5 research outputs found
Rationalizing the Lacking of Inversion Symmetry in a Noncentrosymmetric Polar Racemate: An Experimental and Theoretical Study
The total charge density of PYRAC,
a polar (<i>Pca</i>2<sub>1</sub>) organic racemate with <i>Z</i>′ =
2, was derived from high-resolution single-crystal X-ray diffraction
data at <i>T</i> = 100(2) K and periodic DFT calculations.
The PYRAC asymmetric unit consists of a hydrogen-bonded pair of conformationally
different enantiomers, A and B<sub>i</sub>, where the subscript “i”
indicates a reversed absolute configuration. The lattice stability
was compared with that of centrosymmetric possibly competing structures,
with the aim of understanding why a noncentrosymmetric lattice framework
is obtained from a racemic mixture. The likelihood of specific intermolecular
recognition processes among different conformers of PYRAC in the very
first stages of nucleation was investigated by DFT simulations in
vacuo. Two competing, equivalent interconversion pseudorotatory paths
between the most stable A and the least stable B conformers were found.
It results that molecules spend most of their time (≈53%) in
the A conformation, whereas the B one is far less populated (≈7%).
Therefore, centrosymmetric AA<sub>i</sub> adducts are formed very
frequently in the reaction liquor, whereas the BB<sub>i</sub> ones
are rare. Nevertheless, AA<sub>i</sub> pairs produce crystal forms
with cohesive energies and densities significantly less favorable
than those estimated for the noncentrosymmetric heterochiral AB<sub>i</sub> ones. Therefore, preference for <i>Z</i>′
= 2 in conjunction with noncentrosymmetric point and space groups
results from the thermodynamic control of the crystallization process.
The capability of forming extended hydrogen bond chains throughout
the lattice appears to be a prerequisite to bind together the fundamental
AB<sub>i</sub> repeating units
Rationalizing the Lacking of Inversion Symmetry in a Noncentrosymmetric Polar Racemate: An Experimental and Theoretical Study
The total charge density of PYRAC,
a polar (<i>Pca</i>2<sub>1</sub>) organic racemate with <i>Z</i>′ =
2, was derived from high-resolution single-crystal X-ray diffraction
data at <i>T</i> = 100(2) K and periodic DFT calculations.
The PYRAC asymmetric unit consists of a hydrogen-bonded pair of conformationally
different enantiomers, A and B<sub>i</sub>, where the subscript “i”
indicates a reversed absolute configuration. The lattice stability
was compared with that of centrosymmetric possibly competing structures,
with the aim of understanding why a noncentrosymmetric lattice framework
is obtained from a racemic mixture. The likelihood of specific intermolecular
recognition processes among different conformers of PYRAC in the very
first stages of nucleation was investigated by DFT simulations in
vacuo. Two competing, equivalent interconversion pseudorotatory paths
between the most stable A and the least stable B conformers were found.
It results that molecules spend most of their time (≈53%) in
the A conformation, whereas the B one is far less populated (≈7%).
Therefore, centrosymmetric AA<sub>i</sub> adducts are formed very
frequently in the reaction liquor, whereas the BB<sub>i</sub> ones
are rare. Nevertheless, AA<sub>i</sub> pairs produce crystal forms
with cohesive energies and densities significantly less favorable
than those estimated for the noncentrosymmetric heterochiral AB<sub>i</sub> ones. Therefore, preference for <i>Z</i>′
= 2 in conjunction with noncentrosymmetric point and space groups
results from the thermodynamic control of the crystallization process.
The capability of forming extended hydrogen bond chains throughout
the lattice appears to be a prerequisite to bind together the fundamental
AB<sub>i</sub> repeating units
Discovery of Covalent Inhibitors of Glyceraldehyde-3-phosphate Dehydrogenase, A Target for the Treatment of Malaria
We developed a new class of covalent
inhibitors of Plasmodium falciparum glyceraldehyde-3-phosphate
dehydrogenase, a validated target for the treatment of malaria, by
screening a small library of 3-bromo-isoxazoline derivatives that
inactivate the enzyme through a covalent, selective bond to the catalytic
cysteine, as demonstrated by mass spectrometry. Substituents on the
isoxazolinic ring modulated the potency up to 20-fold, predominantly
due to an electrostatic effect, as assessed by computational analysis
Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the <i>N</i>‑Methyl‑d‑aspartate Receptor as Potential Imaging Agents for Brain
Abnormal
activity of various <i>N</i>-methyl-d-aspartate
receptor (NMDAR) subtypes has been implicated in a wide
variety of neurological disorders such as Alzheimer’s disease,
schizophrenia, and epilepsy. Imaging agents for PET and SPECT that
target NMDARs in a subtype-selective fashion may enable better characterization
of those disorders and enhance drug development. On the basis of a
pyrazoline derivative that demonstrated neuroprotective effects in
vivo, we synthesized a series of <i>para</i>-substituted
analogues and measured their affinities to various NMDAR subtypes.
Compounds <b>4a</b>–<b>c</b> and <b>4e</b> showed greater, nanomolar affinity for the GluN1/2A subtype versus
GluN1/2B. Dicarbomethoxy (pro-drug) analogues of [<sup>124/125</sup>I]<b>4d</b> and [<sup>11</sup>C]<b>4e</b> (i.e., [<sup>124/125</sup>I]<b>11d</b> and [<sup>11</sup>C]<b>11e</b>) were generated and tested for NMDAR binding specificity in ex vivo
autoradiography and brain biodistribution studies. Although NMDAR-specific
binding could be demonstrated for [<sup>125</sup>I]<b>11d</b> and [<sup>11</sup>C]<b>11e</b> through autoradiography and
biodistribution studies, imaging of neither [<sup>124</sup>I]<b>11d</b> nor [<sup>11</sup>C]<b>11e</b> could demonstrate
brain penetration sufficient for detection by PET
Structure and Affinity of Two Bicyclic Glutamate Analogues at AMPA and Kainate Receptors
Ionotropic
glutamate receptors (iGluRs) are involved in most of the fast excitatory
synaptic transmission in the central nervous system. These receptors
are important for learning and memory formation, but are also involved
in the development of diseases such as Alzheimer’s disease,
epilepsy and depression. To understand the function of different types
of iGluRs, selective agonists are invaluable as pharmacological tool
compounds. Here, we report binding affinities of two bicyclic, conformationally
restricted analogues of glutamate (CIP-AS and LM-12b) at AMPA (GluA2
and GluA3) and kainate receptor subunits (GluK1–3 and GluK5).
Both CIP-AS and LM-12b were found to be GluK3-preferring agonists,
with <i>K</i><sub>i</sub> of 6 and 22 nM, respectively,
at recombinant GluK3 receptors. The detailed binding mode of CIP-AS
and LM-12b in the ligand-binding domains of the AMPA receptor subunit
GluA2 (GluA2-LBD) and the kainate receptor subunits GluK1 (GluK1-LBD)
and GluK3 (GluK3-LBD) was investigated by X-ray crystallography. CIP-AS
stabilized all three receptor constructs in conformations similar
to those with kainate. Remarkably, whereas LM-12b bound in a similar
manner to CIP-AS in GluA2-LBD and GluK3-LBD, it introduced full closure
of the ligand-binding domain in GluK1-LBD and formation of a D1-D2
interlobe hydrogen bond between Glu441 and Ser721, as also observed
with glutamate. As the binding affinity of LM-12b at GluK1 is ∼8-fold
better than that for CIP-AS (<i>K</i><sub>i</sub> of 85
and 656 nM, respectively), it shows that small changes in agonist
structure can lead to prominent differences in structure and function