Increasing Anticancer Prodrugs Selectivity: The Synthesis of Hydrogen Peroxide-Inducible DNA Cross-Linking Agents with Different Substituent Groups
Mentor 1
Dr. Xiaohua Peng
Location
Union Wisconsin Room
Start Date
24-4-2015 10:30 AM
End Date
24-4-2015 11:45 AM
Description
One of the widely used chemotherapy to treat cancer is DNA cross-linking agent. Cross-linking is when a molecule is introduced into a cell, it can link with the two strands of DNA. When the DNA cross-linking agents are released into the body, DNA interstrand cross-links occur. The interstrand cross-links can block DNA transcription and replication by preventing separation of two DNA strands due to a covalent chemical bond formed between DNA double strands. The major disadvantage of the existing anticancer agents is their poor selectivity. Tumor cells contain high levels of reactive oxygen species due to the increased active metabolism. The reactive oxygen species include hydrogen peroxide, superoxide and hydroxyl radical. Hydrogen peroxide is stable and can be generated from nearly all sources of oxygen radicals. Taking advantage of this difference, we are developing a type of hydrogen peroxide-inducible DNA cross-linking agents which are expected to specifically kill cancer cells. In this study, we are creating hydrogen peroxide-activated quinone methide (QM) prodrugs that will be tested for its DNA cross-linking ability. The goal is to develop an optimized synthetic route for making these molecules. We use organic synthesis to create molecules that can form molecules that will create QM intermediate in the presence of starting with simple benzoic molecules. With the molecules made, we can use denaturing polyacrylamide gel electrophoresis which test the DNA cross-linking ability between the DNA and the prodrug and the rate at which it cross-links. We are examining how the introduction of different substituent groups affects the DNA cross-linking by looking cross-linking yields. The ultimate goal is to advance DNA cross-linking agents which are important for improving the selectivity of anticancer drugs by using the technique of cancer-targeting DNA cross-linking.
Increasing Anticancer Prodrugs Selectivity: The Synthesis of Hydrogen Peroxide-Inducible DNA Cross-Linking Agents with Different Substituent Groups
Union Wisconsin Room
One of the widely used chemotherapy to treat cancer is DNA cross-linking agent. Cross-linking is when a molecule is introduced into a cell, it can link with the two strands of DNA. When the DNA cross-linking agents are released into the body, DNA interstrand cross-links occur. The interstrand cross-links can block DNA transcription and replication by preventing separation of two DNA strands due to a covalent chemical bond formed between DNA double strands. The major disadvantage of the existing anticancer agents is their poor selectivity. Tumor cells contain high levels of reactive oxygen species due to the increased active metabolism. The reactive oxygen species include hydrogen peroxide, superoxide and hydroxyl radical. Hydrogen peroxide is stable and can be generated from nearly all sources of oxygen radicals. Taking advantage of this difference, we are developing a type of hydrogen peroxide-inducible DNA cross-linking agents which are expected to specifically kill cancer cells. In this study, we are creating hydrogen peroxide-activated quinone methide (QM) prodrugs that will be tested for its DNA cross-linking ability. The goal is to develop an optimized synthetic route for making these molecules. We use organic synthesis to create molecules that can form molecules that will create QM intermediate in the presence of starting with simple benzoic molecules. With the molecules made, we can use denaturing polyacrylamide gel electrophoresis which test the DNA cross-linking ability between the DNA and the prodrug and the rate at which it cross-links. We are examining how the introduction of different substituent groups affects the DNA cross-linking by looking cross-linking yields. The ultimate goal is to advance DNA cross-linking agents which are important for improving the selectivity of anticancer drugs by using the technique of cancer-targeting DNA cross-linking.
