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SYNTHETIC STUDIES ON PROTEIN KINASE D, BOTULINUM NEUROTOXIN A1 LIGHT CHAIN, AND NUCLEAR ANDROGEN RECEPTOR MODULATORS, AND EFFORTS TOWARDS THE TOTAL SYNTHESIS OF 9-DESMETHYLPLEUROTIN

Johnson, James (2017) SYNTHETIC STUDIES ON PROTEIN KINASE D, BOTULINUM NEUROTOXIN A1 LIGHT CHAIN, AND NUCLEAR ANDROGEN RECEPTOR MODULATORS, AND EFFORTS TOWARDS THE TOTAL SYNTHESIS OF 9-DESMETHYLPLEUROTIN. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The first chapter outlines the synthesis of pyrazolo[3,4-d]pyrimidines as inhibitors of Protein Kinase D, a potential target for cancer therapy. The second chapter describes the synthesis of novel inhibitors of Botulinum Neurotoxin A1. First, the synthesis of a constrained analog that contains a dibenzo[b,g][1,5]thiazocine is discussed. Second, we explore the use of a Staudinger aza-Wittig reaction to produce 1,2,4-triazines and report the progress towards an inhibitor of BoNT/A with increased metabolic stability.
The third chapter describes the development of antagonists of the androgen receptor, a potential target for the treatment of castration-resistant prostate cancer. A small library of analogs was synthesized to assess a structure-activity relationship of a hit compound. The new lead compound was tested in vivo and further optimized to improve its metabolic stability. This chapter also describes the synthesis of small molecule affinity labeled conjugates to identify the mechanism of action of the antagonists. The final chapter of this dissertation describes the progress towards the total synthesis of 9-desmethylpleurotin.

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Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Johnson, JamesJKJ6@pitt.eduJKJ6@pitt.edu0000-0001-7553-147X
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWipf, Peterpwipf@pitt.edupwipf0000-0001-7693-5863
Committee MemberCurran, Denniscurran@pitt.educurran
Committee MemberHorne, W. Sethhorne@pitt.eduhorne
Committee MemberWang, Zhouwangz2@upmc.eduwangz2@upmc.edu
Date: 29 September 2017
Date Type: Publication
Defense Date: 28 April 2017
Approval Date: 29 September 2017
Submission Date: 5 June 2017
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 495
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Total Synthesis, Androgen Receptor, Protein Kinase D, Botulinum Neurotoxin A1 Light Chain
Date Deposited: 29 Sep 2018 05:00
Last Modified: 29 Sep 2018 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/30984

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