4 research outputs found
Quantum Descriptors for Predicting and Understanding the Structure–Activity Relationships of Michael Acceptor Warheads
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 Cβ charge accompanying carbanion
formation. The least expensive reactant-only properties, the electrophilicity
index, and the Cβ 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 Cα 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
Quantum Descriptors for Predicting and Understanding the Structure–Activity Relationships of Michael Acceptor Warheads
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 Cβ charge accompanying carbanion
formation. The least expensive reactant-only properties, the electrophilicity
index, and the Cβ 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 Cα 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
Quantum Descriptors for Predicting and Understanding the Structure–Activity Relationships of Michael Acceptor Warheads
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 Cβ charge accompanying carbanion
formation. The least expensive reactant-only properties, the electrophilicity
index, and the Cβ 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 Cα 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
Characterizing Hydrogen-Bond Interactions in Pyrazinetetracarboxamide Complexes: Insights from Experimental and Quantum Topological Analyses
Experimental and topological analyses
of dipalladium(II) complexes with pyrazinetetracarboxamide ligands
containing tetraethyl (<b>1</b>), tetrahexyl (<b>2</b>), and tetrakis(2-hydroxyethyl) ethyl ether (<b>3</b>) are
described. The presence of two very short O---O distances between
adjacent amide carbonyl groups in the pincer complexes revealed two
protons, which necessitated two additional anions to satisfy charge
requirements. The results of the crystal structures indicate carbonyl
O---O separations approaching that of low barrier hydrogen bonds,
ranging from 2.413(5) to 2.430(3) Å. Solution studies and quantum
topological analyses, the latter including electron localization function,
noncovalent interaction, and Bader’s quantum theory of atoms
in molecules, were carried out to probe the nature of the short hydrogen
bonds and the influence of the ligand environment on their strength.
Findings indicated that the ligand field, and, in particular, the
counterion at the fourth coordination site, may play a subtle role
in determining the degree of covalent association of the bridging
protons with one or the other carbonyl groups