Structure-activity relationships for substituted bis(acridine-4-calrboxamides): A new class of anticancer agents

Citation
Sa. Gamage et al., Structure-activity relationships for substituted bis(acridine-4-calrboxamides): A new class of anticancer agents, J MED CHEM, 42(13), 1999, pp. 2383-2393
Citations number
37
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
00222623 → ACNP
Volume
42
Issue
13
Year of publication
1999
Pages
2383 - 2393
Database
ISI
SICI code
0022-2623(19990701)42:13<2383:SRFSB>2.0.ZU;2-3
Abstract
A series of acridine-substituted bis(acridine-4-carboxamides) linked by a ( CH2)(3)N(Me)(CH2)(3) chain have been prepared by reaction of the isolated i midazolides of the substituted acridine-4-carboxylic acids with N,N-bis(3-a minopropyl)methylamine. These dimeric analogues of the mixed topoisomerase I/II inhibitor N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA), cur rently in clinical trial, show superior potencies to the corresponding mono meric DACA analogues in a panel, of cell lines, including wild-type (JL(C)) and mutant (JL(A) and JL(D)) forms of human Jurkat leukemia. The latter mu tant lines are resistant to topoisomerase II targeted agents because of low er levels of the enzyme. Analogues with small substituents (e.g., Me, Cl) a t the acridine 5-position were clearly superior, with IC50's as low as 2 nM against the Lewis lung carcinoma and 11 nM against JL(C). Larger substitue nts at any position caused a steady decrease in potency, likely due to lowe ring of DNA binding affinity. A small series of analogues of the most poten t bis(5-methylDACA) compound, with second substituents (Me and Cl) in the 1 - or 8- position had broadly similar potencies to the 5-Me compound, indica ting that, while the 1- and 8-substituents are acceptable, they add little to the enhancing effect of the 5-methyl group. All of the compounds were at least equitoxic (some up to 4-fold more cytotoxic) against the mutant Jurk at lines than in the wild-type, consistent with a relatively greater effect on topoisomerase I compared with topoisomerase II. The bis(5-methylDACA) c ompound was found to inhibit the action of purified topoisomerase I in a ce ll-free assay. Compounds were on average 10-fold less cytotoxic in an MCF7 breast cancer line overexpressing P-glycoprotein than in the wild-type line and showed some selectivity for colon tumor lines in the NCI human tumor c ell line panel. Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo at substan tially lower doses than DACA. The bis(acridine-4-carboxamides) represent a new and interesting class of potent topoisomerase inhibitors.