Covalent modifications of biomolecules, such as DNA and proteins, by natural products or their analogs are the mechanism of action of a number of current drugs. The syntheses of these covalent modifiers, such as propellane-type ?-methylene-?-lactones in this proposal, rely on the methodologies in our current synthetic toolbox. Inspired by the biosynthesis of natural products, we propose to generalize the key transformations to enlarge our synthetic toolbox. Meanwhile, natural products have served as the main source of current drugs due to their structural diversity. About one half of current small-molecule drugs on the market are natural products or their synthetic analogs. Natural product synthesis has benefited drug discovery by providing a supply alternative to the natural source, and by making more active analogs. In this R15 proposal, we aim to develop the synthesis of propellane-type ?-methylene-?-lactones inspired by our biomimetic syntheses of hitorins A and B. Hitorins A and B were isolated from the Chloranthus japonicas, a species that was a traditional medicine to treat gastrointestinal disorders in Japan. This proposal is divided into three Specific Aims.
In Aim 1 (Biomimetic synthesis of hitorins A and B based on our modified biosynthetic proposal), we modified the current biosynthetic proposal of hitorins A and B into a radical cascade reaction. Our preliminary results strongly support our new proposal.
Aim 2 (A general method to synthesize propellane-type ?-methylene-?-lactones): a cascade reaction was found to synthesize propellane-type ?-methylene-?-lactones during our exploration of Aim 1. The detailed mechanism and a broad synthetic capability will be explored in Aim 2.
In Aim 3 (Biological studies of a focused library of propellane-type ?-methylene-?-lactones), we will collaborate with biologists to screen our library of synthetic propellane-type ?-methylene-?-lactones against different cancer cell lines.
We aim to find a lead compound to further investigate the interaction between that compound and biomolecules in the cancer cells. From the proposed research, we will have an in-depth understanding of organic reactions and fundamental chemical principles. My undergraduate co-workers will receive comprehensive training in synthetic organic chemistry. This R15 grant will also be beneficial to SUNY-Albany for a better research environment.
The proposed research will (1) provide a new synthetic method to synthesize biomolecule modifiers and facilitate related chemical biology studies; (2) provide an in-depth comprehension of the biosynthesis of natural products; (3) offer a better understanding of chemical principles; and (4) train undergraduate students in the research area of organic synthesis. The anticipated outcome of this proposal will speed up related drug discovery researches.
