Synthesis And Biological Evaluation Of Pyrrolopyrimidines As Akt Inhibitors

Maligancy has become a serious threat to human health and survival due to the characteristics of high incidence, high fatality rate and low cure rate. It has been the most important of human lethal factor. The further study on the occurrence and development of malignancy made it possible to treat tumor on target. Currently, the drugs targeting cellular signaling pathway has attracted attention from researchers, Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway plays a key role in cell growth and survival. PI3K/Akt signaling pathway is over-activated in many cancers, such as acute and chronic leukemia, lymphoma, multiple tumors, myeloma and ovarian cancer, pancreatic cancer, endometrial cancer, liver cancer, prostate cancer. it may be a good way to prevent the sustained activation of signaling pathway for the targeted therapies of cancer. Akt plays a key role in PI3K/Akt signaling pathway. Along with deepening study to PI3K/Akt signaling pathway and Akt, which has been suggested as one of the most attractive targets for new anticancer drug development.Many Akt inhibitors have been reported in the literature, according to the different binding sites and mechanisms, the inhibitors can be divided into ATP competitive inhibitors, allosteric inhibitors, phosphatidylinositol analogue inhibitors and pseudosubstrate inhibitors, currently, the study of ATP competitive inhibitors and allosteric inhibitiors has become a hot issue. GDC0068, AZD5363, GSK2110183 and GSK2141795, the ATP competitive inhibitors, are in Phase Ⅰ or Ⅱ clinical trials; allosteric inhibitor MK2206 is in Phase II clinical trials.Based on the analyses of the interaction between the ATP-competitive inhibitors and the binding sites of AKT, we designed and synthesized the series E. To improve the activities of the compounds in series E, we designed the series K by introducing the piperidine ring into the structure of E series,.The target compounds (E-series and K-series) were obtained from 4-chloro -7H-pyrrolo [2,3-d] pyrimidine as the starting material via chlorination, bromination, methylation reaction and nucleophilic substitution reaction, amino protection, piperidine ring preparation, nitrile hydrolysis reaction, amidation reaction and amino deprotection reaction, we have synthesized 38 compounds, the structure of compounds were identified by 1H NMR,13C NMR or MS. The compounds are firstly reported in this paper.The results of biological evaluation indicated that E series displayed potent Aktl inhibitory activities and PC-3 cell, LNCaP cell growth inhibitory activities, compound E-19 showed Aktl inhibitory activity with an IC50 of 18nM and cell inhibitory activity against PC-3 cell lines with an IC50 of 21 uM. But compare to GSK690693, the Aktl inhibitory activities of series E is still need to improve. Based on the results of series E, wo optimized the structure to get the series K, In this series, wo obtained 15 target compounds, which showed more potent Aktl inhibitory activities and PC-3 cell inhibitory activities, the compound K-9 and K-13 showed most potent inhibitory activities against Aktl with inhibition rates of 91% and 94% at 40 nM concentration, respectively. Moreocer, compound K-9 also inhibited PC-3 cell with an IC50 of 6uM. The docking study showed that the piperidine ring structure of the compounds in series K can form a hydrogen bond with Glu 234 in the Acid hole, while the compounds in series E weren’t into the Acid hoie, Which may be the reason that series K show more potent inhibitory activities than series E.In the next work, we will test the selectivity to other kinases and further optimize the structure to lay the foundation for screening anticancer drugs.