Design,Synthesis And Biological Evaluation Of Mimics Of Aromathecin As Potent Anticancer Agents

Natural products and their derivatives have historically been a major source of chemical pharmaceuticals.Their role in the drug discovery process is especially pronounced in the areas of anticancer agents,where the fractions of the drugs derived from natural products amount to 60%.Topoisomerase ?(Topo ?)was a promising target in antitumor drug development.Currently,the derivatives of camptothecin,a natural antitumor product,have clinically been widely used as anticancer drugs targeting to Topo I.However,several disadvantages of camptothecins,such as low solubility,poor stability,high toxicity,and the occurrence of durg-resistance,have limited its applicationt in clinical practice.The discovery of new anticancer agents based on the more stable skeletons of natural products targeting to Topo ? has become an important field in the development of new anticancer pharmaceuticals.In this dissertation,thirty mimics of aromathecin,a derivative of 22-hydroxyacuminatine—a natural alkaloid targeting to Topo ?,were designed,synthesized in the guidance of the Topo ?pharmacophore model.The antiproliferative activity of these mimics was evaluated in vitro against four selected human cancer cell lines.The results indicated that most of them exhibited potent anticancer activity with an IC50 value range from 0.31 to 11.97 ?M.Detailed biological exploration of the selected compound 3e revealed that it could induce S phase cell cycle arrest and mitochondria mediated apoptosis which could be futher confirmed by the results of the Annexin V-FITC assay,depression of mitochondrial membrane potential(??m),the elevation of reactive oxygen species(ROS)level and intracellular[Ca2+]level.Furthermore,Western blot analysis showed that 3e up-regulated the levels of Bak,and down-regulated the level of Bcl-2,Bax,Bcl-xL confirming the apoptosis inducing properties.The gel electrophoresis assay showed that 3e exhibited interaction with DNA directly and also had significant inhibitory effects on the activity of Topo ?.Docking analysis of the crystal structure indicated that compounds could gain access to three active sites in the protein-DNA complex.This work might serve as a rational basis for possible design of novel anticancer drugs targeting to Topo ?.The information gained by our study provides a reference toward discovering novel anti-cancer agents as well.