title: Synthesis and in-vitro anticancer evaluation of bis-tacrine congeners.
abstract: In the search for potential new anticancer drugs, an efficient synthesis of bis-tetrahydroaminoacridine (bis-tacrine) and its congeners was accomplished by bis-amination of 9-chlorotetrahydroacridine and its congeners under heated conditions. The critical chlorides were efficiently prepared from o-aminoaromatic acids and cycloketones in-situ in the presence of phosphorus oxychloride. In-vitro cytotoxic evaluation of the compounds was carried out against a panel of 60 human cancer cell lines. Among them, butyl-linked bis-tacrine (5b) exhibited the strongest cytotoxic profile with GI50 (concentration causing 50% growth inhibition) values of approximately 0.04-0.08 microM against breast, colon, melanoma and non-small lung cancer cells. Congeners bearing a longer alkyl chain were on average 30- to 100-fold less cytotoxic against these cancer cells. Shorter connecting alkyl chains of bis-tacrine or its congeners dramatically decreased the cytotoxic effects. Compound 5b has been selected for further biological evaluation of its anticancer profile.
authors.affiliation: School of Pharmacy, National Defence Medical Center, Taipei, Taiwan, Republic of China. hmk@ndmctsgh.edu.tw
authors.forename: M K
authors.initials: MK
authors.lastname: Hu
mesh_terms: D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D013619:Tacrine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D002800:Cholinesterase Inhibitors; D013619:Tacrine