자료유형  

 학위논문

Control Number  

0016931949

International Standard Book Number  

9798379649012

Dewey Decimal Classification Number  

370

Main Entry-Personal Name  

Luu-Nguyen, Hong Quang.

Publication, Distribution, etc. (Imprint  

[S.l.] : Stanford University., 2021

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2021

Physical Description  

1 online resource(506 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 84-12, Section: A.

General Note  

Advisor: Burns, Noah;du Bois, Justin;Wender, Paul.

Dissertation Note  

Thesis (Ph.D.)--Stanford University, 2021.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Protein kinase C (PKC), a family of upstream serine/threonine kinases, is of immense research interest due to its prominent roles in various diseases. Proteins in the PKC family can be modulated by small molecules possessing diverse structures such as diacyl glycerols (DAG), bryostatin 1, tigliane diterpenoids (phorbol esters, prostratin, tigilanol tiglate etc.), ingenol esters, etc. Despite marked structural differences among these classes of molecules, they all bind to the same C1 regulatory domains of PKC isozymes, and thus, induce downstream signaling transduction events that can be utilized for therapeutic developments. A few clinical indications by PKC modulators include: i) HIV/AIDS eradication, ii) treatment of Alzheimer's disease, and iii) cancer immunology. To enable further translational research concerning PKC modulators, I utilized functionoriented synthesis to develop scalable syntheses of novel bryostatin and tigliane analogs, culminating in the work presented herein.This dissertation begins with a broad review on the clinical relevance of PKC (Chapter 1). First, I will discuss the biology of PKC, from its post-translational modification to its mode of activation by endogenous DAG ligands. PKC isozymes control important roles in cellular signaling network such that a slight change in their structures can have significant biological consequences. A summary of clinically relevant small molecules targeting PKC will be provided. This will include a short overview of ATPbinding catalytic inhibitors as tool compounds for biological research, and clinical candidates for cancer treatment. I will then summarize clinical indications of C1-domain allosteric modulators that have fueled significant interest from the clinical community since their initial isolations.Chapter 2 will provide a review of function-oriented synthesis (FOS) as a tool for translating nature's library. Nature for billions of years has produced myriad natural products which now serve as templates for therapeutic developments. Many natural products have been of huge clinical interest. However, only a small fraction of them eventually become drugs, further reinforcing that natural products are neither evolved nor optimized for human use. Hence, FOS offers multiple strategies for nature-inspired therapeutic optimization. FOS is not only limited to the realms of natural products. Taking inspiration from nature, synthetic chemists can begin to engineer new therapeutic leads, new catalysts, new materials, or even new functions! Function-oriented synthesis is an iterative, evolving process allowing innovation through chemistry to create new products that benefit society.Chapter 3 and Chapter 4 detail my FOS approaches toward bryostatin analogs. Bryostatin 1, a marine macrocyclic polyketide, has attracted unprecedented interdisciplinary attention thanks to its clinical impacts. However, isolation of bryostatin 1 from natural source has been exceedingly low yielding, threatening its clinical utility and precluding close-in derivatization for therapeutic optimization. Only recently (2017) did Wender and co-workers produce a scalable route toward synthetic bryostatin 1, solving the supply problem for clinical research and opening new opportunities for close-in derivatization. Throughout my extensive studies.

Subject Added Entry-Topical Term  

Study abroad.

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Cancer.

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Immunotherapy.

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Success.

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Oxidation.

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Brain research.

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Mutation.

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Decomposition.

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Chemistry.

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Hydrogenation.

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Natural products.

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Secondary schools.

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Drug dosages.

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Alzheimers disease.

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Aging.

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Immunology.

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Neurosciences.

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Organic chemistry.

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Secondary education.

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Therapy.

Added Entry-Corporate Name  

Stanford University.

Host Item Entry  

Dissertations Abstracts International. 84-12A.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:642501