The Design, Synthesis And Bioassay Of Copper Chaperones Atox1 And CCS Inhibitors, And The Synthesis Of Pramipexole Impurity

Copper is one of trace elements that are essential for human. Copper Chaperones play an important role in the copper-utilization of cells. Anomaly of cellular copper ion concentration is closely related with the occurrence and progression of cancer. Suppressing copper chaperones Atox1 and CCS leads to a significantly reduced proliferation of cancer cells by disrupting the copper-utilization of cancer cells such as lung cancer cells, acute leukemia cells and so on. So the studies of inhibitors of Atox1 and CCS are of great importance to the treatment of cancer. Based on the previous research, leading compound DC-AC50 was modified to find high-activity and low-toxicity inhibitors by means of computer-aided drug design.On the basis of structural information provided by docking model between Compound DC-AC50 and Atox1 or CCS, two compounds were obtained by cyclization or methylation of N atom in the amide and showed no inhibiting effect on the cancer cells. By replacing phenyl segment with aromatic substituents and changing the position and species of substituents on the benzene ring, 33 compounds were synthesized. Among them, the activity of Compound 1-28 was better than that of Compound DC-AC50, while the activity of Compound 1-25 was similar with that of DC-AC50. Two compounds were obtained by replacing aromatic amine with fatty amine, the results of the two compounds and some ring-opening intermediates showed no compound possessed better activity than that of Compound 1-28.Pramipexole dihydrochloride monohydrate is one of the second-generation non-ergolinic dopamine receptor agonists widely used to treat Parkinson disease. BI-II786 BS is one of the pramipexole impurities found in the tablet of pramipexole dihydrochloride,it is of great importance to the designation of pramipexole generics. To date, there is no report about the synthesis of BI-II786 BS due to the complexity of its structure. Route B and route C were designed based on the previous research of BI-II786 BS in our group. Both routes made use of Mitsunobu Reaction to achieve our desired configuration. But route B was failed because of problem in the deprotection at the last step. Fortunately, BI-II786 BS was obtained by route C which did not have the shortcomings of route B.