11 research outputs found
Natural Tetraponerines: A General Synthesis and Antiproliferative Activity
A stereocontrolled
general methodology to access all natural tetraponerines from (+)-<b>T1</b> to (+)-<b>T8</b> is detailed. Two consecutive indium-mediated
aminoallylations with the appropriate enantiomer of chiral <i>N</i>-<i>tert</i>-butylsulfinamide and a thermodynamic
control at the aminal stereocenter allow the formation of each natural
tetraponerine with excellent stereoselectivity. The use of 4-bromobutanal
in the first aminoallylation leads to the formation of 5–6–5
tetraponerines, while 5-bromopentanal is required to build the scaffold
of 6–6–5 tetraponerines. A cross-metathesis reaction
of the second aminoallylation product with <i>cis</i>-3-hexene
is used to elongate the side chain up to 5 carbons so as to prepare
the tetraponerines <b>T5</b> to <b>T8</b>. The anticancer
activity of these heavier tetraponerines against four different carcinoma
human cell lines is examined, observing a promising cytotoxic activity
of (+)-<b>T7</b> against breast carcinoma cell line MCF-7
Syntheses and Cytotoxicity of (<i>R</i>)- and (<i>S</i>)‑7-Methoxycryptopleurine
Two
efficient protocols are described for the transformation of
a key chiral homoallyllic sulfinamine intermediate in four steps into
enantioenriched 7-methoxycryptopleurine. While one of the protocols
relied on a rhodium catalyzed linear hydroformylation process, the
alternative approach was based on a ring-closing metathesis from the
corresponding <i>N-</i>allyl-sulfinamine. The cytotoxic
evaluation of both enantiomers of the target compound demonstrated
that the (<i>R</i>)-compound is much more potent than its
antipode against the four cancer cell lines examined
<i>cis</i>-Platinum Complex Encapsulated in Self-Assembling Cyclic Peptide Dimers
A new cyclic peptide
dimer that encapsulates cisplatin complexes
in its internal cavity is described. The resulting complex showed
cytotoxic activity at A2780 ovarian cancer cell lines independent
of acquired platinum resistance
Effect of Bulky <i>N</i>‑Dibenzofuranylmethyl Substitution on the 5‑HT<sub>2</sub> Receptor Affinity and Efficacy of a Psychedelic Phenethylamine
The introduction of arylmethyl substituents on the amine
nitrogen
atom of phenethylamines and tryptamines often results in profound
increases in their affinity and functional activity at 5-HT2 serotonin receptors. To probe the sensitivity of this effect to
substantially larger N-substituents, ten derivatives
of the well-characterized psychedelic phenethylamine 2C–B were
prepared by appending different dibenzo[b,d]furylmethyl (DBFM) moieties to the basic nitrogen. The
DBFM group attached to the amino group through its 1-, −2-,
or 3-position decreased affinity and agonist activity at the 5-HT2A/2C receptors. Substitution through the 4-position usually
favored affinity for all three 5-HT2 receptor subtypes
with compound 5 exhibiting 10- and 40-fold higher affinities
at the 5-HT2A and 5-HT2C receptors, respectively,
but less than fourfold selectivity among the three receptor subtypes.
Nevertheless, all were relatively weak partial 5-HT2AR
agonists, mostly in the low micromolar range, but full or nearly full
agonists at the 5-HT2C subtype as determined in a calcium
mobilization assay. Molecular docking simulations suggested that the
dibenzofuryl portion dives more deeply into the orthosteric binding
site of the 5-HT2A than the 5-HT2C receptor,
interacting with the Trp3366.48 toggle switch associated
with its activation, while the phenylamine moiety lies close to the
extracellular side of the receptor. In conclusion, a very bulky N-substituent on a phenethylamine 5-HT2 receptor
agonist is tolerated and may increase affinity if its orientation
is appropriate. However, the Gq protein-mediated potencies
are generally low, with low efficacy (relative to 5-HT) at the 5-HT2A receptor, somewhat higher efficacy at the 5-HT2B subtype, and full or nearly full efficacy at the 5-HT2C subtype
Enantiospecific Recognition at the A<sub>2B</sub> Adenosine Receptor by Alkyl 2‑Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates
A novel
family of structurally simple, potent, and selective nonxanthine
A<sub>2B</sub>AR ligands was identified, and its antagonistic behavior
confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates
(<b>16</b>) were designed by bioisosteric replacement of the
carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones.
The scaffold (<b>16</b>) documented herein contains a chiral
center at the heterocycle. Accordingly, the most attractive ligand
of the series [(±)<b>16b</b>, <i>K</i><sub>i</sub> <b>=</b> 24.3 nM] was resolved into its two enantiomers by
chiral HPLC, and the absolute configuration was established by circular
dichroism. The biological evaluation of both enantiomers demonstrated
enantiospecific recognition at A<sub>2B</sub>AR, with the (<i>S</i>)-<b>16b</b> enantiomer retaining all the affinity
(<i>K</i><sub>i</sub> <b>=</b> 15.1 nM), as predicted
earlier by molecular modeling. This constitutes the first example
of enantiospecific recognition at the A<sub>2B</sub> adenosine receptor
and opens new possibilities in ligand design for this receptor
Discovery of 3,4-Dihydropyrimidin-2(1<i>H</i>)‑ones As a Novel Class of Potent and Selective A<sub>2B</sub> Adenosine Receptor Antagonists
We
describe the discovery and optimization of 3,4-dihydropyrimidin-2(1<i>H</i>)-ones as a novel family of (nonxanthine) A<sub>2B</sub> receptor antagonists that exhibit an unusually high selectivity
profile. The Biginelli-based hit optimization process enabled a thoughtful
exploration of the structure–activity and structure–selectivity
relationships for this chemotype, enabling the identification of ligands
that combine structural simplicity with excellent hA<sub>2B</sub> AdoR
affinity and remarkable selectivity profiles
Effect of Nitrogen Atom Substitution in A<sub>3</sub> Adenosine Receptor Binding: <i>N</i>‑(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists
We
report the first family of 2-acetamidopyridines as potent and
selective A<sub>3</sub> adenosine receptor (AR) antagonists. The computer-assisted
design was focused on the bioisosteric replacement of the N1 atom
by a CH group in a previous series of diarylpyrimidines. Some of the
generated 2-acetamidopyridines elicit an antagonistic effect with
excellent affinity (<i>K</i><sub>i</sub> < 10 nM) and
outstanding selectivity profiles, providing an alternative and simpler
chemical scaffold to the parent series of diarylpyrimidines. In addition,
using molecular dynamics and free energy perturbation simulations,
we elucidate the effect of the second nitrogen of the parent diarylpyrimidines,
which is revealed as a stabilizer of a water network in the binding
site. The discovery of 2,6-diaryl-2-acetamidopyridines represents
a step forward in the search of chemically simple, potent, and selective
antagonists for the hA<sub>3</sub>AR, and exemplifies the benefits
of a joint theoretical–experimental approach to identify novel
hA<sub>3</sub>AR antagonists through succinct and efficient synthetic
methodologies
Effect of Nitrogen Atom Substitution in A<sub>3</sub> Adenosine Receptor Binding: <i>N</i>‑(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists
We
report the first family of 2-acetamidopyridines as potent and
selective A<sub>3</sub> adenosine receptor (AR) antagonists. The computer-assisted
design was focused on the bioisosteric replacement of the N1 atom
by a CH group in a previous series of diarylpyrimidines. Some of the
generated 2-acetamidopyridines elicit an antagonistic effect with
excellent affinity (<i>K</i><sub>i</sub> < 10 nM) and
outstanding selectivity profiles, providing an alternative and simpler
chemical scaffold to the parent series of diarylpyrimidines. In addition,
using molecular dynamics and free energy perturbation simulations,
we elucidate the effect of the second nitrogen of the parent diarylpyrimidines,
which is revealed as a stabilizer of a water network in the binding
site. The discovery of 2,6-diaryl-2-acetamidopyridines represents
a step forward in the search of chemically simple, potent, and selective
antagonists for the hA<sub>3</sub>AR, and exemplifies the benefits
of a joint theoretical–experimental approach to identify novel
hA<sub>3</sub>AR antagonists through succinct and efficient synthetic
methodologies
A Positive Allosteric Modulator of the Serotonin 5‑HT<sub>2C</sub> Receptor for Obesity
The 5-HT<sub>2C</sub>R agonist lorcaserin,
clinically approved
for the treatment of obesity, causes important side effects mainly
related to subtype selectivity. In the search for 5-HT<sub>2C</sub>R allosteric modulators as safer antiobesity drugs, a chemical library
from Vivia Biotech was screened using ExviTech platform. Structural
modifications of identified hit VA240 in synthesized analogues <b>6</b>–<b>41</b> afforded compound <b>11</b> (<i>N</i>-[(1-benzyl-1<i>H</i>-indol-3-yl)methyl]pyridin-3-amine,
VA012), which exhibited dose-dependent enhancement of serotonin efficacy,
no significant off-target activities, and low binding competition
with serotonin or other orthosteric ligands. PAM <b>11</b> was
very active in feeding inhibition in rodents, an effect that was not
related to the activation of 5-HT<sub>2A</sub>R. A combination of <b>11</b> with the SSRI sertraline increased the anorectic effect.
Subchronic administration of <b>11</b> reduced food intake and
body weight gain without causing CNS-related malaise. The behavior
of compound <b>11</b> identified in this work supports the interest
of a serotonin 5-HT<sub>2C</sub>R PAM as a promising therapeutic approach
for obesity
Modulation of cAMP-Specific PDE without Emetogenic Activity: New Sulfide-Like PDE7 Inhibitors
A forward chemical genetic approach
was followed to discover new
targets and lead compounds for Parkinson’s disease (PD) treatment.
By analysis of the cell protection produced by some small molecules,
a diphenyl sulfide compound was revealed to be a new phosphodiesterase
7 (PDE7) inhibitor and identified as a new hit. This result allows
us to confirm the utility of PDE7 inhibitors as a potential pharmacological
treatment of PD. On the basis of these data, a diverse family of diphenyl
sulfides has been developed and pharmacologically evaluated in the
present work. Moreover, to gain insight into the safety of PDE7 inhibitors
for human chronic treatment, we evaluated the new compounds in a surrogate
emesis model, showing nonemetic effects