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Synthesis of Oxidatively Cleavable Cyclic Nucleotide Monophosphate Prodrugs

Glanzer, Amy (2024) Synthesis of Oxidatively Cleavable Cyclic Nucleotide Monophosphate Prodrugs. Master's Thesis, University of Pittsburgh. (Unpublished)

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Cyclic dinucleotides are potential cancer therapeutics due to their function as agonists of stimulator of interferon genes (STING), which plays an important role in innate immune signaling processes. However, cyclic dinucleotides therapeutic uses are limited due to a few factors, including poor bioavailability and undesired off-target effects, such as non-selective STING activation leading to autoimmune diseases. To mitigate these issues, we envisioned synthesizing vinyl boronate-masked prodrugs of cyclic dinucleotides that would selectively release in conditions that mimic oxidative stress. Unfortunately, efforts towards these prodrugs were unsuccessful due to issues with purification.
Cyclic nucleotide monophosphates, such as 3’,5’-cyclic adenosine monophosphate (cAMP) and 3’,5’-cyclic guanosine monophosphate (cGMP) are known as secondary messengers that regulate various cellular functions, such as memory, metabolism, gene regulation, and immunity. Additionally, many prodrugs have been developed using cyclic nucleotide monophosphates that release biologically active molecules, such as anti-hepatitis C and anti-cancer properties. We envisioned developing prodrugs of cyclic nucleotide monophosphates tagged with a vinyl-boronate handle that could selectively release the active cyclic nucleotide monophosphate when exposed to increased levels of hydrogen peroxide. Cells exhibit higher levels of hydrogen peroxide when under oxidative stress. Synthetic efforts successfully led to the formation of a boronate-containing 3’,5’-cyclic thymidine nucleotide monophosphate that selectively releases when exposed to conditions that mimic oxidative stress. The development of a boronate-containing cyclic nucleotide monophosphate allows for the opportunity to further develop prodrugs that can selectively target diseased cells.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Glanzer, Amyamg368@pitt.eduamg368
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorFloreancig,
Committee MemberLiu,
Committee MemberIslam,
Date: 10 January 2024
Date Type: Publication
Defense Date: 28 November 2023
Approval Date: 10 January 2024
Submission Date: 7 November 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 119
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: Boronate prodrugs
Date Deposited: 10 Jan 2024 13:44
Last Modified: 10 Jan 2024 13:44

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  • Synthesis of Oxidatively Cleavable Cyclic Nucleotide Monophosphate Prodrugs. (deposited 10 Jan 2024 13:44) [Currently Displayed]


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