Design, Synthesis And Evaluation Activity Of MTOR Signaling Pathway Inhibitor

Mammals rapamycin target protein (mTOR) signaling pathway is animportant signal pathway in cells, the way to highly conserved inevolution, mainly through PI3K/Akt/mTOR signaling pathwaysphosphorylated activated to regulate cell division, promote genetranscription and translation, such as signal, so as to control the proteinsynthesis to regulate cell growth.Tumor disease is the greatest threat to human health, the drug forcancer treatment are under a lot of research and development. Manytumor cells exist in the coding mTOR signaling pathway related proteingene mutation, abnormal expression of these proteins can cause excessiveactivation pathways, lead to cancer the happening of the disease. As theresearchers on the signal transduction system and related moleculartargets for drug research, targeted therapy has become a great prospectsfor development of tumor treatment.Now think mTOR signaling pathway is an important target cancertreatment, the excessive activation is closely related to the occurrence anddevelopment of tumor. MTOR protein has six functional domains,including near the upstream kinase domain structure is FRB (FKBP12-rapamycin binding) domain structure, it is the combination of theFKBP12-rapamycin complex site, in rapamycin specific inhibitingmTOR plays an important role: rapamycin can be combined with intracellular receptor FKBP12FKBP12-rapamycin complex formation,and combined with protein mTOR FRB district, inhibiting mTOR kinaseactivity, thus inhibiting mTOR signaling pathways. The activity ofinhibiting mTOR signaling pathways can inhibit the proliferation oftumor cells and induce the apoptosis of tumor cells and reversal ofcytotoxic drug resistance of tumor cells.Traditional mTOR signaling pathway inhibitor representative forrapamycin and its derivatives, including Tanzania seamus and accordingto the dimension of therapy has been approved for the treatment of renalcell carcinoma. But rapamycin is36carbon atoms large ring lactone classcompound, its low bioavailability, poor water-soluble shortcomings.Looking for exploitation degree is high, the inhibition of small moleculeinhibitors with good effect, is one of the focus of pharmaceuticalchemistry workers. According to the principle of rapamycin inhibitingmTOR protein, forming complexes can be determined with FKBP12isinhibition of key points. FKBP12belongs to FKBPs (FK506bindingproteins) protein family, is a kind of highly homologous receptor bindingprotein, has become a hot research topic in the field of related disciplines.The purpose of this study is based on FKBPs protein targets, thesynthesis of new type of mTOR signaling pathway inhibitor, used for thetreatment of tumor cells. N3081is our laboratory previously proteinsynthesis is used to inhibit FKBPs small molecule inhibitors of a class of novel structure, used in the treatment of Alzheimer’s disease (Alzheimer ’sdiseases, AD). This N3081structure characteristics, the research on thecomprehensive characteristics of rapamycin inhibitors, design a newinhibitor; Cysteine as starting materials, by multistep reactions,20newcompounds synthesized. By1h-nmr and MS detection means such asstructure analysis and identification of target compounds, confirmed theirchemical structure is consistent with the expected design structure, andthe synthetic compounds were not seen by the literature. The antitumorfunction of the new synthetic compounds for the active evaluation, theresults show that a total of11compounds of AGS respectively, MDA-MB-231cells with different degree of inhibition, prove its antitumoractivity. This study also the structure-activity relationship of activecompounds. This study is the first time the FKBPs as mTOR signalingpathway inhibitor of target protein, anticancer actiity and synthesizedcompounds, this is the innovation of this study.