Structural Modification and Biological Studies of the Antitumor Natural Products Miliusanes as Novel Cancer Therapeutic Agents

Cancer, a leading cause of death in the world, has become the most onerous health problem that afflicts the world public. Many anticancer drugs have been developed in the last few decades, but all of them are limited in use due to their narrow therapeutic indices and severe side effects, and almost all of them will eventually encounter resistance from cancer cells. The search and discovery of novel anticancer agents are therefore imperative. Natural products have proven to be a rich source of anticancer compounds with more than half of the current agents in clinical use being such molecules. In our ongoing search for novel anticancer active compounds from plant resources, a cluster of novel compounds with a rare C-18 skeleton, designated as the miliusanes, were discovered from Miliusa sinensis. These plant natural compounds displayed potent activity against a panel of human cancer cell lines in in vitro, as well as, in in vivo studies. In a hollow fiber in vivo mouse model study, two miliusanes showed potent inhibition against cancer cell growth. Xenograft mouse model experiment using HCT116 human colon cancer cell line further revealed that one of the miliusane compounds showed significant tumor inhibition response at the doses of 20 and 30 mg/kg. Further, three miliusanes (miliusol, miliusate and miliusane I) were evaluated in the NCI 60 cell line panel, and the NCI 60 cell line COMPARE analysis revealed that this group of compounds may possess a potentially novel anticancer mechanism of action. Thus, considering their anticancer potency and structural novelty, this type of molecules are deemed worthy of in-depth chemical and biological studies. The current project is our continuing efforts to discover novel and potent anticancer agents in order to develop new chemical entity drugs amenable to the treatment of cancer. To achieve this goal, the following objectives and tasks are proposed: 1) to elucidate anticancer effects of the miliusanes through different approaches including characterization of transforming phenotype and cDNA gene analysis; 2) to synthesize structurally novel miliusane derivatives to optimize their anticancer activities and therapeutic potentials; 3) to assess the anticancer efficacy of the newly synthesized miliusanes through in vitro and in vivo studies as well as to determine the pharmacokinetic effects of the selected miliusanes in animals. It is our expectation that anticancer candidates with strong therapeutic efficacy will emerge upon the completion of the proposed studies.