Design and Synthesis of HDACi Derivatives for Cancer Treatment
Poster Number
31
Format
Poster Presentation
Faculty Mentor Name
Qinliang Zhao
Faculty Mentor Department
University of the Pacific, Department of Chemistry
Abstract/Artist Statement
Cancer, the second leading cause of death worldwide, entails the unregulated growth and proliferation of abnormal human cells anywhere in the body with the ability to infiltrate and destroy healthy tissue. Histone deacetylase enzymes (HDAC) are widely overexpressed in a number of cancers, likely contributing to the silencing of various anti-cancer regulatory factors, including tumor suppressor genes, cell-cycle inhibitor genes, and apoptosis inducer genes, by condensing the chromatin through deacetylation of histones in nucleosomes. HDAC inhibitors (HDACi) bind to the zinc active site of the HDAC to prevent catalysis of deacetylase activity, thereby allowing expression of tumor suppressive genes and leading to cell apoptosis. These inhibitors consist of a main scaffold, zinc-binding group, and a protein recognition surface domain (cap). By conjugating the HDAC inhibitor to the platinum anticancer drug through the coordination site on the cap and fine tuning its structure, selectivity of the bifunctional platinum drugs may increase while mitigating negative side effects of treatment.
Two HDACi, derivatives L04 and L18, were synthesized, purified, and subsequently characterized by mass spectrometry and 1H NMR. Derivative L04 containing a 2-methylpyridine cap was based on FDA-approved HDACi vorinostat. Derivative L18 with a pyridine cap was based on FDA-approved HDACi panobinostat. By modifying the cap group of the HDACi derivative, specificity of Pt-HDACi conjugates toward cancer cells may be enhanced when the HDACi ligand could target the overexpressed HDAC enzymes in resistant cancer cell lines.
Location
Information Commons, William Knox Holt Memorial Library and Learning Center
Start Date
29-4-2023 10:00 AM
End Date
29-4-2023 1:00 PM
Design and Synthesis of HDACi Derivatives for Cancer Treatment
Information Commons, William Knox Holt Memorial Library and Learning Center
Cancer, the second leading cause of death worldwide, entails the unregulated growth and proliferation of abnormal human cells anywhere in the body with the ability to infiltrate and destroy healthy tissue. Histone deacetylase enzymes (HDAC) are widely overexpressed in a number of cancers, likely contributing to the silencing of various anti-cancer regulatory factors, including tumor suppressor genes, cell-cycle inhibitor genes, and apoptosis inducer genes, by condensing the chromatin through deacetylation of histones in nucleosomes. HDAC inhibitors (HDACi) bind to the zinc active site of the HDAC to prevent catalysis of deacetylase activity, thereby allowing expression of tumor suppressive genes and leading to cell apoptosis. These inhibitors consist of a main scaffold, zinc-binding group, and a protein recognition surface domain (cap). By conjugating the HDAC inhibitor to the platinum anticancer drug through the coordination site on the cap and fine tuning its structure, selectivity of the bifunctional platinum drugs may increase while mitigating negative side effects of treatment.
Two HDACi, derivatives L04 and L18, were synthesized, purified, and subsequently characterized by mass spectrometry and 1H NMR. Derivative L04 containing a 2-methylpyridine cap was based on FDA-approved HDACi vorinostat. Derivative L18 with a pyridine cap was based on FDA-approved HDACi panobinostat. By modifying the cap group of the HDACi derivative, specificity of Pt-HDACi conjugates toward cancer cells may be enhanced when the HDACi ligand could target the overexpressed HDAC enzymes in resistant cancer cell lines.