title: Novel DNA-directed alkylating agents: design, synthesis and potent antitumor effect of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker.
abstract: A series of phenyl N-mustard-9-anilinoacridine conjugates via a carbamate or carbonate linker was synthesized for antitumor evaluation. The carbamate or carbonate linker is able to lower the reactivity of the phenyl N-mustard pharmacophore and thus, these conjugates are rather chemically stable. The in vitro studies revealed that these derivatives possessed significant cytotoxicity with IC(50) in sub-micromolar range in inhibiting human lymphoblastic leukemia (CCRF-CEM), breast carcinoma (MX-1), colon carcinoma (HCT-116) and human non-small cell lung cancer (H1299) cell growth in vitro. Compounds 10a, 10b, 10e, 10i, and 15a were selected for evaluating their antitumor activity in nude mice bearing MX-1 and HCT-116 xenografts. Remarkably, total tumor remission was achieved by these agents with only one cycle of treatment. Interestingly, no tumor relapse was found in mice treated with 10a over 129 days. This agent is capable of inducing DNA interstrand cross-linking in human non-small lung cancer H1299 cells in a dose dependent manner by modified comet assay and has a long half-life in rat plasma.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Naval
authors.initials: N
authors.lastname: Kapuriya
authors.forename: Kalpana
authors.initials: K
authors.lastname: Kapuriya
authors.forename: Huajin
authors.initials: H
authors.lastname: Dong
authors.forename: Xiuguo
authors.initials: X
authors.lastname: Zhang
authors.forename: Ting-Chao
authors.initials: TC
authors.lastname: Chou
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Te-Chang
authors.initials: TC
authors.lastname: Lee
authors.forename: Wen-Chuan
authors.initials: WC
authors.lastname: Lee
authors.forename: Tung-Hu
authors.initials: TH
authors.lastname: Tsai
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Naliapara
authors.forename: Tsann-Long
authors.initials: TL
authors.lastname: Su
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002219:Carbamates / Q000737:chemistry*; D002254:Carbonates / Q000737:chemistry*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D000166:Acridines; D018906:Antineoplastic Agents, Alkylating; D002219:Carbamates; D002254:Carbonates; D004247:DNA