9-SUBSTITUTED ACRIDINE-DERIVATIVES WITH LONG HALF-LIFE AND POTENT ANTITUMOR-ACTIVITY - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS

A series of DNA-intercalating 9-anilinoacridines, namely 9-(phenoxyacr idines, 9-(phenylthio)acridines, and 9-(3',5'-disubstituted anilino)ac ridines, were synthesized as potential antitumor agents with inhibitor y effects on DNA topoisomerase II. Unlike amsacrine (m-AMSA), these ag ents were designed to avoid the oxidative metabolic pathway. These acr idine derivatives were, therefore, expected to have long half-life in plasma. Both 9-phenoxyacridines and 9-(phenylthio)acridines were found to have moderate cytotoxicity against mouse leukemia L1210 and human leukemic HL-60 cell growth in culture. Among 9-(3',5'-disubstituted an ilino)acridines, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA) was found to be a potent topoisomerase II inhibitor and exhibited sign ificant antitumor efficacy both in vitro and in vivo. Chemotherapy of solid-tumor-bearing mice with 10, 10, and 5 mg/kg (QD x 4, ip) AHMA, V P-16, and m-AMSA, respectively, resulted in more tumor volume reductio n by AHMA than by VP-16 or m-AMSA for E0771 mammary adenocarcinoma and B-16 melanoma. For Lewis lung carcinoma, AHMA was as potent as VP-16 but more active than m-AMSA. Structure-activity relationships of AHMA derivatives are discussed.