Very recently we described the synthesis and antitumor properties of N4-azabicyclo[3.2.2]nonane thiosemicarbazones (TSCs) derived from acyl diazines (Easmon, J, et. al. J. Med. Chem. 2001, 44, 2164-2171). Although the compounds were potent antiproliferative agents, only a moderate inhibition of tumor growth (40%) was observed accompanied by high in vivo toxicity. In a continued effort to obtain more efficacious compounds, we have synthesized TSC-derivatives bearing N4-methyl and cycloaliphatic moieties. The cytotoxic activities of the TSCs were evaluated in a panel of human tumor cell lines by the MTT assay. TSCs bearing terminal cycloaliphatic amines and especially a pyrrolidine moiety exhibited potent cytotoxic activity against Burkitt's lymphoma Ca 46 (IC50 = 0.002-0.59 μM), HeLa cervical (IC50 = 0.0003-0.057 μM), and Colon HT-29 (IC50 = 0.0005-0.47 μM) cells. Several of the highly active TSCs were tested in vivo in CD1 nude mice bearing various tumor xenografts. The compound Hexahydro-1H-azepine-1-thiocarboxylic acid 2-[1-(3-methyl-2-pyrazinyl)ethylidene}hydrazide (EPH 280) applied at doses of 20-25 mg/kg in mice bearing H460 human lung carcinoma xenograft resulted in a 70% reduction in tumor burden. Treatment of DLD1 colon adenocarcinoma cells with 40 nM of EPH 280 resulted in the increase of the phosphorylation of HSP 27 which was determined to occur at the ser-82 site. Financial support by the Austrian Science Foundation (FWF) is generally acknowledged (project no. P 09879-MED).

[Proc Amer Assoc Cancer Res, Volume 47, 2006]