Cytisine-Flavonoid Conjugates:Synthesis And Antitumor Structure-Activity Relationship Research

Objective and significance: Tonkinensine B is a new skeleton compound with triple-negative breast cancer inhibitory activity isolated from sophora tonkinensis of Chinese medicine.According to the previous reseach,(-)-Cytisine and(-)-Maackiain were used as raw materials to synthesized them by biomimetic synthesis method.As(-)-Maackiain was difficult to obtain in large quantities,further studies on the synthesis and biological activity of Tonkinensine B had been limited.On the basis of previous research,(-)-Maackiain was replaced by a series of natural flavonoid compounds with good biological activity in this research.Under the guidance of molecular docking software,the Cytisine-Flavonoid conjugates were constructed and synthesised.In addition,triple negative breast cancer cells MDA-MB-231 were applied to determine the antitumor activity of synthetic compounds.The structure-activity relationship was explored in order to provide a basis for the discovery of this type of lead compound with good biological activity.Research methods: Firstly,a series of compounds with Cytisine-Flavonoid skeleton were constructed based on previous research.The molecular docking technology was applied to virtually screen compounds based on triple negative breast cancer cell targets.Then,the aforementioned Cytisine-Flavonoid compounds and their derivatives were synthesized.Subsequently,the human breast cancer cells MDA-MB-231 were used to determine the antitumor activity of the obtained compounds using the MTT method and compared with the results of molecular docking.Finally,the structure-activity relationship of the compounds was investigated.Research results: A series of Cytisine-Flavonoid conjugates were constructed using molecular docking technology,and synthesized by aminomethylation reaction with natural compounds(-)-Cytisine and a series of flavonoids as raw materials.The in vitro activity test results showed that the synthesized compounds had good cytotoxicity against MDA-MB-231 cells,which were basically consistent with the previous molecular docking simulation results,and their structure-activity relationship was further invesgated.Conclusion: Molecular docking technology can better assist the construction of Cytisine-Flavonoid conjugates.The compounds with Cytisine-Flavonoid skeleton had the good inhibitory effect on human breast cancer MDA-MB-231 cells.Cytisine-Flavonoid conjugates synthesized with(-)-Cytisine which introduces chlorine atom at 5 position or 7-hydroxyflavone as raw material had more significant antitumor activity.Research significance and application prospects: Nowadays,breast cancer has become the top of female malignancies.Triple-negative breast cancer is a special type of breast cancer subtype.As a type of high-risk breast cancer,there is currently no unique treatment method for triple-negative breast cancer.Therefore,it is extremely urgent to find a new class of drugs for this disease.At present,natural compounds are important sources for the discovery and development of new anticancer drugs.This research was based on(-)-Cytisine and a series of flavonoids with good biological activity.By using molecular docking technology,chemical synthesis methods,in vitro activity measurement experiments and structure-activity relationship investigation,the Cytisine-Flavonoid conjugates have good cytotoxicity to MDA-MB-231 cells.The research provides more references for the exploring and development of new antitumor lead compounds with better activity.