title: 9-substituted acridine derivatives with long half-life and potent antitumor activity: synthesis and structure-activity relationships.
abstract: A series of DNA-intercalating 9-anilinoacridines, namely 9-phenoxyacridines, 9-(phenylthio)acridines, and 9-(3',5'-disubstituted anilino)acridines, were synthesized as potential antitumor agents with inhibitory effects on DNA topoisomerase II. Unlike amsacrine (m-AMSA), these agents were designed to avoid the oxidative metabolic pathway. These acridine 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 anilino)acridines, 3-(9-acridinylamino)-5-(hydroxymethyl)aniline (AHMA) was found to be a potent topoisomerase II inhibitor and exhibited significant 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, VP-16, and m-AMSA, respectively, resulted in more tumor volume reduction 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.
authors.affiliation: Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Su
authors.forename: T C
authors.initials: TC
authors.lastname: Chou
authors.forename: J Y
authors.initials: JY
authors.lastname: Kim
authors.forename: J T
authors.initials: JT
authors.lastname: Huang
authors.forename: G
authors.initials: G
authors.lastname: Ciszewska
authors.forename: W Y
authors.initials: WY
authors.lastname: Ren
authors.forename: G M
authors.initials: GM
authors.lastname: Otter
authors.forename: F M
authors.initials: FM
authors.lastname: Sirotnak
authors.forename: K A
authors.initials: KA
authors.lastname: Watanabe
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006207:Half-Life; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors