Part one: investigations of voltage-gated sodium channels in the central and peripheral nervous systems; Part two: carbocyclization of unsaturated thioesters under palladium catalysis
Abstract/Contents
- Abstract
- Voltage-gated sodium channels (NaVs) are membrane-bound proteins responsible for the initiation of action potentials in electrically excitable cells. Naturally occurring guanidinium toxins, including (+)-saxitoxin (STX), target the outer pore of NaVs with remarkable selectivity and potency. Inspired by a growing interest to understand the role of NaVs in healthy and aberrant biological functioning in neurons, we have synthesized fluorescent analogues of STX and applied them to the visualization of NaVs in primary cell cultures and tissue. Of these fluorophores, STX-coumarin (STX-Cou) has distinguished itself for its potency and utility in live neurons; studies with STX-Cou in primary neuronal cultures represent the first reported imaging of NaVs in such cells. Our work to synthesize and evaluateSTX-Cou binding as well as to assess the utility of this fluorophore for selective NaV imaging in neurons through fluorescence microscopy is described herein. We have initiated efforts to study NaVs in the peripheral nervous system. Our work, conducted in collaboration with Prof. Ben Barres' lab (Dept. of Neurobiology), has revealed a form of NaV regulation in dorsal root ganglion neurons mediated by the surrounding glial cell network. The characterization of this interaction as well as key mechanistic insights are presented. Finally, inspired by the complex polycyclic architectures of STX and other guanidinium toxins, we have developed and introduced new synthetic strategies for the construction of carbo- and heterocycles from the appropriate linear precursors. In particular, we describe the palladium-catalyzed, copper- and zinc-mediated cyclization of thioesters with pendant olefins and alkynes to form the corresponding ketone products. This work offers new synthetic methods for the preparation of cycloalkanone compounds and also provides additional impetus for the continued discovery of methods for late-stage cyclization of acyclic molecules.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2015 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Thottumkara, Arun Poothatta |
|---|---|
| Associated with | Stanford University, Department of Chemistry. |
| Primary advisor | Du Bois, Justin |
| Thesis advisor | Du Bois, Justin |
| Thesis advisor | Chen, James |
| Thesis advisor | Kanan, Matthew William, 1978- |
| Advisor | Chen, James |
| Advisor | Kanan, Matthew William, 1978- |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Arun Poothatta Thottumkara. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2015. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2015 by Arun P Thottumkara
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...