Design, Synthesis And Antitumor Activity Of Parthenolide Derivative

Parthenolide is a sesquiterpene lactone compound,which has received extensive attention due to its diverse biological activities.Parthenolide has anti-inflammatory,antiviral,anti-tumor and other pharmacological activities.Studies have shown that parthenolide also has significant anti-proliferative properties against other types of human cancers,including breast cancer,lung cancer,prostate cancer,liver cancer,brain cancer,pancreatic cancer,and bone cancer,especially cancer stem cells including leukemia.The anticancer properties of parthenolide are mainly related to the control of a variety of tumor-related biological processes,such as inflammation,proliferation,angiogenesis and metastasis.However,it has recently been found that the mechanism of pharmacological effects of this molecule on anti-tumor cells includes inhibition of transcription factor NF-κB and related signaling pathways,activation of p53 pro-apoptotic protein Bcl-2,induction of oxidative stress,and changes in epigenetic mechanisms.In order to obtain better antitumor active compounds,people are currently interested in reconstructing this natural product scaffold to obtain derivatives with enhanced efficacy and improved drug properties.In this study,the C-14 position of parthenolide was modified,and 16compounds that had not been reported in the literature were synthesized by introducing carboxylic acid and amino substituted groups through oxidation,condensation and iodination.The structures of the new compounds were confirmed by ¹H-NMR,¹³C-NMR and HR-ESI-MS.The anti-tumor activity of 16 compounds was evaluated in vitro by human non-small cell lung cancer A549,human breast cancer cells MDA-MB-231 and MCF-7,and adriamycin was used as a positive control drug.The results of MTT assay showed that all compounds had good antitumor activity against A549 cells,but they were weaker than the positive control.The antitumor activity against MDA-MB-231 cells was weak,while some compounds were comparable to the positive control.Some compounds also have certain antitumor activity against MCF-7 cells.The IC₅₀of compound ZA-5 on A549 cells was 1.03μM,and the IC₅₀ of compound ZA-1 on three tumor cells was 1.29μM,8.31μM and 3.56μM,respectively.The IC₅₀ of compound ZB-1 on three tumor cells was 2.40μM,5.33μM and 4.17μM,respectively.The analysis of its structure-activity relationship showed that the compound had high selectivity to A549 cells.The introduction of benzofuran-7-carboxylic acid,ethacrynic acid,and rebosinic acid fragment links to the C-14 of parthenolide contributed to the improvement of the antitumor activity of parthenolide.Plate cloning experiments showed that compound ZA-5 could significantly affect the proliferation of A549 cells.With the increase of concentration,the inhibition of A549 cell proliferation was more obvious.The effect of compound ZA-5 on the apoptosis of A549 cells was detected by flow cytometry.The results showed that the apoptosis rate of A549 increased significantly with the increase of compound ZA-5 concentration,showing a dose-dependent apoptosis.At the concentration of 2μM,the apoptosis rate of ZA-5 induced apoptosis was significantly higher than that of parthenolide,which further indicated that structural modification of parthenolide contributed to the improvement of activity.The results showed that the compound had good antitumor activity against A549 cells,but it had certain cytotoxicity against NRK-52E cells.In the later stage,it can be combined with anti-tumor,reduce the amount of compounds and further explore the pharmacological activity of compounds,further clarify the mechanism of action of compounds,and is expected to develop into new anti-tumor drugs.