Function-oriented synthesis : design, synthesis, and evaluation of novel protein kinase C modulators
Abstract/Contents
- Abstract
- Protein kinase C (PKC), a family of central signaling kinases, is of immense research interest due to its prominent roles in various devastating diseases for which there are no cures. The first part of my dissertation research is concerned with bryostatin 1, a scarce marine natural product and a potent PKC modulator. Even though bryostatin 1 is in the forefront of multiple clinical investigations (HIV/AIDS eradication, Alzheimer's disease, cancer immunotherapy etc.), it is not evolved nor optimized for human use, and is unlikely to succeed in this one-size-fits-all approach. Therefore, design, synthesis, and evaluation of synthetically accessible bryostatin analogs through function-oriented synthesis continues to be important. From the scalable synthesis of bryostatin 1, I participated in a collaborative effort to prepare and evaluate close-in derivatives of bryostatin 1, adjuvant leads for enhanced cancer immunotherapy. Using computer-guided, function-oriented synthesis, I also developed an accessible synthesis of the most simplified bryostatin analogs to date, in which one analog possesses strikingly similar potency to that of bryostatin 1, the parent compound. I also developed an asymmetric bifunctional allylation platform that is amenable to broad substrate scopes, further improving the scalable synthesis of bryostatin 1. This methodology successfully led to the synthesis of a novel des-A-ring bryostatin analog that possesses single digit nanomolar binding affinity to a conventional and a novel PKC isoform. Lastly, I am also working on tigilanol tiglate that shares very close structural similarity with phorbol esters. However, unlike phorbol esters, a class of potent tumor promoters, tigilanol tiglate can rapidly ablate tumor and at the same time induce remarkable wound healing activity via intratumoral injection. Tigilanol tiglate is currently being clinically evaluated (Phase II) with a broad range of tumors, especially accessible cutaneous, subcutaneous, and nodal tumors that are refractory to conventional therapy. Its activity is proposed to be the result of selective activation of conventional PKC isoforms. Our work is the first, and currently the only, demonstration of laboratory preparation of tigilanol tiglate and analogs, which would have a huge impact on their future supply.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Luu-Nguyen, Hong Quang |
|---|---|
| Degree supervisor | Wender, Paul A |
| Thesis advisor | Wender, Paul A |
| Thesis advisor | Burns, Noah |
| Thesis advisor | Du Bois, Justin |
| Degree committee member | Burns, Noah |
| Degree committee member | Du Bois, Justin |
| Associated with | Stanford University, Department of Chemistry |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Quang Luu-Nguyen. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/fz359hn4573 |
Access conditions
- Copyright
- © 2021 by Nguyen Hong Quang Luu
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