5 research outputs found
NMR and Computational Studies of the Configurational Properties of Spirodioxyselenuranes. Are Dynamic Exchange Processes or Temperature-Dependent Chemical Shifts Involved?
Spirodioxyselenurane <b>4a</b> and several substituted
analogs
revealed unexpected <sup>1</sup>H NMR behavior. The diastereotopic
methylene hydrogens of <b>4a</b> appeared as an AB quartet at
low temperature that coalesced to a singlet upon warming to 267 K,
suggesting a dynamic exchange process with a relatively low activation
energy. However, DFT computational investigations indicated high activation
energies for exchange via inversion through the selenium center and
for various pseudorotation processes. Moreover, the NMR behavior was
unaffected by the presence of water or acid catalysts, thereby ruling
out reversible Se–O or benzylic C–O cleavage as possible
stereomutation pathways. Remarkably, when <b>4a</b> was heated
beyond 342 K, the singlet was transformed into a new AB quartet. Further
computations indicated that a temperature dependence of the chemical
shifts of the diastereotopic protons results in convergence upon heating,
followed by crossover and divergence at still higher temperatures.
The NMR behavior is therefore not due to dynamic exchange processes,
but rather to temperature dependence of the chemical shifts of the
diastereotopic hydrogens, which are coincidentally equivalent at intermediate
temperatures. These results suggest the general need for caution in
ascribing the coalescence of variable-temperature NMR signals of diastereotopic
protons to dynamic exchange processes that could instead be due to
temperature-dependent chemical shifts and highlight the importance
of corroborating postulated exchange processes through additional
computations or experiments wherever possible
Effects of Methoxy Substituents on the Glutathione Peroxidase-like Activity of Cyclic Seleninate Esters
Cyclic
seleninate esters function as mimetics of the antioxidant
enzyme glutathione peroxidase and catalyze the reduction of hydrogen
peroxide with a stoichiometric thiol. While a single electron-donating
methoxy substituent <i>para</i> to the selenium atom enhances
the catalytic activity, <i>m</i>-methoxy groups have little
effect and <i>o</i>-methoxy substituents suppress activity.
The effects of multiple methoxy groups are not cumulative. This behavior
can be rationalized by opposing mesomeric and steric effects. Oxidation
of the product disulfide via its thiolsulfinate was also observed
Structure–Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase
Human tissue transglutaminase (hTG2)
is a multifunctional enzyme.
It is primarily known for its calcium-dependent transamidation activity
that leads to formation of an isopeptide bond between glutamine and
lysine residues found on the surface of proteins, but it is also a
GTP binding protein. Overexpression and unregulated hTG2 activity
have been associated with numerous human diseases, including cancer
stem cell survival and metastatic phenotype. Herein, we present a
series of targeted covalent inhibitors (TCIs) based on our previously
reported Cbz-Lys scaffold. From this structure–activity relationship
(SAR) study, novel irreversible inhibitors were identified that block
the transamidation activity of hTG2 and allosterically abolish its
GTP binding ability with a high degree of selectivity and efficiency
(<i>k</i><sub>inact</sub>/<i>K</i><sub>I</sub> > 10<sup>5</sup> M<sup>–1</sup> min<sup>–1</sup>).
One optimized inhibitor (<b>VA4</b>) was also shown to inhibit
epidermal cancer stem cell invasion with an EC<sub>50</sub> of 3.9
ÎĽM, representing a significant improvement over our previously
reported “hit” <b>NC9</b>
Structure–Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase
Human tissue transglutaminase (hTG2)
is a multifunctional enzyme.
It is primarily known for its calcium-dependent transamidation activity
that leads to formation of an isopeptide bond between glutamine and
lysine residues found on the surface of proteins, but it is also a
GTP binding protein. Overexpression and unregulated hTG2 activity
have been associated with numerous human diseases, including cancer
stem cell survival and metastatic phenotype. Herein, we present a
series of targeted covalent inhibitors (TCIs) based on our previously
reported Cbz-Lys scaffold. From this structure–activity relationship
(SAR) study, novel irreversible inhibitors were identified that block
the transamidation activity of hTG2 and allosterically abolish its
GTP binding ability with a high degree of selectivity and efficiency
(<i>k</i><sub>inact</sub>/<i>K</i><sub>I</sub> > 10<sup>5</sup> M<sup>–1</sup> min<sup>–1</sup>).
One optimized inhibitor (<b>VA4</b>) was also shown to inhibit
epidermal cancer stem cell invasion with an EC<sub>50</sub> of 3.9
ÎĽM, representing a significant improvement over our previously
reported “hit” <b>NC9</b>
Structure–Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase
Human tissue transglutaminase (hTG2)
is a multifunctional enzyme.
It is primarily known for its calcium-dependent transamidation activity
that leads to formation of an isopeptide bond between glutamine and
lysine residues found on the surface of proteins, but it is also a
GTP binding protein. Overexpression and unregulated hTG2 activity
have been associated with numerous human diseases, including cancer
stem cell survival and metastatic phenotype. Herein, we present a
series of targeted covalent inhibitors (TCIs) based on our previously
reported Cbz-Lys scaffold. From this structure–activity relationship
(SAR) study, novel irreversible inhibitors were identified that block
the transamidation activity of hTG2 and allosterically abolish its
GTP binding ability with a high degree of selectivity and efficiency
(<i>k</i><sub>inact</sub>/<i>K</i><sub>I</sub> > 10<sup>5</sup> M<sup>–1</sup> min<sup>–1</sup>).
One optimized inhibitor (<b>VA4</b>) was also shown to inhibit
epidermal cancer stem cell invasion with an EC<sub>50</sub> of 3.9
ÎĽM, representing a significant improvement over our previously
reported “hit” <b>NC9</b>