title: Potent antitumor 9-anilinoacridines bearing an alkylating N-mustard residue on the anilino ring: synthesis and biological activity.
abstract: A series of N-mustard derivatives of 9-anilinoacridine was synthesized for antitumor and structure-activity relationship studies. The alkylating N-mustard residue was linked to the C-3' or C-4' position of the anilino ring with an O-ethylene (O-C(2)), O-butylene (O-C(4)), and methylene (C(1)) spacer. All of the new N-mustard derivatives exhibited significant cytotoxicity in inhibiting human lymphoblastic leukemic cells (CCRF-CEM) in culture. Of these agents, (3-(acridin-9-ylamino)-5-{2-[bis (2-chloroethyl)amino]ethoxy}phenyl)methanol (10) was subjected to antitumor studies, resulting in an approximately 100-fold more potent effect than its parent analogue 3-(9-acridinylamino)-5-hydroxymethylaniline (AHMA) in inhibiting the growth of human lymphoblastic leukemic cells (CCRF-CEM) in vitro. This agent did not exhibit cross-resistance against vinblastine-resistant (CCRF-CEM/VBL) or Taxol-resistant (CCRF-CEM/Taxol) cells. Remarkably, the therapeutic effect of 10 at a dose as low as one tenth of the Taxol therapeutic dose [i.e., 1-2mg/kg (Q3Dx7) or 3mg/kg (Q4Dx5); intravenous injection] on nude mice bearing human breast carcinoma MX-1 xenografts resulted in complete tumor remission in two out of three mice. Furthermore, 10 yielded xenograft tumor suppression of 81-96% using human T-cell acute lymphoblastic leukemia CCRF-CEM, colon carcinoma HCT-116, and ovarian adenocarcinoma SK-OV-3 tumor models.
authors.affiliation: Laboratory of Bioorganic Chemistry, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Valeriy A
authors.initials: VA
authors.lastname: Bacherikov
authors.forename: Ting-Chao
authors.initials: TC
authors.lastname: Chou
authors.forename: Hua-Jin
authors.initials: HJ
authors.lastname: Dong
authors.forename: Xiuguo
authors.initials: X
authors.lastname: Zhang
authors.forename: Ching-Huang
authors.initials: CH
authors.lastname: Chen
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Lin
authors.forename: Tsong-Jen
authors.initials: TJ
authors.lastname: Tsai
authors.forename: Rong-Zau
authors.initials: RZ
authors.lastname: Lee
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
authors.forename: Tsann-Long
authors.initials: TL
authors.lastname: Su
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry; D000677:Amsacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D012074:Remission Induction; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D000677:Amsacrine; C022202:9-anilinoacridine