Benzophenone Based Cyanocinnamic acid and Carboxycoumarins as Mitochondrial Pyruvate Carrier Inhibitors for the Treatment of Nonalcoholic Steatohepatitis

Abstract

Mitochondrial Pyruvate Carrier (MPC) allows pyruvate to enter the mitochondrial matrix to be used in the citric acid cycle. Inhibiting MPC has shown to be a potential treatment for Non-Alcoholic Steatohepatitis (NASH). NASH is projected to overtake Hepatitis C as the leading cause of liver transplants in the United States. The cause of NASH is elevated accumulation of lipids in hepatocytes; however, the mechanisms leading to hepatic fibrosis are unclear. Currently, there are no approved drugs for treating NASH. Recently, thiazolidiendiones have shown to be potential treatments for NASH due to their ability to inhibit MPC. However, these compounds suffer from severe side effects including osteoporosis, heart failure, and increase in bladder cancer. Cyanocinnamic acid and carboxycoumarin have been found to be highly useful pharmacophores for potent inhibition of MCT and MPC. These pharmacophores have exhibited low cytotoxicity against rapidly proliferating cancer cells. Additionally, these biologically active molecules have been found to be generally well tolerated as evidenced by our previous work in several animal models. Additionally, benzophenones are pharmacologically privileged structural entities with favorable pharmacokinetic properties. In this regard, we hypothesized that introduction of cyanocinnamic acid and carboxycoumarin onto the benzophenone scaffold would provide novel candidate compounds with favorable pharmaceutical and pharmacological properties. We also envisioned that if the synthesized compounds exhibit potent MPC inhibition, along with pharmaceutical properties such as oral bioavailability, high metabolic stability, then they could be further developed as therapeutic agents for the treatment of NASH. In this thesis, we have designed, synthesized, and characterized novel benzophenone containing cyanocinnamic acid and carboxycoumarin derivatives as potential MPC inhibitors. We have also synthesized a morpholino cyanocinnamic acid derivative as a water soluble MPC inhibitor. All the synthesized candidate compounds have been evaluated for their cell proliferation inhibition properties against 5 different human and murine cancer cell lines. This study indicated that the test compounds were generally not cytotoxic, even at high concentrations. The test compounds were then evaluated for their pyruvate driven respiration inhibition properties as a means to test their efficacy as potential MPC inhibitors. The benzophenone containing cyanocinnamic acid and carboxycoumarin derivatives were found to inhibit pyruvate driven respiration at 10 µM concentration.