Synthesis And Biological Evaluation Of Matrine Derivatives As Potential Anticancer Agents

Matrine(C15H24N2O),one of the major alkaloid components of the traditional Chinese medicine Sophora alopecuroides roots,has a wide range of pharmacological effects.However,the low bioavailability and bioactivity of matrine have limited its utility as a therapeutic drug.Therefore,many researchers have been working on generation of its derivatives and analogues by total synthesis or structural modification in order to improve its activity and bioavailability.In our previous study,we selected matrine as a lead compound and successfully identified that introduction of double bond and aromatic ring at 14 site of matrine skeleton could largely increase its anticancer activity.In this study,a variety of N-substituted pyrroles and indoles were introduced on the 14 site of matrine skeleton which resulted in designing 58 new matrine derivatives.Moreover,it is well known that sulfur atom is an isostere of oxygen atom.Based on this idea,a variety of aromatic ring were introduced on the 14 site of thiomatrine skeleton which resulted in designing 30 new thiomatrine derivatives.All compounds displayed better antiproliferative activity than matrine and compound A6 and B21 exhibited the most significant growth inhibition to three cancer cells with IC50 values in range of 3.42-8.05 ?M.Compound C-28 exhibited the most significant growth inhibition to four cancer cells.Further studies indicated that compound A6 and C28 exerted its anti-cancer activity by inducing apoptosis and arrest CNE2 and SMMC-7721 cells at G2/M phase.Compound B21 exerted its anti-cancer activity by inducing apoptosis.Western blot analysis revealed that compound C28 could induce apoptosis by activating caspase-3,increasing expression of cleaved caspase-3 and reducing the ratio of Bcl-2/Bax.