Abstract The 1,2,3,4-tetrahydroisoquinoline moiety is commonly found in biologically active molecules of either natural or synthetic origin, making its derivatives excellent candidates as potential pharmaceutical agents. The tetraydroisoquinoline family of alkaloids includes potent cytotoxic agents that display a range of biological properties such as antitumor and antimicrobial activities studied thoroughly over the past 25 years, starting with the isolation of naphthyridinomycin in 1974. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) is considered to be a possible endogenous anti-parkinsonism agent that is present in the mouse, rat, monkey and human brain. Therefore, the discovery of novel and safer anticancer drugs represents a challenging goal for our research program. In the current investigation, we synthesized a few analogs maintaining the tetrahydroisoquinoline moiety with modifications on the phenyl ring by introducing groups with various electronic, steric and lipophilic properties. The starting material, 2-aminoisoquinoliniumiodide was obtained by the reaction of hydroxylamine-O-sulfonic acid, water, and isoquinoline after heating at 90 oC for 2 h. The reaction mixture was cooled to room temperature, potassium carbonate added, and the water was evaporated. Ethanol was added to the solid residue and the insoluble potassium sulfate was filtered out. Hydroiodic acid was added to the filtrate, and the resulting solution was placed in a freezer for overnight. The precipitate was filtered out, washed with ethanol, and dried in vacuo. The crude product was used for the next step without further purification. Reaction of the 2-aminoisoquinoliniumiodide with substituted benzoyl chlorides/benzenesulfonyl chlorides in anhydrous tetrahydrofuran containing triethylamine gave stable benzoyl/benzenesulfonyl imino ylides. This was followed by reduction with sodium borohydride in absolute ethanol, which furnished the target compounds, 1-(substituted benzoyl/benzenesulfonylamino)-1,2,3,4-tetrahydroisoquinolines. These compounds were evaluated for their in vitro anti cancer activity on MCF-7, MDA-MB-231 and Ishikawa breast cancer cell lines. The cytotoxicity activities of the compounds were tested using tomaxifen as a control. The 1-benzoyl amino-1,2,3,4-tetrahydroisoquinoline showed most potent cytotoxicity with an IC50 values 0.23, 0.63, 0.74 µg/mL on Ishikawa, MCF-7 and MDA-MB-231, respectively. This research was supported by NIH/RCMI Grant # G12 RR03020 and Pharmaceutical Research Center NIH/NCRR Grant 1 C06 RR12512-01. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 735.