Synthesis, Cytotoxicity, and Antitumor Activity of Copper(II) and Iron(II) Complexes of 4N-Azabicyclo[3.2.2]nonane Thiosemicarbazones Derived from Acyl Diazines

A series of thiosemicarbazones (TSCs) (bearing a 4N-azabicyclo[3.2.2]nonane moiety) derived from 3-acylpyridazines, 4-acetylpyrimidines, and 2-acetylpyrazines (1−8) were synthesized as potential antitumor agents. TSCs 1−8 exhibited potent cytotoxic activity against human acute lymphoblastic leukemia CCRF-CEM cells (IC50 = 0.05−0.77 μM) and colon adenocarcinoma HT-29 cells (IC50 = 0.011−2.22 μM). Copper II complexes of TSCs 1−8 showed significant improvement in cytotoxic activity against HT-29 cells (IC50 = 0.004−1.51 μM) by a factor of 3. However, complexation of ligands 1, 2, 4, and 6 with Fe(II) results in lowering of cytotoxic activity by a factor of ∼7. In clonogenic assays involving human tumor cells of different tumor origins, compounds 5, 7, 8, and their copper complexes 5Cu(II), 7Cu(II), and 8Cu(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 l...