Carder, Evan
(2019)
Synthetic Efforts Toward P97 AAA+ ATPase and P75 Neurotrophin Receptor Inhibitors.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The first chapter presented in this dissertation describes the synthesis of diverse 3-sulfanyl-1,2,4-triazole allosteric p97 AAA+ ATPase inhibitors for structure activity/property relationship (SAR/SPR) investigations. This work supported an iterative medicinal chemistry strategy that led to the systematic development of allosteric p97 inhibitors that demonstrated single-digit nanomolar biochemical potency. We were able to scale-up selected analogues to the gram-scale. Further, we synthesized inhibitors to covalently modify p97, as well as potential p97 protein degraders that utilize the hydrophobic tag (HyT) strategy. The second chapter describes a gram-scale synthesis of known p75 neurotrophin receptor inhibitors LM11A-31 and LM11A-24 without the requirement for chromatography. Subsequent investigation of LM11A-31 key pharmacophore features was evaluated through a molecular docking study and the synthesis of LM11A-31 derivatives for SAR investigations. The pursuit of novel p75NTR inhibitors led to the synthesis of the LM11A-31 and LM11A-24 hybrid analog series as well as the 5-aminooxazole series. The chapter is concluded with efforts toward the 5-aminooxazole series, leading to the development of novel methodology that enabled C-5 regioselective direct amination followed by C-2 direct (het)arylation of 4-cyanooxazole.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
26 September 2019 |
| Date Type: |
Publication |
| Defense Date: |
26 July 2019 |
| Approval Date: |
26 September 2019 |
| Submission Date: |
8 August 2019 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
546 |
| 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: |
P97 AAA+ ATPase, P75 Neurotrophin Receptor, Medicinal Chemistry, Inhibitors |
| Date Deposited: |
26 Sep 2019 21:32 |
| Last Modified: |
26 Sep 2020 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37337 |
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