Synthesis of Calcitroic Acid to Determine its Potential for Prevention of Colon Cancer
Mentor 1
Alexander E Arnold
Location
Union Wisconsin Room
Start Date
28-4-2017 1:30 PM
End Date
28-4-2017 4:00 PM
Description
The vitamin D receptor (VDR) is a member of the nuclear receptor family and regulates gene transcription responsible for cellular processes and calcium homeostasis. The receptor is activated by vitamin D and its corresponding metabolites. The most active metabolite is 1,25-dihydroxyvitamin D3 (calcitriol). However, the lifetime of this potent vitamin D analog is very brief due to fast enzymatic conversion. As a result, calcitroic acid is formed predominately in the liver and kidney and secreted into the colon via bile or eliminated by urine. In the colon, VDR is highly expressed and believed to respond to high concentrations of harmful bile acids such as lithocholic acid with CYP3A4 regulation. Subsequent enzymatic hydroxylation of lithocholic acid reduces irritant and toxic effects that have shown to cause irritable bowel syndrome and the development of colorectal cancer. Our hypothesis is that calcitroic acid, which is secreted together with digestive fluids, is an additional regulatory ligand for VDR in the intestines in order to initiate the breakdown of harmful bile acids. Therefore, increased uptake of vitamin D supplements could potentially decrease the risk of irritable bowel syndrome and colorectal cancer. In order to investigate this hypothesis, calcitroic acid and its metabolites have to be synthesized. Calcitroic acid synthesis consists of 11 steps. The first step is an ozonolysis reaction to generate a diol from plant-based ergocalciferol, second and third are conversion of diol to tosylate and protection of tosylate group, fourth is chain extension by substituting tosylate group with cyanide followed by 7 more additional steps. Once we have synthesized large amounts of calcitroic acid, we will generate possible phase 2 metabolites and carry out cell-based and enzymatic analysis.
Synthesis of Calcitroic Acid to Determine its Potential for Prevention of Colon Cancer
Union Wisconsin Room
The vitamin D receptor (VDR) is a member of the nuclear receptor family and regulates gene transcription responsible for cellular processes and calcium homeostasis. The receptor is activated by vitamin D and its corresponding metabolites. The most active metabolite is 1,25-dihydroxyvitamin D3 (calcitriol). However, the lifetime of this potent vitamin D analog is very brief due to fast enzymatic conversion. As a result, calcitroic acid is formed predominately in the liver and kidney and secreted into the colon via bile or eliminated by urine. In the colon, VDR is highly expressed and believed to respond to high concentrations of harmful bile acids such as lithocholic acid with CYP3A4 regulation. Subsequent enzymatic hydroxylation of lithocholic acid reduces irritant and toxic effects that have shown to cause irritable bowel syndrome and the development of colorectal cancer. Our hypothesis is that calcitroic acid, which is secreted together with digestive fluids, is an additional regulatory ligand for VDR in the intestines in order to initiate the breakdown of harmful bile acids. Therefore, increased uptake of vitamin D supplements could potentially decrease the risk of irritable bowel syndrome and colorectal cancer. In order to investigate this hypothesis, calcitroic acid and its metabolites have to be synthesized. Calcitroic acid synthesis consists of 11 steps. The first step is an ozonolysis reaction to generate a diol from plant-based ergocalciferol, second and third are conversion of diol to tosylate and protection of tosylate group, fourth is chain extension by substituting tosylate group with cyanide followed by 7 more additional steps. Once we have synthesized large amounts of calcitroic acid, we will generate possible phase 2 metabolites and carry out cell-based and enzymatic analysis.
