Synthesis, cytotoxicity, and antitumor activity of copper(II) and iron(II)complexes of N-4-azabicyclo[3.2.2]nonane thiosemicarbazones derived from acyl diazines

A series of thiosemicarbazones (TSCs) (bearing a N-4-azabicyclo[3.2.2]nonan e moiety) derived from 3-acylpyridazines, 4-acetylpyrimidines, and 2-acetyl pyrazines (1-8) were synthesized as potential antitumor agents. TSCs 1-8 ex hibited potent cytotoxic activity against human acute lymphoblastic leukemi a CCRF-CEM cells (IC50 = 0.05-0.77 muM) and colon adenocarcinoma HT-29 cell s (IC50 = 0.011-2.22 muM). Copper II complexes of TSCs 1-8 showed significa nt improvement in cytotoxic activity against HT-29 cells (IC50 = 0.004-1.51 muM) by a factor of 3. However, complexation of ligands 1, 2, 4, and 6 wit h Fe(II) results in lowering of cytotoxic activity by a factor of similar t o7. In clonogenic assays involving human tumor cells of different tumor ori gins, compounds 5, 7, 8, and their copper complexes 5Cu(II), 7Cu(II), and 8 Cu(II) exhibited remarkable cytotoxic activities with mean IC50 values of 6 , 0.18, 1, 1, 0.37, and 0.37 nM, respectively. In particular, the compounds were highly effective against human colon carcinoma and large and small ce ll lung carcinoma cells. The TSC derivative 5 was evaluated in vivo in nude mice bearing LXFL 529 human large cell lung carcinoma cells. With respect to antitumor activity, application of 30 mg/kg/d resulted in moderate inhib ition (42%) of tumor growth. No effect on tumor growth was observed at a do se of 10 mg/kg/d. However, a dose of 40 or 60 mg/kg/d resulted in 50 and 75 % death, respectively, in the treated mice, indicating the high toxicity of these compounds. Using human liver microsomes, compound 5 was found to be rapidly and highly metabolized in vitro. In actual fact, only 2% of the unm etabolized compound could be detected in the incubation medium after 5 min. The IC50 for cell proliferation (0.006-0.022 muM) elicited by these compou nds is much lower than that of the inhibition of [C-14]cytidine incorporati on into DNA (0.18-3.32 muM). These compounds are also noncell cycle specifi c agents. Interestingly, compounds 5, 5Cu(II), and 8 were found to be poten t inducers of apoptosis in Burkitt's lymphoma cells.