| Protein kinase is a kind of important enzyme which is relevant to catalyzeprotein phosphorylation. They play a vital role in cell signaling and activate a seriesof complex process such as cell metabolism, growth, cell differentiation, proliferationand other functions. So, if the dysregulations of kinases happen, a serious of diseasesrelated to these functions have been caused. For these reasons, protein kinases havebecome one of the most comprehensive classes of therapeutic targets, and proteinkinase inhibitors are also becoming potential anticancer drug candidates.This thesis mianly introduces the design and syntheses of piperdylpyridinederivatives as potential allosteric kinase inhibitors and their anticancer activity. It isdivided into two chapters, the first one summaries the current of kinase inhibitors,provides examples of kinase inhibitors and their classification according to theirmechanism of action, on the basis of these argument, we introduce the purpose andsignificance of our experiments.During the past two decades, kinase inhibitors with characteristics of highefficiency, low toxicity and selective has become an important goal in today’santi-tumor drugs research. So far, more than ten effective protein kinase inhibitorshave successively listed, at the same time, more novel highly active drugs are atvarious stages of clinical trials. In accordance with the mechanism of action, kinaseinhibitors can be divided into four classes. Type I inhibitors bind to the ATP site of thekinase’s active conformation. They modulate the kinase activity by directly competewith ATP for the same binding site. For this reason, they are also termed as“ATP-competitive inhibitors”. The sequence of amino acids in the ATP binding sitesare highly conserved among kinases and other ATP binding proteins. As a result, TypeI inhibitors typically have poor selectivity profile. Some kinase has an inactiveconformation because its active loop turns off180degree. Type II inhibitors canoccupy the new conformation that is a smaller hydrophobic pocket, in there the inhibitors complex with kinase by hydrophobic exchange, just a few hydrophobicinteraction, therefore, type II has highly selectivity but weakly activity. Type IIIinhibitors, namely allosteric kinase inhibitors, can occupy the adenine region andactive conformation. Imatinib, as the first listed inhibitors, is one of type III inhibitors.Type IV inhibitors complex with the region which is far away the ATP site, althoughthey have highly selectivity, they can not be used widely. So, the research of type IIIinhibitors is an efficacious way to cure cancer.The second chapter describes the design and syntheses of piperdylpyridinederivatives as potential allosteric kinase inhibitors and evaluation of their anticanceractivity. By analyzing allosteric conformation of kineses and their inhibitors, as wellas their X-ray co-crystal structures, we proposed a pharmacophore model withbi-cyclic piperdylpyridine. The template serves as a connect, bridging the originaladenine binding region and the hydrophobic cavity vacated by the DFG-fragment.Firstly, we synthesized pharmacophore piperdylpyridine core(2-6) via six stepreactions, such as one-pot Suzuki coupling reaction、sodium borohydride reductionreaction e.t. Then, we get more than80compounds as a drug-like small molecularlibrary. Finally, this library was screened in cell assays against HeLa cells for theiranti-proliferative activities. By the preliminary test, we find11active compounds, itis worth noting that the active compounds all most contain pyrimidine, so theyindicate that pyrimide may interact with protein by hydrogen bond.On the basis of the presentation of the two top chapters, we conclude thatleading a pyrimidine into our pharmacophore piperdylpyridine core right can improvethe activity of compounds, therefore, in the future of the research we will find morepotential selective allosteric kinase inhibitors by this way. |
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