Design, synthesis, and biological evaluation of matrine derivatives possessing piperazine moiety as antitumor agents

Using matrine (1) as the lead compound, a series of new piperazinyl matrine derivatives were designed, synthesized and evaluated for their antitumor activities in vitro and in vivo. Structure activity relationship (SAR) analysis indicated that introduction of substituted piperazine on matrine might significantly enhance the antiproliferative activity. Moreover, types of substituents of piperazine exhibited great different effects on the antiproliferative activity of target compounds against Bel-7402 and RKO cell lines. The in vivo antitumor assay results revealed that some of the target derivatives possessed better therapeutic efficacy than matrine and low toxicity. More importantly, among the newly synthesized compounds, M16 and M26 possessed strong antitumor activity against the two cell lines. Moreover, six of the synthesized compounds M1 , M3 , M7 , M10 , M11 and M17 proved to be of much better therapeutic efficacy than matrine via in vivo antitumor assay. The study provides a theoretical basis for further structural optimizations and discovery of the antitumor pathways of this kind of compounds.