Design,Synthesis And Antitumor Activity Of Steroidal Pyridine Derivatives Based On Molecular Docking

At present,cancer has become one of the main factors threatening public health,and research on cancer has become a research hotspot at home and abroad.According to reports,cancer has been the second leading cause of death in North America and Europe.Therefore,the development of new anticancer drugs has become an important part of the world’s new drug research field.Steroid derivatives have obvious effects in anti-tumor and anti-inflammatory,which have attracted wide attention’of drug design scholars.Megestrol,alpha-hydroxyprogesterone and medroxyprogesterone,heterocyclic steroids and curcumin derivatives have emerged as the starting point for anticancer research and have shown excellent anticancer potential.Compounds with a steroidal structure have shown good development prospects in anti-tumor.Pyridine and its derivatives are important heterocyclic compounds,which are widely used in many fields such as medicine and pesticides.In recent years,the types of pyridine derivatives have become more and more refined.Among them,a typical pyridine derivative has a structure of a 2-amino-3-cyanopyridine derivative.Such derivatives are commonly used in pesticides and have been increasingly used in the medical field in recent years,and have biological activities against cancer and AIDS.In this study,a 2-amino-3-cyanopyridine ring was used as the parent molecular skeleton,and a steroid was introduced as a pharmacophore at the C6 position.A series of steroidal pyridine derivatives were designed,and their anti-tumor was predicted by molecular docking software simulation.After activity,it is synthesized as a small molecule inhibitor and tested and screened for antitumor activity in vitro.The specific results are as follows:(1)Sixteen compounds were designed using MOE molecular docking software,and the compounds were docked with Survivin protein.The binding data of each compound was less than-8.It indicates that the compound has strong binding ability to the target protein,and the binding ability of 2f and 2p is the strongest.(2)16 kinds of steroidal pyridine derivatives(2a-2p)were successfully synthesized,and the 16 compounds were characterized by MP,1H-NMR,13C-NMR,IR and HR-ESI-MS to determine the compound as the target compound..In vitro activity screening of four human tumor cells Hela229,Hepg2,Skov3,and MCF-7 was performed.The results showed that the compounds 2f and 2p had the best anti-value-adding activity against the four cells,which were higher than the positive drug 5-Fu.The IC50 values of the anti-value-increasing activities of the two cells were 8.14 ± 0.17 μM,12.39 ± 0.14,respectively.μM,5.088±0.05 μM and 8.81±0.25 μM.The IC50 values of 2p anti-value-adding activities for these four cells were 8.457 ± 0.14 μM,13.84 ± 1.04μM,7.025 ± 0.33 μM and 6.283 ± 0.12 μM,respectively.The experimental results are in agreement with the docking results.(3)Compound 2f was used to detect the in vitro activity of four human tumor cells Skov3,U251,Huh7 and A375,and trypan blue exclusion test was performed.The results showed that the compound had the most significant effect on Skov3,and further flow cytometiy was used.The pro-apoptotic effect of the compound on Skov3 cells and the period of apoptosis were investigated.