Compared to the great achievement in the development of anti-malarial drugs based on the natural product artemisinin,limited success has been accomplished in the discovery of anticancer artemisinin analogues (artemalogs).The unknown either targeting or non-targeting anticancer mechanisms and the poor druggability are the major obstacles of current artemalogs.To generate structurally more diverse artemalogs,we recently conducted an alternative medicinal chemistry campaign by constructing various heterocyclic functionalities at the less explored sites including C-6 and-9 positions through 1,3-dipolar cycloaddition or click reaction,thus affording a series of structurally novel artemalogs.Several compounds demonstrated superior in vitro antiproliferative effects against various cancer cell lines with IC50 values in nanomolar ranges.We further investigated the effects of artemisinin and three potent artemalogues on protein expression in whole A549 cells by using mass spectrometry-based global chemical proteomics approach,and systematically identified dozens of significantly up-and down-regulated proteins through quantitative proteomic analysis,some of which are involved in essential biological processes.These findings will provide valuable inputs to discover more potent artemalogs and to further uncover the anticancer mechanisms.