Synthesis and anti-HER2-positive breast cancer properties of a derivative of lapatinib
Objective To synthesize a derivative of lapatinib and determine its efficacy in treating HER2-positive breast cancer,and the underlying mechanism.Methods Acetylated lapatinib(compound Ⅰ)was synthesized through Steglich esterification catalyzed by DCC-DMAP,with aspirin as the acylation reagent.The anti-HER2-positive breast cancer cell proliferation capacity of compound Ⅰ was assessed with CCK8 and plate cloning assays,while the target of compound Ⅰ was predicted through molecular docking.The regulatory impact of compound Ⅰ on AMPK/mTOR pathway proteins in BT474 cells was elucidated by Western blot.Results The structure of compoundⅠ was confirmed by 1H NMR,13C NMR,and MS analyses.The IC50 of compound Ⅰ against BT474 cells were(112.05±3.21)nmol·L-1(24 h),(35.87±0.79)nmol·L-1(48 h),and(4.98±0.05)nmol·L-1(72 h),respectively.Compound Ⅰ greatly inhibited the clonal formation of BT474 cells.Molecular docking showed that compound Ⅰ had strong binding affinity with EGFR,HER2,AMPK,mTOR,and AKT1.Western blot showed that compound Ⅰ was notably increased in the expression levels of p-AMPK and AMPK,surpassing the stimulatory effect observed with lapatinib.Additionally,compound Ⅰ significantly decreased the levels of EGFR,HER2,p-AKTl,AKT1,p-mTOR,and mTOR.Conclusion Compound Ⅰ exhibits more potent anti-HER2-positive breast cancer proliferation activity compared to lapatinib.This effect is primarily mediated via the activation of AMPK,inhibition of AKT1 and mTOR,and modulation of the AMPK/mTOR pathway.
lapatinib derivativeSteglich esterification reactionanti-proliferationHER2 positive breast cancer
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