Design And Synthesis Of Sulfonamide Substituted Phenylpyrimidine Derivatives As Potential Allosteric Kinase Inhibitors

Cancer is one of the major diseases affecting human health, the treatment in the20thcentury is mainly to surgery, radiation therapy and chemotherapy, and they could causeserious side effects. While targeted therapy can reduce the dosage to reduce toxicity andimprove the therapeutic effect, is becoming a new trend in cancer treatment.Many cancer cells exhibit abnormal signal transduction pathway, the overexpressionof the receptor downstream signaling pathway leads to excessive cell proliferation andtumorigenesis. Non-normalization of protein kinase will lead to uncontrolled cellgrowth and metabolism, and therefore it becomes the most important "a new target" tocancer.This article is divided into two chapters, the first part focuses on the developmentstatus and the classification of protein kinases, and clarifies the superiority of allosterickinase inhibitors. Protein kinase are also referred to as protein phosphakinases, it isresponsible for the transformation of ATP-γ phosphoryl in the end to the specific aminoacid residues, resulting in protein phosphorylation. As early as1954, kinases’ activity isdiscovered, the studies of protein kinase inhibitors has made considerable progress, suchas the listing of imatinib,nilotinib, gefitinib, and sunitinib and so on.According to the complexation with the substrate in different manners, kinaseinhibitors is divided into four categories: Type I kinase inhibitor can link kinase domainbetween C-and N-terminal region by forming1-3hydrogen bonds with the hinge, it isalso called competitive inhibitor of ATP; Type II kinase inhibitor named allostericinhibitor, occupies the hydrophobic region exposed by the reverse of the activation loop(DFG) nearing ATP binding pocket; Type III allosteric inhibitors accounts for two locations all above-mentioned, It is worth mentioning that imatinib can interacts withtargeted kinase through this mode. Such inhibitors have not only highly selectivecharacteristics like type II inhibitor, but also it has high efficiency; Type IV kinaseinhibitors has its action sites far away from the ATP, it is difficult to carry out in-depthresearch for its irregularity. So we decided to develop a novel class of type III kinaseinhibitors.The second part focuses on the design and synthesis of sulfonamide substitutedphenylpyrimidine allosteric kinase inhibitors and explore its anticancer activity. Duringthe crystal structure study of imatinib and other allosteric inhibitors, we design aphenylpyrimidine nucleus by theoretical calculations, which substituted as sulfonamidegroup in the pyrimidine moiety, at last, we introduce aromatic acid, adipose acid andurea at the benzene moiety. By bioassay, we found5componds as the IC50less than10μM, Besides, we found some componds which imports pyrimidine to the nucleus canimprove activity. During derivatized the intermediate and bioassay, we also acquire9activity compounds, and the best activity(2-15-2d) can reach113nM.By design and optimization of the experimental routes, together with variousderivatization, we established a compound library about phenylpyrimidine nucleuswhich consists of48componds. By preliminary anticancer activity screening, weobtained a series of compounds which have excellent biological activity. And by discussthe structure-activity relationship, we get a new direction for our subsequent research.