The Total Synthesis of Zetekitoxin AB



 DESCRIPTION (provided by applicant): This research project encompasses the total synthesis of the remarkably potent guanidinium poison, zetekitoxin AB (ZTX). ZTX has an exceptional ability to block volatage-gated sodium channels (NaV) with picomolar activity. However, the structural features responsible for its increased activity compared to related guanidinium poisons remains unknown. Synthetic efforts toward ZTX will be based on previously synthesized intermediates accessed in the sponsoring lab's synthesis of the related guanidinium toxin, gonyautoxin (GTX). The route is highlighted by a rhodium-catalyzed oxidative cyclization to access ZTX's bis-guanidinium core. Synthetic methodology will be explored and developed accordingly to access ZTX's macroclactam and N-hydroxycarbamate functionalities. A flexible synthesis of ZTX would allow a focused examination of ZTX analogues that could provide insight into specific interactions with sodium channels. Electrophysiology assays will be performed using whole-cell voltage-clamp techniques against all sodium channel isoforms (NaV1.1-9 and NaX), as ZTX has only been tested against three isoforms to date. This will provide an information rich approach to reveal specificity towards any individual channel isoform. A specific isoform inhibitor with picomolar activity would be an extremely valuable tool to study the distribution of specific channel isoforms in injured neurons. Protein mutagenesis will also be used to probe proposed interactions with specific amino acid residues hypothesized to be crucial for small molecule binding. This project's overall goal is to complete the total synthesis of ZTX and increase understanding of NaV channels with respect to ZTX's binding efficacy. The knowledge accrued from this study could lead to new simplified small molecules that hold promise for treating inflammation and neuropathic pain.