Synthesis and Evaluation of Novel Photoisomerizable Small Molecules as Chemical Tools

Tubulin, a central component of the cellular cytoskeleton is critical for the formation of the mitotic spindle in mitosis. Without this dynamic protein, a cell is unable to properly divide. As a result, a number of cancer drugs target tubulin, and prevent the cell from properly undergoing mitosis. A class of drugs known as mitotic inhibitors disrupt tubulin polymerization by acting to stabilize or destabilize tubulin polymer formation. While these drugs are often used to treat disease, they may also be used as biochemical tools to study tubulin polymerization. However, these molecules often lack precise spatial and temporal control, rendering them inadequate to fully study a dynamic process such as tubulin polymerization. Recently, photoisomerizable compounds have gained attention due to their increased spatial and temporal control. Azo‐stilbene compounds are well known to be photoisomerizable between the cis and the trans form at 400‐600nm. This photoisomerization gives azo‐stilbene compounds great power as biochemical tools. Certain mitotic inhibitors have a stilbene backbone, which make azo‐stilbene compounds the ideal starting point for the discovery of photoisomerizeable tubulin polymerization inhibitors. We have developed a library of azo‐stilbenes, which we have supplemented with rationally designed compounds, for the purpose of inhibiting tubulin polymerization. We will discuss the synthesis of these compounds and their activity as novel azo‐stilbene tubulin binders, as well as the implications of our findings for the synthesis of next‐generation compounds to inhibit tubulin polymerization.