Design, Synthesis And Antitumor Activity Of Glaucocalyxin A Molecular Probes

Glaucocalyxin A（GLA）is one of the main components of rabdosia japonica（burm.f.）hara var.glaucocalyx（maxim.）hara,which has efficient antitumor activity.The bioactive center locate at theα,β-unsaturated cyclopentanone block.However,due to the poor solubility of GLA in water,it has been limited in the field of pharmaceutical research.Our goal is improved its solubility in water by modifying on GLA molecule under keeping the bioactive center.And then find the higher antitumor activity molecule as candidate probe,further to find the target receptor protein.The synthetic route of the probes is shown as following:1.Six GLA acetal derivatives were synthesized from GLA and aldehydes by nucleophilic addition on the bis-hydroxy group at the 7th and 14th of GLA.Of them,two acetal derivatives are terminal-nitrogen-containing tag-free probe molecules,and four acetal derivatives are terminal-alkyne-containing tag-free probe molecules.2.Twelve biotin-tagged GLA probe molecules were prepared by Click reaction from the four GLA terminal-alkyne-containing molecules described above and terminal-azide biotin.In addition,one biotin-tagged GLA probe molecule with different linker was prepared by reacting GLA terminal-NH₂-containing molecule with biotin.All synthesized compounds were characterized by ¹H-NMR,¹³C-NMR and HR-ESI-MS.3.The in vitro antitumor activities of GLA tag-free probe molecules and biotin-tagged GLA probe molecules were tested by MTT method on three kinds of tumor cell lines（human cervical cancer cell line Hela,human breast cancer cell line MCF-7 and human promyelocytic leukemia cell line HL-60）.Of the synthesized compounds,only eight had been tested,the others are in progress.The results shown that the inhibitory activities of the compounds 1b,2b,3d,4d,15,16,17 and 18against MCF-7 and HL-60 cells were lower than that of the parent compound.3d has weaker inhibitory activity on HL-60 cells(IC₅₀,50.1μM).16 also has weaker inhibitory activity against Hela cells(IC₅₀,67.7μM).Interstingly,Compound 15exhibited higher inhibitory activity against Hela cells with lower IC₅₀（26.9μM）,which was lower than that of its parent compound(IC₅₀,29.6μM).Next,this compound will be used to bind and identify the target protein.The antitumor activity of other synthetic compounds is still under investigation.