Syntheses And Antitumor Activities Of Small Molecular Novel Thiourea Derivatives

Copper is an essential element for most living organisms including humans involved in many biological pathways. In cancerous tissues, copper is found to be enriched compared to normal tissues, promoting angiogenesis and tumor growth. Therefore, much attention has been paid to copper complexes as anticancer agents recently.Thiourea-containing compounds have been found to have antiviral, antibacterial and antitumor activity. Thioureas have the ability to form complexes with transition metal ions, and thiosemicarbazones have been reported to form copper complexes having antiproliferative activity.In this thesis, we designed and synthesized a series of small molecular thiourea derivatives from benzoyl isothiocyanate. Three of these thiourea derivatives Gly-TU, DiTU and TriTU are water soluble, while the other three Ad-TU, n-BuTU and EDTU are water insoluble. They have low cytotoxity to all five human cancer cell lines (Bcap37, Hela, A549, HT29, HepG2) and one normal human fibroblasts cell line HFL-1 in vitro. Their anticancer activities were tested using BCap37 tumor bearing BALB/c nude mice. TriTU exhibited the highest tumor-inhibition rate of 40.5%, but had no anti-metastasis ability as tested in 4T1-GFP-LUC tumor metastasis model. We preliminarily explored tumor inhibition mechanism of these synthesized thiourea derivatives. It showed that they could lower plasma copper in 2h after intravenous injection, the plasma copper returned to normal level at 6h and 12h. In addition, copper complexes formed by thiourea derivatives demonstrated much stronger cytotoxity towards BCap37 than these compounds themselves.In conclusion, TriTU, one of the synthesized thiourea derivatives, has exhibited some tumor inhibition activity. The copper depletion may be the mechanism of its antitumor activity.