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Salamoun, Joseph M (2017) SYNTHESIS OF THIOPHENE-CONTAINING HETEROCYCLES AND THEIR APPLICATION AS ANTICANCER AGENTS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Five-membered heterocycles represent a privileged scaffold in drug discovery and are the focus of analog design. The first chapter presents the synthesis and biological evaluation of analogs of NSC 652287, which targets the renal carcinoma cell line A498. The Pd-catalyzed Suzuki-Miyaura cross-coupling with halogenated furan, thiophene, and selenophene led to generally high overall yields for the construction of heterocyclic triads. C-H bond activation provided an efficient strategy for the Pd-catalyzed cross-coupling at C(2) of oxazoles. Further analog variation was achieved with a copper-catalyzed azide-alkyne cycloaddition to form a 1,4-substituted 1,2,3-triazole. Potency and selectivity of the final hydroxymethyl products were determined in the NCI-60 cell assay. Two lead compounds were tested in vivo and compared to NSC 652287. The evaluation of these compounds continues with a thermal shift assay coupled with differential mass spectrometry for biological target identification. The chemical stability of select triads are also discussed.
The second chapter details the synthesis of thienopyridone and thienopyrimidine dione analogs as inhibitors of protein tyrosine phosphatase 4A3 (PTP4A3), an attractive anticancer target. Derivatization by photooxygenation led to a compound with a unique structural motif, high potency, and excellent selectivity towards PTP4A3. An automated synthesis strategy using Lilly’s Automated Synthesis Lab was employed for analog synthesis.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Salamoun, Joseph Mjms442@pitt.edujms442
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWipf,
Committee MemberDeiters,
Committee MemberKoide,
Committee MemberLazo,
Date: 28 September 2017
Date Type: Publication
Defense Date: 1 August 2017
Approval Date: 28 September 2017
Submission Date: 10 August 2017
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 148
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: Synthesis and discovery of small molecule anticancer agent.
Date Deposited: 29 Sep 2017 00:20
Last Modified: 29 Sep 2017 00:20


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