Derivatizing Chiral 1,2-Diaminocyclohexane-Based HDAC Inhibitors for Pt Coordination
Faculty Mentor Name
Qinliang Zhao
Research or Creativity Area
Natural Sciences
Abstract
Stereochemistry in drug design is of significant importance, providing increased selectivity for biological targets and influencing pharmacokinetics, toxicity, and the drug's safety profile. Some families of platinum (Pt)-based chemotherapy drugs have been modified to incorporate chiral ligands. Oxaliplatin, a Pt-based chemotherapy drug, utilizes a derivative of 1,2-diaminocyclohexane (DACH), specifically the (trans-R,R)-1,2-diaminocyclohexane configuration, which has proven effective against various forms of cancer, including solid tumors. Studies of (R, R)-DACH-Pt have shown superior results compared with the S,S-enantiomer, which exhibits lower biological activity. Incorporation of chiral ligand design is being investigated from the modification of the surface recognition domain (CAP) of Histone Deacetylase inhibitors (HDACi). Design and modifications of the ligands contain R, R-, R, S-, S, S-, and S, R-DACH in the CAP domain. The synthesis of the HDACi derivatives includes L17, a precursor of the chiral ligands synthesized: L33-2, L33-3, and L32-2. Pt centers are introduced via metalation to form HDACi-Pt complexes, which are then evaluated in vitro for effectiveness. Attaching an HDACi, with a focus on chiral ligands, to a Pt center as a non-leaving group provides a rational approach to targeting two anticancer mechanisms in a single complex. This project aims to develop a multifunctional anticancer drug that is more efficient by improving its toxicity, selectivity, and therapeutic effectiveness against solid tumors. Ligands, HDACi, and Pt complexes have been characterized by instrumental analysis using nuclear magnetic resonance (NMR), mass spectrometry (MS), and High-performance liquid chromatography (HPLC). Attaching an HDACi to a Pt center as a non-leaving group provides a rational approach to targeting two anticancer mechanisms by one single complex. This project aims to develop a multifunctional anticancer drug that is more efficient by improving its toxicity, selectivity, and therapeutic effectiveness against cancer.
Derivatizing Chiral 1,2-Diaminocyclohexane-Based HDAC Inhibitors for Pt Coordination
Stereochemistry in drug design is of significant importance, providing increased selectivity for biological targets and influencing pharmacokinetics, toxicity, and the drug's safety profile. Some families of platinum (Pt)-based chemotherapy drugs have been modified to incorporate chiral ligands. Oxaliplatin, a Pt-based chemotherapy drug, utilizes a derivative of 1,2-diaminocyclohexane (DACH), specifically the (trans-R,R)-1,2-diaminocyclohexane configuration, which has proven effective against various forms of cancer, including solid tumors. Studies of (R, R)-DACH-Pt have shown superior results compared with the S,S-enantiomer, which exhibits lower biological activity. Incorporation of chiral ligand design is being investigated from the modification of the surface recognition domain (CAP) of Histone Deacetylase inhibitors (HDACi). Design and modifications of the ligands contain R, R-, R, S-, S, S-, and S, R-DACH in the CAP domain. The synthesis of the HDACi derivatives includes L17, a precursor of the chiral ligands synthesized: L33-2, L33-3, and L32-2. Pt centers are introduced via metalation to form HDACi-Pt complexes, which are then evaluated in vitro for effectiveness. Attaching an HDACi, with a focus on chiral ligands, to a Pt center as a non-leaving group provides a rational approach to targeting two anticancer mechanisms in a single complex. This project aims to develop a multifunctional anticancer drug that is more efficient by improving its toxicity, selectivity, and therapeutic effectiveness against solid tumors. Ligands, HDACi, and Pt complexes have been characterized by instrumental analysis using nuclear magnetic resonance (NMR), mass spectrometry (MS), and High-performance liquid chromatography (HPLC). Attaching an HDACi to a Pt center as a non-leaving group provides a rational approach to targeting two anticancer mechanisms by one single complex. This project aims to develop a multifunctional anticancer drug that is more efficient by improving its toxicity, selectivity, and therapeutic effectiveness against cancer.
