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Synthesis and Release of Boronate-Caged Monophosphates and Covalent Modifiers

McCloskey, Mitchell J.R. (2024) Synthesis and Release of Boronate-Caged Monophosphates and Covalent Modifiers. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

The boronate ester has emerged as a viable alternative to traditional prodrug caging motifs. Upon reaction with hydrogen peroxide, boronates are converted to alcohols, which can undergo further decaging based on the larger caging structure. The selectivity of this reaction for boronates allows site selective release of bioactive molecules in cells containing high levels of oxidative stress.
The Floreancig group has initiated a program concerning the oxidative release of boronate-caged monophosphate prodrugs, and their applications for the treatment of viral infections. This document describes the synthesis and oxidative release of two boronate-caged monophosphates. The results reveal the greater efficacy of the boryl allyloxy cage compared to the more commonly used p-borylbenzyl cage. In addition, a modified boronate cage, in which the pinacol (Pin) group is replaced with ethyl pinacol (Epin), exhibited enhanced hydrolytic stability.
This document also describes the synthesis of boronate-caged covalent modifiers containing α,β-unsaturated carbonyls, as well as their release rates and thiol reactivity. Initial results indicate facile release of caged enones and enals, as well as their elevated rates of thiol addition relative to dimethyl acrylamide. Modifying α,β-unsaturated carbonyls with β substituents may allow the tuning of electrophilic reactivity. Finally, initial synthetic efforts toward a boronate-caged KRAS(G12C) covalent inhibitor were successful.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
McCloskey, Mitchell J.R.mjm421@pitt.edumjm4210000-0002-3690-5464
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFloreancig, Paul E.florean@pitt.edu
Committee MemberBrummond, Kay M.kbrummon@pitt.edu
Committee MemberDeiters, Alexanderdeiters@pitt.edu
Date: 10 January 2024
Date Type: Publication
Defense Date: 4 December 2023
Approval Date: 10 January 2024
Submission Date: 4 December 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 138
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: Organic synthesis, kinetics, monophosphate, covalent modifiers
Date Deposited: 14 Feb 2025 15:56
Last Modified: 14 Feb 2025 15:56
URI: http://d-scholarship.pitt.edu/id/eprint/45598

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