Synthesis And Anti-non-small Cell Lung Carcinoma Activity Of Novel Tetrandrine Derivatives

Objective:Studies have shown that tetrandrine（Tet）,the main component of traditional Chinese medicine,plays a significant role in reversing multidrug resistance and anti-tumor.In this paper,tetrandrine was substituted on C-5 position in order to obtain better anti-tumor compounds.Methods:Based on the structure characteristics of tetrandrine,a bromine substituted intermediate was obtained by reaction with bromine acetic acid solution at low temperature.The goal compounds were synthesized by Suzuki-Miyaura coupling reaction with the selected boric acid derivatives and the products`structures were confirmed by the melting point、ESI-MS、¹H-NMR and ¹³C-NMR.The inhibitory activity of the compounds against human non-small cell lung cancer（NSCLC）A549 was determined by MTT method.The Tet,intermediate and the broad-spectrum antitumor drug doxorubicin were used as positive control drugs simultaneously.According the inhibitory rate at the concentration of 10μM,these compounds whose inhibitory rate was higher than that of positive control drugs were selected for further screening.The IC₅₀0 value was obtained to exactly evaluated their anti-tumor activity.Results:Twenty compounds were synthesized in this paper.The purity and structures of these compounds were identified by the melting point,ESI-MS,¹H-NMR and ¹³C-NMR.The results of MTT assay showed that their inhibition rate on NSCLC A549 was higher than 50%except Y12 and Y13 when the concentration was 10μM,and the inhibitory rates of Y5,Y6,Y9 and Y11 were even higher than three positive control drugs.The IC₅₀0 value of Y5,Y6,Y9 and Y11 were higher than Tet by 3.52%¹9.88%.Conclusion:The structures of 20 compounds were identified and confirmed by the melting point,ESI-MS,¹H-NMR and ¹³C-NMR.With the exception of Y11 and Y12,the other compounds were not reported.Its antitumor activity in vitro was tested by MTT method.The inhibitory effect of compound Y1^Y11,Y14^Y20 on NSCLC A549 was obvious when the concentration was 10μM.The IC₅₀0 values of compounds Y5,Y6,Y9 and Y11were all less than 5μM based on the results of primary screening and rescreening,The preliminary conclusion of the structure-activity relationship was as follows:large groups can enhance the anti-tumor activity of derivatives;when phenylboric acid was used as substituent group,isopropyl group and t-butyl group on benzene ring have better activity than ethyl;the substitution activity of furan ring is better than that of pyridine ring;and the biological activity of aromatic heterocyclic substituent site is different.The antitumor activity of arylheterocyclic compounds decreased when they were substituted by halogens,whereas alkoxyl groups increased in comparison with aromatic heterocycles.The anti-NSCLC A549 activity of cycloolefin phenylboric acid was slightly lower.The results provided a basis for the following studies on the selection of substituents and the mechanism of anti-tumor action.