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.
pubmed-meshheading:3625706-Amsacrine, pubmed-meshheading:3625706-Animals, pubmed-meshheading:3625706-Antineoplastic Agents, pubmed-meshheading:3625706-Cell Line, pubmed-meshheading:3625706-Doxorubicin, pubmed-meshheading:3625706-Drug Resistance, pubmed-meshheading:3625706-Leukemia, Experimental, pubmed-meshheading:3625706-Leukemia P388, pubmed-meshheading:3625706-Structure-Activity Relationship
Potential antitumor agents. 52. Carbamate analogues of amsacrine with in vivo activity against multidrug-resistant P388 leukemia.
Journal Article, Research Support, Non-U.S. Gov't