The purpose of this project is to synthesize baccatin-free anticancer agents using the procedure developed by the Ojima group. Previous studies have shown that such 'taxoid mimics' have weak cytotoxic activity against cancer cell lines. Therefore, the purpose of this project is to synthesize new 'taxoid mimics' that will more closely imitate the structure and activity of paclitaxel.

One of the most commonly used drugs to treat cancer is Taxol® (paclitaxel). The compound stabilizes the microtubules within a cancer cell, thus preventing the cell from undergoing mitosis and eventually leading to programmed cell death, or apoptosis1. Since this mechanism of action is shared with other natural compounds such as epothilones, eleutherobin, and discodermolide, scientists began looking for structural similarities among these molecules. Through the use of molecular modeling and 2-D NMR techniques, a common pharmacophore was proposed by the Ojima group2. This pharmacophore suggests that the baccatin core serves as a scaffold to ensure the proper orientation of important side chains. According to these studies, the baccatin core could be replaced by a much simpler scaffold with a similar three-dimensional structure.

Such a scaffold-mimicking core (Figure 1) was previously studied by the Ojima group3. After synthesizing this core from D-hydroxyproline, the skeleton will be modified by epoxidation of the double bond. The C-2 and C-13 taxoid side chains will then be synthesized and added in the proper positions (Figure 2). All new compounds will be fully characterized by NMR spectroscopy and mass spectrometry. The cytotoxicity of the final compounds will be evaluated in vitro against various cancer cell lines.

This research was supported by a fellowship (to T.H.) from the Simons Foundation and grants from the National Institutes of Health (to I.O.).