Amonafide is a DNA intercalator and topoisomerase II inhibitor in clinical 
development for the treatment of neoplastic diseases. Amonafide contains a free 
arylamine, which causes it to be metabolized in humans by N-acetyl transferase-2 
(NAT2) into a toxic form. To eliminate the NAT2 acetylation of amonafide while 
retaining the anticancer properties, we have synthesized nine derivatives that 
are structurally similar to amonafide that should not be acetylated. Eight 
derivatives have arylamines at the 6-position (vs. 5-position of amonafide) and 
one derivative completely lacks the arylamine. The derivative with a free amine 
in the 6-position and one with a substituted amine in the 6-position are not 
acetylated, whereas amonafide is extensively acetylated as determined by an NAT2 
assay. The biological activities of these compounds were evaluated to determine 
whether they behaved similarly to amonafide in purified systems and in vitro. We 
found that three compounds had similar cancer cell-selective growth inhibition 
to amonafide, while retaining similar subcellular localization, DNA 
intercalation and topoisomerase II inhibition activities. In addition, these 
compounds were able to eliminate a marker of metastatic potential, the 
perinucleolar compartment. These three compounds (named numonafides) might thus 
allow for better patient management than those treated with amonafide; hence, 
they should be developed further as potential clinical replacements for 
amonafide or as novel anticancer drugs.