Potential antitumor agents. 52. Carbamate analogues of amsacrine with in vivo activity against multidrug-resistant P388 leukemia.
Study of a series of aniline-substituted 9-anilinoacridines related to the antileukemic drug amsacrine showed that a 1'-carbamate group provided increased activity against the multidrug-resistant P388/ADR leukemia subline in vivo. Since activity against such resistant tumors is of great clinical significance, a series of acridine-substituted carbamate derivatives were evaluated against both wild-type and ADR/resistant P388 leukemia and the Lewis lung solid tumor in vivo. Structure-activity relationships for all three tumor lines were similar, with 3-halo-5-methyl and 3-halo-5-methoxy compounds proving the most active. This substitution pattern also provided the highest DNA binding. Such compounds (particularly the 3-chloro-5-methyl and 3-chloro-5-methoxy) have in vivo activity against wild-type P388 and Lewis lung comparable to that of the best amsacrine analogues previously developed (greater than 50% cures), as well as P388/ADR activity. This work essentially completes the development of the amsacrine series of antitumor agents.
D000677:Amsacrine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002460:Cell Line; D004317:Doxorubicin / Q000627:therapeutic use; D004351:Drug Resistance; D007941:Leukemia P388 / Q000188:drug therapy*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D000677:Amsacrine; D004317:Doxorubicin