Cascade Reactions for Biologically Active Natural Products

Project Summary / Abstract
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 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. Specifically, we will prepare substituted:
phenols, indoles, furans, and related structures. 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 alkaloid natural products.

Grant Number: 7R01GM140183-05
NIH Institute/Center: NIH
Principal Investigator: CHRISTOPHER BEAUDRY