6 research outputs found
Gymnopeptides A and B, Cyclic Octadecapeptides from the Mushroom <i>Gymnopus fusipes</i>
Mycochemical
study of the mushroom <i>Gymnopus fusipes</i> led to the
discovery of two new cyclopeptides. The two compounds,
named as gymnopeptides A and B, are unprecedented highly <i>N</i>-methylated cyclic octadecapeptides. Detailed spectroscopic studies,
Marfey’s analysis, and a preliminary molecular modeling study
suggested that both are natural cyclic β hairpins. The isolated
compounds exhibited striking antiproliferative activity on several
human cancer cell lines, with nanomolar IC<sub>50</sub> values
Significant Activity of Ecdysteroids on the Resistance to Doxorubicin in Mammalian Cancer Cells Expressing the Human ABCB1 Transporter
Multidrug resistance (MDR) is a major cause of failure
of cancer
chemotherapy. Fifty-eight ecdysteroids, herbal analogues of the insect
molting hormone and their semisynthetic derivatives, were tested for
their activity against L5178 mouse T-cell lymphoma cells (non-MDR)
and their subcell line transfected with pHa <i>MDR</i>1/A
retrovirus overexpressing the human ABCB1 efflux pump (MDR cell line).
The compounds showed very low antiproliferative activities but modulated
the efflux of rhodamine 123 mediated by the ABCB1 transporter. Roughly
depending on the polarity, mild to strong synergism or antagonism
was observed by combining ecdysteroids with doxorubicin, and specific
structure–activity relationships were also found. Our results
show the effect of ecdysteroids on MDR cancer cells for the first
time. Less polar derivatives may serve as valuable leads toward a
potent and safe resistance modulator. Biological significance of the
resistance-increasing activity of the most abundant phytoecdysteroids
including 20-hydroxyecdysone is yet to be clarified
Synthesis of Urea Derivatives in Two Sequential Continuous-Flow Reactors
A continuous-flow system consisting
of two sequential microreactors
was developed for the synthesis of nonsymmetrically substituted ureas
starting from <i>tert</i>-butoxycarbonyl protected amines.
Short reaction times could be achieved under mild conditions. In-line
FT-IR analytical technique was used to monitor the reaction, including
the formation of the isocyanate intermediate, thus allowing optimization
of the reagent ratios. The mechanistic role of the applied base was
also clarified. The setup was successfully utilized for the synthesis
of several urea derivatives including the active pharmaceutical ingredient
cariprazine
Discovery and Preclinical Characterization of 3‑((4-(4-Chlorophenyl)-7-fluoroquinoline-3-yl)sulfonyl)benzonitrile, a Novel Non-acetylenic Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulator for Psychiatric Indications
Negative allosteric modulators (NAM)
of metabotropic glutamate
receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy
for a number of psychiatric diseases, including anxiety and depression.
Most of the mGluR5 NAM clinical candidates can be characterized by
the central acetylenic moiety that connects the terminal pharmacophores.
Identification of a sulfoquinoline hit via high throughput screening
(HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline
lead compound with the minimal pharmacophore. Optimization of the
core and aryl appendages was performed by scanning and matrix libraries
synthesized by the multiple parallel synthesis approach. Biological
evaluation of matrix libraries provided a number of potent, metabolically
stable, and <i>in vivo</i> active compounds. One of these
compounds, <b>25</b> showed high efficacy and safety in preclinical <i>in vivo</i> models; this allowed its nomination as a novel,
nonacetylenic mGluR5 NAM clinical candidate. Compound <b>25</b> was advanced to first-in-man trials for the treatment of psychiatric
conditions
Discovery of Novel Steroid-Based Histamine H<sub>3</sub> Receptor Antagonists/Inverse Agonists
Steroid-based histamine H3 receptor antagonists (d-homoazasteroids) were designed
by combining distinct structural
elements of HTS hit molecules. They were characterized, and several
of them displayed remarkably high affinity for H3 receptors
with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent H3R
activity together with significant in vivo H3 antagonism.
Optimization of the chemotype was initiated with special emphasis
on the elimination of the hERG and muscarinic affinity. Additionally,
ligand-based SAR considerations and molecular docking studies were
performed to predict binding modes of the molecules. The most promising
compounds (XXI, XXVIII, and XX) showed practically no muscarinic and hERG affinity. They showed
antagonist/inverse agonist property in the in vitro functional tests
that was apparent in the rat in vivo dipsogenia test. They were considerably
stable in human and rat liver microsomes and provided significant
in vivo potency in the place recognition and novel object recognition
cognitive paradigms
Discovery of Novel Steroid-Based Histamine H<sub>3</sub> Receptor Antagonists/Inverse Agonists
Steroid-based histamine H3 receptor antagonists (d-homoazasteroids) were designed
by combining distinct structural
elements of HTS hit molecules. They were characterized, and several
of them displayed remarkably high affinity for H3 receptors
with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent H3R
activity together with significant in vivo H3 antagonism.
Optimization of the chemotype was initiated with special emphasis
on the elimination of the hERG and muscarinic affinity. Additionally,
ligand-based SAR considerations and molecular docking studies were
performed to predict binding modes of the molecules. The most promising
compounds (XXI, XXVIII, and XX) showed practically no muscarinic and hERG affinity. They showed
antagonist/inverse agonist property in the in vitro functional tests
that was apparent in the rat in vivo dipsogenia test. They were considerably
stable in human and rat liver microsomes and provided significant
in vivo potency in the place recognition and novel object recognition
cognitive paradigms