Acetogenins: chemo-enzymatic synthesis and molecular probing of respiratory NADH-dehydrogenases
Summary of the proposed research
Acetogenins are a class of natural products from edible fruits that inhibit Complex I of the respiratory chain, most likely as mimics of the natural substrate ubiquinone. Their selective toxicity against cancer cells was thus far ascribed to ATP depletion as a result of Complex I inhibition. However, many cancer cells are, in fact, less dependent on activity of the respiratory chain than healthy cells due to a shift to fermentation (Warburg effect). We now hypothesize that the selective toxicity rather results from increased production of reactive oxygen species (ROS). In this project, we will use the expertise in the Orru/Ruijter group to develop chemoenzymatic routes to acetogenins and derivatives and the expertise in the Westerhoff/van Spanning group to determine contributions of ATP depletion and ROS production to the cancer cell toxicity of these compounds to corroborate our hypothesis on the mode of action of acetogenins.
Synthetic approaches to acetogenins exploit the pseudosymmetry in these compounds and use epoxide hydrolases for desymmetrization and nantioconvergent processes to afford versatile building blocks that allow the generation of an array of unique acetogenin derivatives according to the principles of biology-oriented synthesis. This approach will allow the efficient synthesis of several acetogenins as well as (simplified) synthetic analogs as unique tools to study the biological effects of Complex I inhibition. A broad palette of assays will be used to accurately determine the influence of acetogenins on respiration rates and ATP and ROS production in mitochondrial systems.
The vertical integration of bio-organic chemistry and molecular cell biology allows an integrative and iterative approach towards development of a fundamental understanding of the respiratory system at the molecular level, as well as towards validation of a hypothesis that Complex I is a target for cancer therapy with acetogenin derivatives as lead compounds, following a newly proposed mechanism for selective toxicity.
