Synthesis And Biological Evaluation Of Novel Piperlongumine Analogues

In economically developed countries, cancer is the leading cause of death. Meanwhile, cancer is the second leading cause of death in developing countries. In the last few decades, a rapid development in cancer treatments has been made. Now, the three main methods for treating cancer are surgery, radiation therapy and chemotherapy. However, surgery and radiation therapy can’t completedly eradicate tumors, especially in the patients with advanced cancer. So chemotherapy plays a more important role. In this field, natural products with anti-tumor activity have received widespread attention. Recently, piperlongumine (PL) was identified to kill cancer cells selectively in vitro and in vivo through a cell-based small-molecule screening and quantitative proteomics. Most recently, the PL-mediated protein glutathionylation of glutathione-binding proteins was proposed to expain its selectively anti-tumor activity. But the decisive molecular mechanism of action (MMOA) is not clear. And in the nature, the resource of piperlongumine is limited. Facile synthesis and modification of piperlongumine analogues is meaningful in order to understand its decisive molecular mechanism of action and optimize its structure.In this project, some compounds were synthesized based on the substructure of piperlongumine. Through analyzing SAR, the decisive molecular mechanism of action was further explored. We divided the lead compound into three parts(A ring, B ring and conjugate-linker) for structural modification. Piperlongumine derivatives with a variety of cricoid and non-cricoid derivatives were synthesized to improve antiproliferative cytotoxicity. The general SAR of the cricoid series demonstrated: enlargement of the size of ring A from five- to seven-membered ring consistently increased cytotoxicity, the length of the conjugate-linker preferred to one carbon-carbon double bond; replacement of three methoxyl groups of PL with methylenedioxy group of piperlonguminine showed comparable potency. The most potent compounds 25c and 26c displayed three-fold greater potency than PL. However, the lack of reproducibility in vivo anti-tumor activity of compound 25c was observed and 25c were evaluated in vitro metabolic stability. Supposedly, the diimide may contribute to the instability of compound 25c. At the same time, considering the cost and convenience of synthesis, a series of non-cricoid derivatives were designed. The SAR from the cellular activity suggested that acrylic amide without substitution is the key pharmacophore. The cellular activity of 32a is comparable with that of PL and easier to synthesis. It is of great significance for subsequent medicinal chemistry research.