Synthesis and in-vitro anticancer evaluation of bistacrine congeners

In the search for potential new anticancer drugs, an efficient synthesis of bis-tetrahydroaminoacridine (bis-tacrine) and its congeners was accomplish ed by bis-amination of 9-chlorotetrahydroacridine and its congeners under h eated conditions. The critical chlorides were efficiently prepared from o-aminoaromatic acids and cycloketones in-situ in the presence of phosphorus oxychloride. In-vit ro cytotoxic evaluation of the compounds was carried out against a panel of 60 human cancer cell lines. Among them, butyl-linked bis-tacrine (5b) exhi bited the strongest cytotoxic profile with G150 (concentration causing 50% growth inhibition) values of approximately 0.04-0.08/muM against breast, co lon, melanoma and nonsmall lung cancer cells. Congeners bearing a longer al kyl chain were on average 30- to 100-fold less cytotoxic against these canc er cells. Shorter connecting alkyl chains of bis-tacrine or its congeners d ramatically decreased the cytotoxic effects. Compound 5b has been selected for further biological evaluation of its anti cancer profile.