Homoharringtonine (HHT) is a clinically used protein translation inhibitor that is used to treat chronic myeloid leukemia. In addition to its FDA-approved role as a leukemia drug, HHT shows exciting promise for the treatment of other hematologic malignancies and tumors. Finally, it is a perfect molecule to use as a probe to investigate protein translation inhibition. HHT is currently prepared through semi-synthesis from naturally derived cephalotaxine. Cephalotaxine is obtained from Asian plum yew trees grown in China. The cost of HHT in particular, along with other leukemia treatments, has been described as ?astronomical? and ?harmful to patients? by a group of 100 leading cancer specialists. This cost results in part from a supply bottleneck reflecting its tree-based sourcing. This project will completely eliminate this supply problem, and provide cephalotaxine and HHT for our studies and those by other research groups. Natural products have been the source of the majority of drugs throughout history, and still are today. The field of chemical synthesis directly contributes to the application of natural products as medicines. Aromatic and heteroaromatic rings are indispensible motifs in biologically active compounds. Thus, chemical reactions that allow for the construction of molecular architectures containing substituted aromatic rings are particularly valuable to human health. Polycyclic nitrogenous molecules, exemplified by the Cephalotaxus alkaloids in this proposal, are also critically important as biologically active molecules and pharmaceuticals. However, polycyclic nitrogenous molecules, such as alkaloids, are notoriously difficult to prepare, often requiring arduous chemical syntheses for preparation. We will develop two new cascade reactions that efficiently prepare: 1. Substituted arenes, and 2. Complex polycyclic alkaloids. The innovativeness of this research is the strategic use of cascade reactions to assemble structures that previously required multiple steps to prepare. A distinguishing feature of this strategy is its inherent efficiency. Additionally, we will showcase these pericyclic cascades in syntheses of natural products and natural product analogs. More widely, this strategy will find immediate application in the preparation of biologically active molecules, such as HHT; chemical probes for biological systems, and related molecules.
This project is a synergistic study of chemical reactivity, synthesis of natural products, and biological evaluation of designed protein translation inhibitors. New chemical reaction development and innovative synthetic strategies are core elements of the proposed chemical syntheses. Design of translation inhibitors and in vitro evaluation of the synthetic molecules will enable investigation of their biological activity with the goal of identifying potential lead compounds for further evaluation.
