New Synthetic Method And Anti-Proliferative Activity Study Of Ribociclib And Its Analogues

Pancreatic cancer is high malignant tumor with mortality.In addition to surgical resection,gemcitabine alone or in combination with other chemotherapeutic drugs are the major therapeutic regimens.However,the median survival period of the patients was not significantly prolonged by gemcitabine-base regimens.Drug resistance and bone marrow suppression are still the common problems.Although FOLFIRINOX(5-FU,leucovorin,irinotecan and oxaliplatin)combined regimen prolonged the median survival period to 11.1 months,the high intensity of chemotherapy severely challenged the tolerance of patient.Therefore,new drugs are in urgent need for pancreatic cancer.Cyclin-dependent kinase(CDK)plays a key role in cell cycle regulation and transcription process.There are almost twenty kinds of CDK kinases found at present.CDK4 and 6 have been proved effective drug targets for cancer therapy.Ribociclib is a selective CDK4/6 inhibitor and was approved to treat the breast cancer when combining with Letrozole by the FDA in 2017.At present,ribociclib has not been on the market in China.In our effort to find new hits for pancreatic cancer,a selective CDK4/6 inhibitor ribociclib exhibited moderate inhibitory activity on the growth of MIA PaCa-2 cells(IC50=15.65 ?M).In order to obtain more active anti-pancreatic cancer compounds and explore the potential of CDK4/6 inhibitors as therapeutic options for pancreatic cancer,we designed a new synthetic method for preparation of ribociclib and its analogs and investigated the anti-proliferative activity of the synthetic pyrrole[2,3-d]pyrimidine compounds in different pancreatic cancer cell lines including of MIA PaCa-2 and BxPC-3 cells.The inhibition effect of the synthetic compounds on CDK4 was also determined in vitro.The preliminary structure-activity relationship analysis showed that both long-chain hydrophilic group substituted at C2-position and arylaminocarboxyl group substituted at C6-position of pyrrole[2,3-d]pyrimidine are beneficial to the antiproliferative activity.The antiproliferative activity is dependent on CDK4 inhibition effect to some extent.The CDK kinase profiling,cell cycle analysis and pharmaceutical properties evaluation were performed for the potential compounds in this study.In summary,two new synthetic routes for ribociclib and its analogs were successfully established in this paper.Total 61 compounds including of 30 target compounds and 31 intermediates,were parpared by using this method.29 of target compounds are novel compounds with their chemical structure characterizated with 1HNMR and HRMS data.A series of 6-(N-substituted phenylamino)acyl substituted pyrrole[2,3-d]pyrimidine compounds possess of significantly increased anticancer activities than ribiciclib against pancreatic cancer cells.The most potential compound C10 displayed a 10-fold more anti-proliferative activity against two pancreatic cancer cell lines comparing to ribociclib.C10 was also identified as an oral available and selective CDK4/6 inhibitor,which is worthy for further study.