Synthesis,Biological Evaluation And Molecular Modeling Of Chalcone Carboxylic Acyl Shikonin Derivatives

Cancer is still one of the highest mortality rate disease in the world.According to research,causes of cancer are very complicated,which involves many molecular mechanisms.And cell mitosis disorder is one of the most important reason of cancer disease.In the whole process of cell mitosis,microtubules play an extremely important role.Mitotic spindle is formed by microtubule polymerization and fasten to the kinetochore of chromosomes when microtubules extend from the cell centrosome during cell mitosis.Therefore,the inhibition of microtubule polymerization has become to be the mode of action for several clinically successful anticancer drugs.Tubulin is the major component of microtubules,and is becoming more and more important as the target of antimitotic drugs.Shikonin is a highly effective natural antitumor drugs,research has shown it can regulate tubulin to achieve the purpose of inhibiting tumor cell growth,I pharmaceutical industry pay great attention to it.Class chalcone derivatives,moreover,the value of the biological activity have been reported for a long time,chalcone ketones compounds due to the particularity of the structure as a popular anti-cancer drug active intermediates,cause the attention of many researchers.Based on these studies,we attempt to use the chalcone as the basic scaffold for the design of a series of novel tubulin polymerization inhibitors,and speculated that these compounds have good antitumor activity.18 novel shikonin derivatives(PMMB-248-PMMB-265)were designed and synthesized and characterized by 1H NMR,MS and elemental analysis.Due to there is no detail activity reported about these 18 compounds,all those compounds then were tested on three tumor cell lines Hela,MCF-7 and A549 in vitro and most of the compounds exhibited excellent antitumor activity.Among all the compounds,compound PMMB-259 showed the most potent in vitro growth inhibitory activity against Hela,MCF-7 and A549 cancer cell lines,with IC50 values of 4.53μM、2.36μM、5.84μM,respectively.The docking study based on tubulin crystal structure(PDB code:1SA0)showed compound PMMB-259 exhibits more affinity for tubulin than colchicine,which rationally proved the reason why these compounds also possess effective inhibitory activity profile against tubulin and helped us to explore the binding modes of these compounds.Furthermore,we also showed that PMMB-259 was a potent inducer of apoptosis in MCF-7 cells and it had cellular effects typical for microtubule interacting agents,causing accumulation of cells in the G2/M phase of the cell cycle.The mitochondrial membrane potential experiment confirmed that the compound could induce cell early apoptosis by mitochondria approach.Additionally,3D-QSAR(3D quantitative structure-activity relationship)model provided more information that could be applied to design new molecules with more potent tubulin inhibitory activity.