Synthesis and Evaluation of Photoswitchable c‐Raf Inhibitor

Abstract

Cancer is one of the leading causes of death in the United States. As a result of its staggering impact, it is unsurprising that scientists have been working diligently to find treatments. Chemotherapeutics and other anticancer drugs have come a long way since their discovery, however the vast majority of them still cause unintended side effects. The main issue with many cancer medications at the moment is the high rate at which healthy, noncancerous cells are damaged along alongside the cancer cells. Highly desirable new treatments for cancer are ones that can selectively target cancerous cells while excluding healthy cells. One way that we can address the problems with the current therapies is by using photoisomerizable compounds, more specifically azo‐stilbenes.Photoisomerizable compounds are molecules that are isomerized by light. In other words, their structure changes when exposed to specific light wavelengths. The azo‐stilbenes, in particular, undergo a trans to cis isomerization when hit with blue or UV light. This isomerization is easily reversible and can be accomplished quickly by irradiating the molecule with a longer wavelength of light (typically >500 nm) or more slowly at room temperature in the absence of light.Photoisomerizable compounds like the azo‐stilbene group have become widely used in many fields, such as functional materials, yet these azo‐compounds have more recently found utility in cancer research due to their ability to be isomerized. These azo‐compounds take one conformation in their trans form and when hit with light isomerize into the cis conformation, thus taking a very different shape. Given that shape complementarity is critical for many drug‐target interactions, this isomerization results in a change in the bioactivity of these molecules. When in their trans form, the azo‐compounds cannot bind to the same target that they can in their cis form. Judicious application of the appropriate wavelengths of light can be used as a switch that will allow for selectivity in cytotoxic treatments. With the use of azo‐stilbenes, off‐target side effects could be greatly reduced and potentially eradicated.One example of a potential target for photo‐switchable therapeutics is c‐Raf. This kinase plays a key role in a pathway that regulates the cellular cycle including the production of new cells and apoptosis, which is dysregulated in some cancers. This work will describe the design, completed synthesis, photokinetic analysis, and preliminary bioactivity measurements for two lead molecules with potential as photoswitchable drugs based upon a previously reported c‐Raf inhibitor.Support or Funding InformationAlbion College Foundation for Undergraduate Research Scholarship and Creativity (FURSCA)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.