligand
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Publication Date
2014-04-03Journal Title
Journal of the American Chemical Society
ISSN
0002-7863
Publisher
ACS
Volume
136
Pages
5860-5863
Language
English
Type
Article
Metadata
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Di, A. M., McLuckie, K. I., & Balasubramanian, S. (2014). Reprogramming the Mechanism of Action of Chlorambucil by Coupling to a GQuadruplex Ligand. Journal of the American Chemical Society, 136 5860-5863. https://doi.org/10.1021/ja5014344
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 M doses, without reac-tivity 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 selec-tively 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 im-portant 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.
Identifiers
External DOI: https://doi.org/10.1021/ja5014344
This record's URL: https://www.repository.cam.ac.uk/handle/1810/245630
Rights
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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