Potential antitumor agents. 40. Orally active 4,5-disubstituted derivatives of amsacrine.

The DNA-intercalating agent amsacrine is an effective drug for the treatment of human leukemias and lymphomas but has minimal solid tumor activity. As a first step in identifying analogues with a wider spectrum of activity, a comparison was made of the in vivo antileukemic (P-388) activity of amsacrine analogues given by oral (po) and intraperitoneal (ip) routes. A series of 4-substituted and 4,5-disubstituted derivatives all showed high activity when administered ip against ip-implanted P-388, but activity varied widely when the compounds were given orally. 4-Methoxy and 4-carbamoyl derivatives proved essentially inactive, whereas 4-methyl and 4-methylcarbamoyl derivatives retained activity. Exceptional oral activity was shown by the 4-methyl-5-methylcarbamoyl derivative, making this amsacrine derivative worthy of further testing.