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Rational design and synthesis of 6,12-guaianolide analogs with an α-methylene–γ-lactam as potential covalent modifiers of SARS-CoV-2 main protease

Meehan, Mariah Caitlin (2024) Rational design and synthesis of 6,12-guaianolide analogs with an α-methylene–γ-lactam as potential covalent modifiers of SARS-CoV-2 main protease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Guaianolides are a subclass of sesquiterpene lactones that possess a wide variety of biological activity often containing α-methylene–γ-butyrolactone moiety. However, this moiety is absent from drug discovery due to its indiscriminate reactivity and toxicity. The goal of my research is to realize the therapeutic potential of guaianolide analogs by expanding upon proof-of-concept studies that support modulating thiol reactivity is a validated strategy to this end. To realize this goal, we envisioned a model with three objectives: 1) predictably tune a lactone bioiostere—the α-methylene–γ-lactam—for optimized covalent reactivity; 2) build up the α-methylene–γ-lactam to optimize non-covalent interactions; and 3) evaluate the bioactivity of covalent guaianolide analogs against a validated protein target. We sought to apply this model to SARS-CoV-2 main protease (Mpro) which possesses a cysteine residue in the active site and has a successful FDA approved covalent drug identified using a fragment-first approach. Herein we report the design, synthesis, and evaluation of covalent guaianolide analogs to target SARS-CoV-2 Mpro. The compound design was guided by virtual docking studies. A small library of guaianolide analogs was synthesized implementing an allenic Pauson–Khand reaction to access the 5,7,5-ring system with a variety of functional groups and stereochemistry, including N-heteroaryl groups on the lactam nitrogen; heteroaryl, cyclopropyl, and hydroxymethyl on the alkyne; and a phenyl group on the allene. The potency of the guaianolide analogs was established using a FRET-based assay. To determine the effect that heteroaryl groups have on thiol reactivity, a series of N-heteroaryl α-methylene–γ-lactams were synthesized, and the rate of glutathione addition was measured. Computational results demonstrated an inverse correlation between electron affinity and the experimental Gibbs free energy of activation. These results led to the development of a single-parameter model that predicted thiol reactivity for novel N-heteroaryl lactams. Importantly, the N-heteroaryl lactams covered the range of thiol reactivity of FDA-approved covalent reactive groups.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Meehan, Mariah CaitlinMCM177@pitt.eduMCM177
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBrummond, Kay
Committee MemberFloreancig,
Committee MemberWang,
Committee MemberHarki,
Date: 13 May 2024
Date Type: Publication
Defense Date: 1 April 2024
Approval Date: 13 May 2024
Submission Date: 5 April 2024
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 356
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: 6,12-guaianolides, allenic Pauson–Khand reaction, tuning thiol reactivity
Date Deposited: 13 May 2024 13:54
Last Modified: 13 May 2024 13:54


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