Synthesis, Anti-Cancer Screening And Mechanistic Study Of Novel Dithiocarbamate Analogues Library

In human and animal tissues, copper is an important essential trace element. Copper can affect many biological pathways in human body. In healthy adults, the necessary copper concentration is 50-100 mg. Copper can be absorbed from the stomach and intestine through protein transporters. Then, copper associated with albumin and transcuprein is deposited in the liver. In blood, the major copper carrying protein is ceruloplasmin and the rest of copper is transported by albumin and histidine. If the balance of copper in cell is impaired, diseases will occur. Over the past two decades, there are a lot of evidences show that the copper plays an important role in inflammation and the growth of tumors. The copper concentration in serum and tumor tissue is significant higher than that of healthy subjects. Therefore, copper became one of the important targets in anti-cancer treatment. There are some efficiently treatments, such as Copper reduction, oxidative stress, copper complexes as the inhibitors of proteasome. Some compounds demonstrate the very potent anti-cancer activity, such as tetrathiomolybdate (TM), Captoril,Zinc and Trientine, (8-hydroxyquinoline) Ox and (5-chloro-7-iodo-8-hydroxyquinoline)CQ.Dithiocarbamates (DTCs) are a sort of metal chelating and antioxidant compounds. These compounds are usually used in treating fungal diseases and bacteria. More recently, researchers have found that various DTC compounds can induce metal uptake, especial copper, and apotosis. More evidences confirm that the DTCs-copper complexes are also an important proteasome inhibitor. Disulfiram (DSF), a disulfide derivative of N, N-diethyldithiocarbamate (deDTC), is used as the alcohol-abuse deterrent with its ability of aldehyde dehydrogenase. Evidences prove that DSF can significantly inducing apoptosis with lower side effects. But the problem is the reaction between DSF and ALDH could decrease the anti-cancer concentration of DSF.Based on the research referred we presumed that by synthesizing and screening a novel library of PDTC analogues, we could find some compounds which have the very potent anti-cancer activity and have no reaction with ALDH. The content of this paper consists with two parts. In the first part, we synthesized and screened the first library of PDTC analogues. In this part, the binding constant between copper and PDTC analogues and structure activity relationship were discussed in this part. In the second part, another library of PDTC was synthesized and screened. Binding constant and SAR were also discussed. By doing this research, some compounds that have the very potent anti-cancer activity were found.The last part is about applying combinatorial chemisy in environmental sciences, we use combinatorial synthesis and high-throughput screening methodologies to discover novel agents for arsenic removal.The major research work and results of the paper are as follows:Part 1. The anti-proliferative effects on MDA-MB-231 cell line were screened with a synthesized novel library of PDTC analogues. The complexes of PDTC analogues and copper were found to have potent anti-proliferative activity, except compound 9#. Bingding constant was determined by UV titration. Structure activity relationship was also discussed.Part 2. The second library of PDTC analogues was synthesized. The biological data obtained from screening compounds by brease cancer cell line MDA-MB-231 and DCIS. UV titration method was used to determin the binding constant between PDTC analogues and copper. Results show that there is certain relationship between binding constant and anti-cancer activity. Computational docking was used to determin the relationship between PDTC analogues and ALDH. Finally, the compounds that have the very potent anti-cancer activity and have no reaction with ALDH were found.Part 3. We plan to establish a platform for doing various combinatorial synthesis and characterization. By using solid phase and solution phase synthesis method to discover novel agents for arsenic removal.Conclusions:1) The high concentrations of copper in tumor cells can be binded with dithiocarbamates, and the copper-dithiocarbamates are effective proteasome inhibitor. The complexes can inhibit tumor cell proliferation and induce cell apoptosis.2) Through discussing the SAR of DTCs analogues, it can be found that the substitutors are very important for the anti-cancer activity. It's helpful for us to optimize the structures of the DTCs analogues to find more potent compounds.3) By using the combinatorial synthesis and high-through screening methods will help accelerating the speed of discover the lead compounds. By optimizing the structure of lead compounds, we can found dithiocarbamates which can inhibit the proliferation of tumor without reacting with ALDH.