| Autor: |
Liu R; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States., Vázquez-Montelongo EA; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States., Ma S; Department of Chemistry, Jess and Mildred Fisher College of Science and Mathematics, Towson University, Towson, Maryland 21252, United States., Shen J; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States. |
| Abstrakt: |
Predictive modeling and understanding of chemical warhead reactivities have the potential to accelerate targeted covalent drug discovery. Recently, the carbanion formation free energies as well as other ground-state electronic properties from density functional theory (DFT) calculations have been proposed as predictors of glutathione reactivities of Michael acceptors; however, no clear consensus exists. By profiling the thiol-Michael reactions of a diverse set of singly- and doubly-activated olefins, including several model warheads related to afatinib, here we reexamined the question of whether low-cost electronic properties can be used as predictors of reaction barriers. The electronic properties related to the carbanion intermediate were found to be strong predictors, e.g., the change in the C β charge accompanying carbanion formation. The least expensive reactant-only properties, the electrophilicity index, and the C β charge also show strong rank correlations, suggesting their utility as quantum descriptors. A second objective of the work is to clarify the effect of the β-dimethylaminomethyl (DMAM) substitution, which is incorporated in the warheads of several FDA-approved covalent drugs. Our data suggest that the β-DMAM substitution is cationic at neutral pH in solution and promotes acrylamide's intrinsic reactivity by enhancing the charge accumulation at C α upon carbanion formation. In contrast, the inductive effect of the β-trimethylaminomethyl substitution is diminished due to steric hindrance. Together, these results reconcile the current views of the intrinsic reactivities of acrylamides and contribute to large-scale predictive modeling and an understanding of the structure-activity relationships of Michael acceptors for rational TCI design. |
