Isolation, identification, bioactivity evaluation and structure-activity relationship studies of tricothecenes and the miliusa constituents

Background: Natural products have attracted high attention due to their great contribution in drug discovery. Many natural products have shown to be effectively against different disease targets including cancer, malaria and HIV. And their structural diversity is a rich resource for the discovery of novel bioactive compounds. This thesis is to explore plant natural products for their potential in treatment of malaria and cancer diseases. Malaria is still considered as a major global health problem, affecting a large population of the world, especially in the developing countries. Effective drug discovery is still one of the main efforts to control malaria, and plant-derived compounds have played the most important role for treatment of malarial disease. In our previous work, we have evaluated more than 2,000 plant extracts against the malaria parasite Plasmodium falciparum. As a result, we discovered dozens of antiplasmodium plant leads. Bioassay guided separation of these active plant extracts led to isolation of some potent antimalarial compounds. Among them, trichothecenes, the sesquiterpenes identified from the plant Ficus fistulosa and Rhaphidophora decursiva, were found to have potent inhibitory activity against P. falciparum with IC50 values in the sub-nano molar range in our previous study (Zhang et al. 2002). However, these compounds are significant cytotoxic. In order to improve the antimalarial activity of the trichothecenes, we evaluated the antimalarial activity of dozens of trichothecenes, and based on the structure-activity relationships (SAR) analysis, we synthesized trichothecene derivatives with low cytotoxicity. On the other hand, cancer has stricken one-third of the world’s population. ii Through our anticancer drug program to discover bioactive leads from thousands of the plant extracts, the extract of Miliusa sinensis Finet et Gagnep. (Annonaceae) was found to exhibit cytotoxic activity against a panel of cancer cell lines. Our previous bioassay-directed fractionation of the leaf, twig and flower extracts of M. sinensis has led to the discovery of a novel class of anticancer lead molecules, which we designated as miliusanes (Zhang et al, 2006). M. balansae, in the same family with M. sinensis, also contains bioactive miliusanes. We thus collected the plant materials of M. balansae to isolated additional new anticancer miliusanes. Objective: The objective of this study is to discover novel antimalarial and anticancer natural compounds from plants using different techniques in combination of extensive literature review, phytochemical separation, SAR analysis, semi-synthesis and biological activity study. Trichothecenes and miliusanes are the two major classes of the compounds, which have been extensively explored in the current thesis for their antimalarial and anticancer potential. Methodology: There was a prior comprehensive review article entitled “Antimalarial activity of plant metabolites” by Schwikkard and Van Heerden (2002), which reported structures of those antiplasmodial active compounds and covered literatures up to the year 2000. As a continuation of their work, antimalarial compounds isolated from plants, including marine plants, which reported in the literatures from 2001 to the end of 2017 have been reviewed and organized according to their plant families. Dozens of trichothecenes have been obtained by us and explored for their SARs.