Synthesis and Modeling of CYP26 Selective Inhibitors

Traumatic brain injury (TBI), caused by sudden trauma to the brain, is a severely disabling disorder that affects more than 1.7 million Americans each year. All Retinoic Acid atRA), the active metabolite of vitamin A, plays an important role in the regulation of neuronal plasticity. Recent studies show that increase in atRA concentration improves learning and memory, increases injury-induced brain-cell generation, and could be used to treat TBI. atRA is absorbed poorly by the body. It also induces its own clearance from the body, resulting in a loss of functionality. The clearance, or metabolism of retinoic acid is predominantly mediated by a certain family of enzymes with one predominant brain isoform, CYP26B1. The research group I am working with has designed a class of selective inhibitors that should eliminate the feedback mechanisms of atRA resistance. They hypothesize that selective inhibition of the enzyme CYP26B1 will increase atRA concentrations in the brain and will treat memory impairment and neuroinflammation from TBI. About 40 candidate structures need synthesis and testing for their capabilities as inhibitors. My research focusses on the selection and synthesis of three candidate structures for these inhibitors. The project has required me to learn and practice synthesis techniques. This includes the use of SciFinder and other online peer-reviewed databases to research the synthesis of these new chemicals and familiarization with instrument analysis such as thin-column chromatography (TLC) and nuclear magnetic resonance (NMR) spectroscopy. I am also using computer modeling software to study the interaction of the molecules I am synthesizing with their biological target. I expect to complete synthesis of at least two of my projects in the next few weeks. These chemicals will then undergo biological testing for toxicity and effectiveness as drugs. If results are promising, they could go on to treat TBI or other ailments