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Synthesis of Small Molecule Antagonists at the Androgen Receptor for Prostate Cancer Treatment and Efforts Toward an Enantioselective Co(II)-Catalyzed Cyclopropanation

Tai, Serene (2018) Synthesis of Small Molecule Antagonists at the Androgen Receptor for Prostate Cancer Treatment and Efforts Toward an Enantioselective Co(II)-Catalyzed Cyclopropanation. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

This thesis describes the synthesis of fluorinated cyclopropane analogues to enhance the metabolic stability of a previously published lead candidate for prostate cancer treatment. A structural unique motif such as the bicyclo[1.1.0]pentane was also incorporated to investigate its potential as cyclopropane bioisostere. Preliminary results from liver microsome and luciferase assays suggested that fluorinations on the cyclopropane carbon atoms have little impact on the metabolic stability. However, fluorination on other labile sites showed enhanced metabolic stability while retaining compound potency. An enantioselective route to improve the original racemic synthesis of these analogues was also investigated. The key step was a Co(II)-salen catalyzed enantioselective cis-cyclopropanation of an olefin with ethyl diazoacetate to provide the cyclopropyl amide in 98% ee over three high-yielding steps.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tai, Sereneset58@pitt.eduset58
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWipf, Peterpwipf@pitt.edu
Committee MemberLiu, Pengpengliu@pitt.edu
Committee MemberFloreancig, Paulflorean@pitt.edu
Date: 26 September 2018
Date Type: Publication
Defense Date: 14 November 2017
Approval Date: 26 September 2018
Submission Date: 30 July 2018
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 259
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Prostate cancer treatment, androgen receptor, cyclopropanation, fluorination, enantioselective cis-cyclopropanation, metabolic stability
Date Deposited: 26 Sep 2018 18:36
Last Modified: 26 Sep 2018 18:36
URI: http://d-scholarship.pitt.edu/id/eprint/35060

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