Design,Synthesis,and Reversal Activity Of Flavonoid Derivatives Against Multidrug Resistance In Cancer

Among all kinds of cancer treatment,chemotherapy is still the main means to treat most cancers.Most cancer patients initially respond to drug treatment,but eventually develop resistance to conventional and targeted chemotherapy during treatment.The inherent or acquired cross-resistance of cancer cells to various chemotherapeutic drugs is called multidrug resistance(MDR).The mechanism of cancer MDR is complex,with one of the main mechanisms being overexpression of the drug delivery protein P-glycoprotein(P-gp).P-gp belongs to efflux transporter.The overexpression of P-gp in cancer cells can use ATP as driving energy to export a variety of chemotherapeutic drugs with unrelated structure and function to the outside of cells,Reduce drug concentration and cell sensitivity to drugs,resulting in multidrug resistance,leading to chemotherapy failure of patients.Since it was reported in 1981 that verapamil can inhibit P-gp activity,many researchers have been committed to the development of P-gp inhibitors,and many compounds have been proved to reverse P-gp-mediated MDR.However,there are no drugs that can block P-gp-mediated drug resistance in clinic at present.The main reason is that these P-gp inhibitors have the disadvantages of high toxicity,large side effects and poor selectivity.Developing effective and safe P-gp inhibitors is the research focus of reversing MDR.Flavonoids belong to the secondary metabolites of polyphenols,which are widely distributed in plants and have great research value,usually with low toxicity.In this study,the flavonoid compounds luteolin and isoglycyrrhizin were used as the lead compounds for structural modification.Six flavonoid derivatives were designed and synthesized by introducing hydrophobic side chains and nitrogen-containing bases into the aromatic ring,hoping to obtain effective and safe P-gp inhibitors.In this study,a preliminary study was carried out on the antitumor activity of the six derivatives synthesized at the cell level in vitro.First,MTT method was used to determine the non-toxic dose of derivatives ISL-1,ISL-2,LUT-1,LUT-2,LUT-3,LUT-4 to breast cancer cell line MDA435/LCC6 and breast cancer drug resistant cell line MDA435/LCC6 MDR.Secondly,MTT method was used to evaluate the sensitivity effect of derivatives ISL-1,ISL-2,LUT-1,LUT-2,LUT-3,LUT-4 and common anti-tumor drug paclitaxel on breast cancer cell line MDA435/LCC6 MDR to paclitaxel,and then compare and screen the tumor reversing activity of the synthesized derivatives.Finally,the MDCK-MDR1 cell model was established to screen and evaluate the flavonoid derivative P-gp inhibitor from the aspects of inhibiting P-gp efflux.The study showed that ISL-1 and ISL-2 of the six derivatives had a good reversal effect on paclitaxel resistance μ At the concentration of m,the reversion times were 4.69 and 4.43,which were equivalent to verapamil.Further transport experiments of ISL-1 and ISL-2showed that the derivatives ISL-1 and ISL-2 were weak substrates of P-gp,and ISL-1 and ISL-2 could significantly inhibit the efflux of P-gp.