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Updated: Jun 13, 2025
Characterization of Synthetic Polymers via Matrix Assisted Laser Desorption Ionization Time of Flight MALDI-TOF Mass Spectrometry
Published on: June 10, 2018
A Predictive Model for Thiol Reactivity of N-Heteroaryl α-Methylene-γ-Lactams─A Medicinally Relevant Covalent
Mariah C Meehan1, Grace E Scofield1, Corrinne E Stahl1
1Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
Abstract:
Herein, we present a systematic study on the effects of electronically diverse heteroarenes on the rate of glutathione (GSH) addition to novel N-heteroaryl α-methylene-γ-lactam covalent reactive groups (CRGs). Despite their unique electronic and drug-like properties, heteroarenes have not been extensively studied as handles for systematically tuning the reactivity of CRGs. Informed by mechanistic insights, we evaluated 16 substrate parameters, including a new heteroaryl Hammett-type substituent constant (σHet), for their correlation with experimental reactivity (ΔG‡exp) as determined by 1H NMR kinetic studies. Of these parameters, electron affinity represents a robust single-parameter predictive model of CRG reactivity with thiols, as demonstrated by test sets of additional N-heteroaryl lactams (MUE = 0.4 kcal/mol) and other α,β-unsaturated amide CRGs (MUE = 0.3 kcal/mol). These N-heteroaryl lactams were subsequently shown to inhibit cysteine protease activity (i.e., papain enzyme) to varying degrees that correlate with both the experimentally observed and predicted reactivity with GSH.
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