Synthesis And Biological Assessment Of New Annonaceous Acetogenin Mimetics Without Terminal Lactone

Annonaceous acetogenins is a large family of fatty acid-derived natural products, most of which display a wide spectrum of biological activities, including cytotoxity and anticancer activity. We have developed several types of acetogenin mimetics exhibiting potent antitumor activity. The representative mimic, AA005, not only shows comparable cytotoxity as natural acetogenins, but also exhibits significant selectivity between normal and cancerous cells. Our work also found that AA005 could inhibit NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial electron transport system, and therefore induced cancer cell death through autophage processes.According to the established structure-activity relationship of AA005, we deduce that the terminal unsaturated-lactone is essential for the cytotoxity of AA005, while the long hydrocarbon chain bearing an ethylene glycol ether moiety is necessary for binding mitochondrial target and potentially a crucial factor for its action selectivity. In this work, we plan to design and synthesize a series of prodrugs by combining a known anticancer drug with the long hydrocarbon chain of AA005, directing selective entrance to cancerous cells over normal cells. We wish such prodrugs could release active drug when they enter the cells. In addition, we designed several florescent probes to verify this proposal. However, all the florescent probes showed no selectivity between cancer cells and normal cells. It reveals that the action selectivity of AA005 was not only caused by its long chain substructure. Another possible reason might be the hydrolysis ability of the synthesized prodrugs. If they could not hydrolyzed, they wouldn’t inhibit cancer cell growth effectively.In the research of florescent probes, we found one florescent probe using rhodamine B as a fluorophore showed strong cytotoxity against cancer cells. Our careful analysis of structure-activity relationship found that the piperazine ring might be the crucial structural factor for its cytotoxity. This led us to continue our second research programme. A number of different nitrogen-heterocycles were introduced to replace the terminal lactone of AA005, resulting in a new series of AA005 mimetics. After biological evaluation, we found that most of these mimetics showed low micromolar inhibitory activities against the growth of cancer cells. For incorporation of nitrogen atom(s), these mimetics present better water solubility than AA005, and are easier to synthesize. The newly developed protocol provides an additional entrance to more potent anticancer agents.