Details

Autor(en) / Beteiligte

• Yin, Huanhuan
• Dong, Jingjing
• Cai, Yingchun
• Shi, Ximeng
• Wang, Hao
• Liu, Guixia
• Tang, Yun
• Liu, Jianwen
• Ma, Lei

Titel

Design, synthesis and biological evaluation of chalcones as reversers of P-glycoprotein-mediated multidrug resistance

Ist Teil von

• European journal of medicinal chemistry, 2019-10, Vol.180, p.350-366

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Overexpression of P-glycoprotein (P-gp) is one of the major causes for multidrug resistance (MDR), which has become a major obstacle in cancer therapy. One hopeful approach to reverse the MDR is to develop inhibitors of P-gp in expression and/or function. Here, we designed and synthesized a series of chalcone derivatives as P-gp inhibitors and evaluated their potential reversal activities against MDR. Among them, the most active compound MY3 had little intrinsic cytotoxicity and showed the highest activity (RF = 50.19) in reversing DOX resistance in MCF-7/DOX cells. Further studies demonstrated that MY3 could increase intracellular accumulation of DOX and inhibit expression of P-gp at mRNA and protein levels. More importantly, MY3 significantly enhanced the efficacy of DOX against the tumor xenografts bearing MCF-7/DOX cells with the precondition of unchanged body weight. Therefore, MY3 might represent a promising lead to develop MDR reversal agents for cancer chemotherapy. [Display omitted] •Twenty nine novel chalcone derivatives were designed and synthesized.•SARs were investigated for further P-gp-mediated MDR reversal modulator discovery.•One novel derivative MY3 showed nontoxic and selective inhibition to P-gp.•The mechanism of the most active compound MY3 acting on P-gp was first proved.•MY3 inhibited the migratory ability of MCF-7 cells and MCF-7/DOX cells.