Synthesis of Histone Deacetylase Inhibitor Platinum Complexes for Bifunctional Anticancer Agents
Poster Number
18B
Research or Creativity Area
Natural Sciences
Abstract
Histone Deacetylase (HDAC), an enzyme involved in the regulation of gene expression via chromatin conformation, is overexpressed in many types of cancer and is a popular target for cancer drugs. Cisplatin, an FDA approved anticancer drug, is an alkylating agent that binds to the DNA of cancer cells to induce cell death. By combining HDAC inhibitors (HDACi) and platinum-based alkylating agents into a single drug, the platinum complex with HDACi could have increased specificity and efficacy as a bifunctional anticancer agent.
Panobinostat and chidamide, two HDACi, are composed of three groups: a protein-recognition cap domain, a linker, and a zinc binding group. The cap domain fits into a groove at the exterior of the pocket, the linker reaches into the pocket, and the zinc binding group binds to the zinc cofactor of HDAC active site. Derivatives of these molecules were designed by modifying the three parts to alter both length and flexibility of the molecule. By additionally modifying the cap to have a platinum coordination site, the HDACi derivative could form a complex with platinum. The complex is composed of two chloride leaving-group ligands, a non-leaving ammonia ligand, and the HDACi derivative, coordinated similarly to the ammonia ligand.
The HDACi derivatives are synthesized via nucleophilic substitution to the cap domain, protection of the coordination site with Boc anhydride, a second nucleophilic substitution, and a condensation reaction to add the zinc binding domain. The Boc protection is then removed and the HDACi will be coordinated to the platinum complex. The synthesized molecules are characterized via NMR spectroscopy, mass spectrometry, and X-ray crystallography. The relative binding efficacy of the HDACi derivatives will be estimated via computational docking studies.
Location
Don and Karen DeRosa University Center (DUC) Poster Hall
Start Date
27-4-2024 10:30 AM
End Date
27-4-2024 12:30 PM
Synthesis of Histone Deacetylase Inhibitor Platinum Complexes for Bifunctional Anticancer Agents
Don and Karen DeRosa University Center (DUC) Poster Hall
Histone Deacetylase (HDAC), an enzyme involved in the regulation of gene expression via chromatin conformation, is overexpressed in many types of cancer and is a popular target for cancer drugs. Cisplatin, an FDA approved anticancer drug, is an alkylating agent that binds to the DNA of cancer cells to induce cell death. By combining HDAC inhibitors (HDACi) and platinum-based alkylating agents into a single drug, the platinum complex with HDACi could have increased specificity and efficacy as a bifunctional anticancer agent.
Panobinostat and chidamide, two HDACi, are composed of three groups: a protein-recognition cap domain, a linker, and a zinc binding group. The cap domain fits into a groove at the exterior of the pocket, the linker reaches into the pocket, and the zinc binding group binds to the zinc cofactor of HDAC active site. Derivatives of these molecules were designed by modifying the three parts to alter both length and flexibility of the molecule. By additionally modifying the cap to have a platinum coordination site, the HDACi derivative could form a complex with platinum. The complex is composed of two chloride leaving-group ligands, a non-leaving ammonia ligand, and the HDACi derivative, coordinated similarly to the ammonia ligand.
The HDACi derivatives are synthesized via nucleophilic substitution to the cap domain, protection of the coordination site with Boc anhydride, a second nucleophilic substitution, and a condensation reaction to add the zinc binding domain. The Boc protection is then removed and the HDACi will be coordinated to the platinum complex. The synthesized molecules are characterized via NMR spectroscopy, mass spectrometry, and X-ray crystallography. The relative binding efficacy of the HDACi derivatives will be estimated via computational docking studies.
