Structure-activity relationships for acridine-substituted analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide

Journal of Medicinal Chemistry
J A SpicerW A Denny

Abstract

The mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) is currently in clinical trial as an anticancer drug. A series of acridine-substituted analogues were prepared, using a new synthetic route to substituted acridine-4-carboxylic acids (conversion of substituted diphenylamine diacid monoesters to the corresponding aldehydes and mild acid-catalyzed ring closure to form the acridines directly). The analogues were evaluated in a panel of cell lines which included wild-type (JLC) and mutant (JLA and JLD) forms of the human Jurkat leukemia line. The latter mutant lines are resistant to topoisomerase II targeted agents due to lower levels of the enzyme. Structure-activity studies suggest that the electronic properties of the substituents do not markedly affect cytotoxicity, but steric bulk is important, with larger groups leading to loss of activity. The compounds fell broadly into two categories. The majority had cytotoxicities similar to (or lower than) that of DACA itself and were equitoxic in all the Jurkat lines, suggesting a relatively greater effect on topoisomerase I compared with topoisomerase II. Most of the 5-substituted derivatives and the 7-Ph compound were more cytotoxic than DA...Continue Reading

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Citations

Sep 25, 1999·Bioorganic & Medicinal Chemistry Letters·O LavergneD C Bigg
Jul 6, 2000·Bioorganic & Medicinal Chemistry·L W DeadyW A Denny
Nov 9, 2012·Journal of Medicinal Chemistry·Andrea KurzwernhartChristian G Hartinger
Nov 13, 2008·Cytotechnology·R E Parchment, A Pessina
Jul 2, 2005·Expert Opinion on Investigational Drugs·W A Denny
May 20, 2015·Organic & Biomolecular Chemistry·Ting-Jun WangMing-Hua Xu
Jun 12, 2012·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Rubén FerreiraRamon Eritja
Jul 27, 2007·Chemistry : a European Journal·Lutz F TietzeChristian Stadler
Mar 14, 2014·Chembiochem : a European Journal of Chemical Biology·Genevieve L EvansJ Shaun Lott
Mar 7, 2003·Journal of Medicinal Chemistry·Leslie W DeadyWilliam A Denny
May 12, 2015·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Jana JanočkováMária Kožurková

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