Synthesis And Antitumor Activities Of Novel Dithiocarbamate Derivatives

As the cofactors or active centers of multiple copper-dependent proteins or enzymes, copper has been shown essential for tumorigenesis, angiogenesis, metastasis and recurrence. Consistently, elevated serum and tissue copper levels have been found in a wide spectrum of human cancers. The endogenous copper may be capitalized in a synthetic lethality approach, where copper complexes with its ligands to form compounds preferentially harming malignant versus normal cells.Dithiocarbamates can form complexes with copper ions, which endow them antibacterial, antiviral, or anticancer activity. For example, the copper complex of disulfiram (DSF) or pyrrolidine dithiocarbamate (PDTC), demonstrated proteasome inhibitory effects and apoptosis-inducing activities.In this thesis, we designed and synthesized a series of dithiocarbamates from amines and CS2 under alkaline conditions, including DDTC, HE-Pr-DTC, PDTC, MBDTC and Ppz-DTC. The MTT assays indicated the in vitro cytotoxities of these compounds except Ppz-DTC against human cancer cell lines (BCap-37, Hela and A549) and a normal human fibroblast cell line (HFL-1). The in vivo antitumor effects of DTCs was proved in human breast tumor xenografts (BCap-37), with tumor inhibition ratios of 39.3%,54.1%,25.1%,40.5%and 43.8%, respectively. Furthermore, DTCs can inhibit tumor growth and metastasis, prolonging the survival of tumor-bearing mice in two 4T1 tumor metastasis model. And the preliminary mechanism study showed that DTCs could lower plasma copper levels in 6 h after intravenous injection. In addition, the presence of Cu2+ boosted the cytotoxicities of DTCs.In conclusion, the synthesized DTCs can inhibit tumor growth and metastasis. Such activity may arise from its copper depletion ability and toxicity of copper complex.