title: Potent antitumor 9-anilinoacridines and acridines bearing an alkylating N-mustard residue on the acridine chromophore: synthesis and biological activity.
abstract: A series of 9-anilinoacridine and acridine derivatives bearing an alkylating N-mustard residue at C4 of the acridine chromophore were synthesized. The N-mustard pharmacophore was linked to the C4 of the acridine ring with an O-ethyl (O-C(2)), O-propyl (O-C(3)), or O-butyl (O-C(4)) spacer. It revealed that all newly synthesized compounds were very potent cytotoxic agents against human leukemia and various solid tumors in vitro. These agents did not exhibit cross-resistance against vinblastine-resistant (CCRF-CEM/VBL) or taxol-resistant (CCRF-CEM/taxol) cells. It also showed that these agents were DNA cross-linking agents rather than topoisomerase II inhibitors. Of these agents, compounds 27a and 27c were shown to have potent antitumor activity in nude mice bearing the human breast carcinoma MX-1 xenograft. The therapeutic efficacies of these two agents are comparable to that of taxol.
authors.affiliation: Laboratory of Bioorganic Chemistry, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan. tlsu@ibms.sinica.edu.tw
authors.forename: Tsann-Long
authors.initials: TL
authors.lastname: Su
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Lin
authors.forename: Ting-Chao
authors.initials: TC
authors.lastname: Chou
authors.forename: Xiuguo
authors.initials: X
authors.lastname: Zhang
authors.forename: Valeriy A
authors.initials: VA
authors.lastname: Bacherikov
authors.forename: Ching-Huang
authors.initials: CH
authors.lastname: Chen
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
authors.forename: Tsong-Jen
authors.initials: TJ
authors.lastname: Tsai
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000609:Aminoacridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000166:Acridines; D000609:Aminoacridines; D000814:Aniline Compounds; D018906:Antineoplastic Agents, Alkylating; C512084:N1-(4-(2-(bis(2-chloroethyl)amino)ethoxy)acridin-9-yl)-5-methoxybenzene-1,3-diamine; C512085:N1-(4-(4-(bis(2-chloroethyl)amino)butoxy)acridin-9-yl)-5-methoxybenzene-1,3-diamine; D009588:Nitrogen Mustard Compounds; D004247:DNA; D004250:DNA Topoisomerases, Type II