Modification and synthesis of histone deacetylase inhibitors for combination with platinum anticancer agents
Poster Number
20A
Introduction/Abstract
Cancer, the second leading cause of death, is a disease that can initiate in almost any part of the body causing uncontrollable cell growth, exerting physical strain on the host, and exhausting valuable nutrients and energy of the organs. Histone deacetylase enzymes are known to be overexpressed in many types of cancer cells, causing DNA to wrap around the protein more tightly, silencing gene transcription which may include the tumor suppressing genes. Combination of histone deacetylase inhibitors (HDACi) with globally approved chemotherapeutic platinum drugs could potentially produce bifunctional drug candidates with increased specificity and decreased cytotoxicity.
Histone deacetylase inhibitors contain three important components: a protein surface recognition domain (cap), a linker, and a zinc binding domain. Structural tuning of inhibitors through any of these components can affect selectivity and binding affinity of the drug. By slightly modifying US FDA approved Vorinostat (SAHA), HDACi derivatives 3, 17, and 30 were designed and synthesized. Derivative 3 has a linker, reduced from a 6-carbon chain to a 5-carbon chain. This derivative would behave as monodentate ligands while reacting with Pt agents. In derivatives 17 and 30, the surface protein recognition domain contains an ethylenediamine group as bidentate coordination sites. General synthesis schemes of the inhibitors include connecting the cap domain and the linker, Boc protection of the amine groups on the cap domain, nucleophilic addition of hydroxylamine to form a hydroxamic acid necessary for zinc binding, and lastly Boc-deprotection. The newly synthesized HDACi derivatives were characterized via ESI-LTQ Mass Spectrometry and 600 MHz Nuclear Magnetic Resonance Spectrometry.
Location
Library and Learning Center, 3601 Pacific Ave., Stockton, CA 95211
Format
Poster Presentation
Modification and synthesis of histone deacetylase inhibitors for combination with platinum anticancer agents
Library and Learning Center, 3601 Pacific Ave., Stockton, CA 95211
Cancer, the second leading cause of death, is a disease that can initiate in almost any part of the body causing uncontrollable cell growth, exerting physical strain on the host, and exhausting valuable nutrients and energy of the organs. Histone deacetylase enzymes are known to be overexpressed in many types of cancer cells, causing DNA to wrap around the protein more tightly, silencing gene transcription which may include the tumor suppressing genes. Combination of histone deacetylase inhibitors (HDACi) with globally approved chemotherapeutic platinum drugs could potentially produce bifunctional drug candidates with increased specificity and decreased cytotoxicity.
Histone deacetylase inhibitors contain three important components: a protein surface recognition domain (cap), a linker, and a zinc binding domain. Structural tuning of inhibitors through any of these components can affect selectivity and binding affinity of the drug. By slightly modifying US FDA approved Vorinostat (SAHA), HDACi derivatives 3, 17, and 30 were designed and synthesized. Derivative 3 has a linker, reduced from a 6-carbon chain to a 5-carbon chain. This derivative would behave as monodentate ligands while reacting with Pt agents. In derivatives 17 and 30, the surface protein recognition domain contains an ethylenediamine group as bidentate coordination sites. General synthesis schemes of the inhibitors include connecting the cap domain and the linker, Boc protection of the amine groups on the cap domain, nucleophilic addition of hydroxylamine to form a hydroxamic acid necessary for zinc binding, and lastly Boc-deprotection. The newly synthesized HDACi derivatives were characterized via ESI-LTQ Mass Spectrometry and 600 MHz Nuclear Magnetic Resonance Spectrometry.
