Reactivity and Dynamics of Enediyne Natural Products

Hamilton College, Clinton NY

Investigators

Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): The goal of this proposed research is to use advanced computational methods to gain a thorough understanding of the mechanism of DNA cleavage by the enediyne family of natural products. This information will guide efforts by experimentalists to synthesize enediyne drugs that are more selective towards tumor cells, and less toxic towards healthy cells. Currently, synthetic efforts are directed by the commonly accepted assumption that the enediyne rings in the natural products cyclize to generate a reactive diradical species that abstracts hydrogen from the DNA backbone. 1-5 However, there are other possibilities. Recent experimental evidence has shown that enediynes can be converted to highly cytotoxic quinones under biological conditions.6 Alternatively, the cyclization and hydrogen atom abstraction could be concerted, without the formation of a diradical intermediate.7 If correct, such mechanisms would force drug designers to radically alter their synthetic strategies. We will use computational methods that integrate high-level electronic structure theory and low-level semiempirical or molecular mechanics methods to accurately model the natural product enediynes. We have several explicit goals for this project. Our first working hypothesis is that enediynes extract hydrogen from DNA through a concerted mechanism during the cyclization of their warheads. Our second working hypothesis is that the sugars attached to the enediyne moiety are responsible for bringing the natural products into contact with DNA. We will test the first hypothesis by obtaining energetic profiles of the possible pathways for cyclization and hydrogen abstraction of the natural products. Then, we will determine which portions of the molecule are essential for the lower reaction pathways found in step one. The second hypothesis will be tested by developing parameters for the enediynes natural products suitable for use with AMBER8. 8.Then, we will run Molecular Dynamics simulations that will show the effect of the enediynes sugars on the DNA recognition process. [unreadable] [unreadable]