Chris Cutler and Dr. Matt Peterson, Chemistry
Summary
The goal of this project was to prepare a library of adenine-based anticancer agents in order to help understand which properties of the molecules contribute to the anticancer activity. I worked in Dr. Peterson’s organic chemistry laboratory for the duration of 2009, synthesizing compounds for anticancer testing. Some were submitted to the NIH for screening against a large panel of cancer cell lines, while others were sent to a collaborator for similar testing. While the results of most of these tests are still forthcoming, the data we have received so far is promising. My work contributed to a publication in an academic journal , and I presented a portion of my research at the Spring Research Conference of BYU’s College of Physical and Mathematical Sciences.
Purpose of the Project
Cancer is a devastating disease and currently no single therapeutic agent is effective at fighting all forms of cancer. Recently, Professor Matt A. Peterson discovered a new class of anticancer compounds that exhibited promising activities against a broad array of cancer cells in vitro. His research also identified several likely modes of action for these compounds, including the identity of several likely biomolecular targets. There are four regions of the molecule that can be modified in order to increase the activity and selectivity of the compounds. The figure at right shows these regions as NE, NW, SE, and SW. Dr. Peterson’s lab had already shown that the NE and NW functional groups were necessary for the observed anticancer activity, but we postulated that the SE and SW groups were not. In order to test this, I synthesized several compounds with differences in the SE and SW regions.
Performance and Results
I followed a multistep synthesis to create a compound in which the central sugar was replaced by an aromatic group. The NE and NW regions remained unchanged, but the SE and SW groups were eliminated. This synthesis was more difficult than we had anticipated, and by the time the compound was completely synthesized we had received more data indicating that the SE group was in fact necessary for anticancer activity, and this approach was shelved without submitting the compound for testing.
The next step was to see whether the SW group was also necessary. Therefore, I worked on a synthetic scheme that would replace the SW group with a group identical to that in the adjacent SE quadrant. On paper this was very attractive because the SW group was difficult to install synthetically. I spent many hours working on this synthesis, eventually finding a sequence of steps that dramatically simplified the procedure and allowed for the efficient production of a compound having an “OTBS” group in both the SE and SW positions, to which the NE and NW groups could then be added. It is this step of the research that I presented at the Spring Research Conference. When submitted for testing, the final compound (bearing a SW “OTBS”) had similar anticancer activity to the original compound, confirming that the SW region will tolerate an altered group while retaining its ability to inhibit cancer cell growth. These results were part of an article published in the journal Bioorganic Medicinal Chemistry Letters in October, 2009.
The “OTBS” groups I installed at the SE and SW positions are greasy, which is important for understanding biological activity. Greasiness, or hydrophobicity, causes a compound to associate with cell membranes. We are interested in determining whether the compound’s activity is a result of being able to pass through membranes or of being anchored to a membrane. Knowing this will help us to identify the biological target of the compound and therefore understanding the mechanism of its anticancer activity. Therefore, I have begun to synthesize a set of compounds with functional groups chemically similar to the “OTBS” group that have varying stability when exposed to acids and bases. The differences in activity of these compounds will help us determine where in the cell the compounds exert their effect, and will therefore provide clues as to how they function.
In addition to the work on the SE and SW groups, I also performed some exploratory work on different procedures for adding the NE group. There are two approaches we have tried. The first is amenable to certain commercially available reagents including slight variations on the aromatic ring, while the second would allow for the convenient and straightforward synthesis of compounds bearing a large variety of aryl or alkyl groups in place of the simple aromatic ring. This line of research has been taken over by another member of the lab research group, and his results are promising. It appears that we will soon be able to create a diverse library of compounds that will help us to optimize the anticancer activity.
Acknowledgment
I want to thank BYU’s Office of Research and Creative Activities for the opportunity to complete this project. I have learned a great deal about laboratory research, and my laboratory skills have improved much through this experience. I am convinced that this research is significant and will contribute to understanding cancer and to finding ways of treating it. In addition, my experience with the ORCA project will help me to gain admission to the graduate programs to which I have applied.
I also thank Matt Peterson for his mentorship, and Jadd Shelton, Marcelio Oliviera, and the other members of the research group for their help in completing the project.