De novo synthesis and biological evaluation of modified saxitoxins for sodium ion channel study
Abstract/Contents
- Abstract
- Access to novel forms of (+)-saxitoxin (STX), a potent and selective inhibitor of voltage-gated sodium ion channels (NaV), has been made possible through de novo synthesis. Saxitoxin is believed to lodge in the outer mouth of the sodium channel pore, thereby stoppering ion flux. Saxitoxin and derivatives thereof represent high-precision pharmacological tools that can be used to gain insight into the structure and integrated cellular function of sodium channel proteins. The preparation and biological evaluation of N21-carbamoyl-modified saxitoxins are described herein. The synthesis plan for assembling these molecules features a robust sequence that enables the preparation of gram quantities of a key nine-membered ring guanidine intermediate. Transformation of this advanced intermediate into a strained 5,6,5-fused tricycle through four-electron olefin oxidation affords an amine-reactive oxazolidinone from which all N21-modified saxitoxins are available. The potencies of STX and all analogous structures have been determined using heterologous gene expression and voltage clamp electrophysiology. These studies show that various N21 substituents are readily accommodated in the STX binding site of the protein with little loss of ligand-receptor binding affinity. This discovery has allowed for the design of photoaffinity and fluorescently labeled saxitoxins, which will serve to further our understanding of the architecture of the STX binding site, and represent a novel set of molecular probes that make possible real-time, live cell investigations of NaV function. Studies utilizing analogues of the pore blocker, saxitoxin, were complimented by an investigation of the aconine alkaloid, aconitine, a known Site II modifier of NaV function. A semi-synthetic pathway used to access derivatives of aconitine is detailed, along with an electrophysiological analysis of the ability of these derivatives to modify the conductive properties of the sodium channel.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2010 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Andresen, Brian Michael |
|---|---|
| Associated with | Stanford University, Department of Chemistry |
| Primary advisor | Du Bois, Justin |
| Thesis advisor | Du Bois, Justin |
| Thesis advisor | Waymouth, Robert M |
| Thesis advisor | Wender, Paul A |
| Advisor | Waymouth, Robert M |
| Advisor | Wender, Paul A |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Brian Michael Andresen. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2010. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2010 by Brian Michael Andresen
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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