Design,Synthesis And Antitumor Activity In Vitro Of Derivatives Of Harmine N~9-Cinnamic Acid

Harmine is a kind of natural product discovered from the national medicinal plant Peganum harmala L.In recent years,its antitumor activity has been concerned.It can not only inhibit tumor growth by inhibiting cyclin dependent kinases and anti-angiogenesis,but also promote cell apoptosis through molecular mechanisms.However,the poor selectivity of it limited its anti-tumor clinical application.It is valuable to search for highly selective anti-tumor drugs of Harmine derivatives.This paper reviewed the antitumor activity of Harmine derivatives,designed and synthesized a series of Harmine N⁹-cinnamic acid derivatives.The antitumor activity and structure-activity relationship of these target compounds were analyzed in vitro,in order to improve the anti-tumor activity while reducing the cytotoxicity caused by DNA intercalation.Then,the structure-activity relationship and mechanism of action were studied.The main contents are as follows:（1）According to Combination Principles,16 title compounds of Harmine derivatives designed and synthesized.The structures of compounds were characterized by ¹H-NMR,¹³C-NMR,ESI-MS and X-ray diffraction methods.（2）The inhibitory activity of the target compounds carried out in cancer cells MCF-7,MDA-MB-231,HepG2,SMCC-7721 and normal cell WI-38 by MTT assay.The results showed that compounds 11a,11b,11c exhibited selective growth inhibitory effects.Especially,compound 11a has the best effect in MDA-MB-231 cells(IC₅₀=13.73±1.53μM),which is significantly higher than that of Harmine(IC₅₀=63.01±2.83μM).And the cytotoxicity to normal cells WI-38 of 16compounds is lower than that of Harmine.（3）The structure-activity relationship analysis revealed N⁹ of Harmine combinated with other groups through a linker with 4carbon atoms showed the best activity.（4）Anticancer mechanism of action study showed,compound 11a caused G2/M arrest of tumor cells.Concurrently,it stimulated apoptosis by gathered specifically in the mitochondria,induced ROS production,reduced mitochondrial membrane potential.It activated Bax,Cleaved Caspase 3,Cleaved PARP while reduced expression of Bcl-2.Without causing DNA damage like Harmine,it showed less cytotoxicity and better selectivity.The above studies fully showed that these compounds have good antitumor activity and broad research prospects.It also provided a certain basis for the study of antitumor activity of Harmine derivatives.