Palladium-catalyzed Synthesis And Anticancer Activity Of Paclitaxel-dehydroepiandrosterone Hybrids

Paclitaxel possesses significant anticancer activity,currentl y serves as the most widel y used clinical antitumor drugs.However,these drugs also have many defects,the multi-drug resistance,neurotoxicity and neutropenia of paclitaxel have gradually emerged accompanying with the clinical application.In addition,paclitaxel is faced with scarcity of natural resources and poor water solubility,difficulties in synthesis,which makes it difficult to meet the increasing clinical demands.Therefore,it is of great significance to design and synthesize novel paclitaxel analogues with enhanced activity or reduced toxic and side effects.Based on the study of structure-activity relationship of paclitaxel,this paper designed the method that combining organic synthesis methodology,splicing principle and drug chemical synthesis methods:The suzuki-miyaura reaction,which is rarely used to modify natural compounds directly,was first used to modify the structure of natural product dehydroepiandrosterone.The paclitaxel-dehydroepiandrosterone hybrids were obtained by replacing the taxane skeleton of paclitaxel with elaborated DHEA.Then,anticancer activity of these hybrids were tested in vitro.In this study,a feasible synthetic route was designed through a series of conditions.Finally,18 new paclitaxel-dehydroepiandrosterone hybrids were obtained and confirmed by ¹H-NMR,¹³C-NMR and HR-ESI-MS.The in vitro anticancer activity against human liver（Hep G-2）cancer cell lines of the hybrids was evaluated by MTT assay and showed most of these hybrids possess potent antiproliferative activity.Among these hybrids,three ones（30b,30g and 30i）with meta-substituents in the phenyl group of D-ring of dehydroepiandrosterone analogues indicated moderate anticancer activity better than the others.The optimal compound 30i,showed the superior anticancer activit y against cell line Hep G-2 with the IC₅₀ values of 26.39μM.