From amsacrine to DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide): selectivity for topoisomerases I and II among acridine derivatives

European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)
G J FinlayB C Baguley

Abstract

A number of acridine derivatives, including the clinical antileukaemia agent amsacrine and the experimental agent DACA (N-[2-(dimethylamino)ethyl]acridine-4-carboxamide), target the enzyme topoisomerase II. We demonstrate here that DACA induces DNA cleavage in the presence of topoisomerase I as well as of topoisomerase II. We also investigate a series of acridine derivatives which link amsacrine to DACA in terms of DNA binding, topoisomerase poisoning and biological activity. The presence of an acridine 4-linked N-2-(dimethylamino)ethyl group provides both a pronounced G-C preference for DNA binding and activity towards topoisomerase I. The removal of the anilino side chain of amsacrine, in combination with the presence of the N-2-(dimethylamino)ethyl group, provides in vitro biological activity against "atypical" multidrug resistant leukaemia lines with low topoisomerase II activity. Among these compounds, suppression of the ionisation of the acridine nitrogen to produce the compound DACA is associated with experimental activity against solid tumours. The addition of an acridine 2-chloro substituent to DACA suppresses the stimulation of topoisomerase II-dependent DNA cleavage but increases stimulation of topoisomerase I cleava...Continue Reading

References

Jan 1, 1978·Nucleic Acids Research·B C Baguley, E M Falkenhaug
Apr 18, 1990·Journal of the National Cancer Institute·G J FinlayW Judd
Jul 4, 1990·Journal of the National Cancer Institute·P SkehanM R Boyd
Dec 17, 1989·Biochimica Et Biophysica Acta·P D'Arpa, L F Liu
Jan 1, 1989·Cancer Investigation·Z A Arlin
Mar 1, 1988·Proceedings of the National Academy of Sciences of the United States of America·D K Trask, M T Muller
Nov 1, 1983·European Journal of Cancer & Clinical Oncology·B C BaguleyW R Wilson
Jan 1, 1995·Cancer Chemotherapy and Pharmacology·B C BaguleyE Marshall
Nov 12, 1993·Journal of Medicinal Chemistry·Y L JaninE Bisagni

❮ Previous
Next ❯

Citations

Jan 5, 2008·Cancer Chemotherapy and Pharmacology·David J A BridewellBruce C Baguley
Aug 6, 2008·Cancer Chemotherapy and Pharmacology·Andrew G JobsonCaroline A Austin
Mar 12, 2009·Cancer Chemotherapy and Pharmacology·Steven J WolfDaniel R Catchpoole
Sep 17, 2013·Cancer Chemotherapy and Pharmacology·Pradeep B LukkaBruce C Baguley
Aug 17, 1996·Mutation Research·L R Ferguson, B C Baguley
Jan 30, 2002·Bioorganic & Medicinal Chemistry Letters·Shouming WangWilliam A Denny
Jul 6, 2000·Bioorganic & Medicinal Chemistry·L W DeadyW A Denny
Mar 22, 2006·Nucleic Acids Research·Kathryn L GilroyCaroline A Austin
Sep 23, 2000·Anti-cancer Drugs·M H NealeI A Cree
May 4, 2001·Anti-cancer Drugs·A J StewartP A Charlton
Dec 13, 2006·Anti-cancer Drugs·Louisa J LewisHelen M Coley
Aug 25, 2011·BMC Cell Biology·Steven J WolfDaniel R Catchpoole
May 3, 2002·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Bruce C Baguley
May 8, 2014·Cancer Chemotherapy and Pharmacology·Ying Yi ChenBruce C Baguley
Jul 2, 2005·Expert Opinion on Investigational Drugs·W A Denny
May 15, 2012·Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy·R SubashiniPavan Kumar Gullanki
May 6, 2009·International Journal of Biological Macromolecules·Zuzana VantováJán Imrich
Sep 14, 2011·Cancer Science·Saadia HassanPeter Nygren
May 12, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Jana JanočkováMária Kožurková
Apr 25, 2013·Expert Opinion on Therapeutic Patents·Daulat B Khadka, Won-Jea Cho
Jun 19, 2010·Mutation Research·Zhigang LinLynnette R Ferguson
Jan 15, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·D J PropperC Twelves
Jul 1, 2004·Bioorganic & Medicinal Chemistry Letters·Ahmed KamalP Praveen Kumar
Oct 1, 2004·Anti-cancer Drugs·Federica Di NicolantonioIan A Cree
Aug 20, 2004·The Journal of Biological Chemistry·Jixun DaiDanzhou Yang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimicrobial Resistance (ASM)

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.

Antimicrobial Resistance

Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections.