Synthesis And Biological Activity Of Novel PI3K/mTOR Inhibitors

Cancer is one of the important disease that harm human health today,the increase in cancer patients and younger trend,led to a sharp rise in demand for antitumor drugs.In 2008,total sales of antineoplastic drugs was 29 billion dollar,and it rapidly grew to 95 billion dollar in 2015.Conventional radiotherapy and chemotherapy in the treatment of cancer have serious side-effects,low selectivity and high toxicity,and are being phased out gradually.New drugs are paid more attention by researchers,since they have many new characteristics such as high selectivity,low toxicity and so on.Rapamycin analogs and kinase inhibitors are widely used in clinical treatment in recent years.Rapamycin analogs mainly work by inhibiting the mammals rapamycin target protein(mTOR),blocking PI3K-AKT-mTOR pathway of signal transmission,thus inhibiting the growth of tumor cell differentiation.In recent years,PI3K/mTOR inhibitors become a new international hot point,scientific statistics showed that PI3K/mTOR signaling pathway is not only widely expressed in various cancers,but also in each of these common types of cancer mechanism and plays an important role.Everolimus and temsirolimus are used for clinical treatments.The traditional rapamycin inhibitors exists the shortcoming of poor water solubility and low bioavailability,and new type of small molecule inhibitors overcome these shortcomings,for example,GSK2126458 and PF-0469150,which are drugs being in clinical trials.In this paper we designed and synthesized 10 new PI3K/mTOR inhibitors targeting rapamycin's target proteins,with PF-04979064 and BEZ235 as reference compound structures,taking cocrystallization experiment results of the related compounds with the target protein into consideration.The correct structure of the compounds were determined by HNMR and LC-MS,and the antitumor activity of compounds were tested in 3 strains of tumor cells by MTT test.The compound with best anticancer activity was selected for process development,to reduce the production cost and enhance the yield,for subsequent security evaluation experiment and GMP production.The final target product was synthesized with the yield of 25%and purity over 98.5%.