Synthesis And Anti-cancer Activity Research Of Aminopyrimidine Derivatives

Cancer is one of the three most serious disease threaten our health. According to W.H.O report, there will be 13.1 million people died in cancer by the year 2030. The most comon method for cancer treat include surgery, radiotherapy and chemotherapy. But for the patients in terminal stage, radiotherapy and chemotherapy were the only way. In cancer treatment, antimitotic agents have a beneficial effect since appeared, they can inhibit tumor cells’ proliferation through inhibiting mitosis and induce apoptosis.Since paclitaxel was found, antimitotic agents were more and more receives takes. With paclitaxel used in clinical, chemists were interested in finding novel antimitotic agents. A centrin called TACC3(Transforming acidic coiled coil 3) was reported had relationship with tumor cells’proliferation, and had potential to be a independent target for cancer therapy. The complex composed with TACC3 and its partner Aurora A was listed as one of "ten targets of cancer therapy".Though there were many proofs suggest that TACC3 is a target for cancer therapy, there’s no TACC3 inhibitor proved can cure for cancer. So the study for TACC3 small molecule inhibitor useing in cancer therapy seems to importunate. In 2010, PNAS reported a small molecule called KHS101, which can inhibit TACC3 to induce nerve cell differentiate for rat. KHS101 had a structure of aminopyrimidine, and this structure existed in many cancer therapy agents. Our experiment in vitro proved that KHS101 had antitumor effect indeed.In this paper, we took KHS101 as a hit compound, keep its privileged structure, made a series modification and obtained a series aminopyrimidine derivates. We screened with breast cancer cells for antiproliferation activity of these compounds, and tested some excellent compounds for their antimigration activity and toxity.We took a series of in vivo experiments with compound 40, and chosed paclitaxel as positive control. The result illustrated that compound 40 had good activity resistance of tumor growth and migration, and had lower toxicity compared with paclitaxel.