Stereoselective synthesis of 1,6-diazecanes by a tandem aza-Prins type dimerization and cyclization process.

We report the stereocontrolled synthesis of 1,6-diazecanes a tandem aza-Prins type reaction of -acyliminium ions with allylsilanes. It involves an aza-Prins type dimerization and cyclization in a single-step operation. This reaction represents the first example of 10-membered N-heterocycle synthesis using an aza-Prins reaction.

Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington's disease mouse model.

The present study describes evaluation of epigenetic regulation by a small molecule as the therapeutic potential for treatment of Huntington's disease (HD). We identified 5-allyloxy-2-(pyrrolidin-1-yl)quinoline (APQ) as a novel SETDB1/ESET inhibitor using a combined and cell based screening system. APQ reduced SETDB1 activity and H3K9me3 levels in a HD cell line model.

Construction of 8-Azabicyclo[3.2.1]octanes via Sequential DDQ-Mediated Oxidative Mannich Reactions of N-Aryl Pyrrolidines.

A concise synthesis of 8-azabicyclo[3.2.1]octanes via sequential oxidative Mannich reactions is described.

Identification of Optically Active Pyrimidine Derivatives as Selective 5-HT Modulators.

A series of pyrimidine derivatives - were synthesized and evaluated for their binding affinities towards 5-HT receptors. With regard to designed molecules -, the influence of the size of alkyl ether and the absolute configuration of a stereogenic center on the 5-HT binding affinity and selectivity was studied. The most promising diasteromeric mixtures and were selected in the initial radioligand binding assay and they were further synthesized as optically active forms starting from optically active alcohols and , prepared by an enzymatic kinetic resolution.

A Potential PET Radiotracer for the 5-HT Receptor: Synthesis and in Vivo Evaluation of 4-(3-[F]fluorophenethoxy)pyrimidine.

The serotonin 2C receptor subtype (5-HT) is an excitatory 5-HT receptor widely distributed throughout the central nervous system. As the 5-HT receptor displays multiple actions on various neurotransmitter systems including glutamate, dopamine, epinephrine, and γ-aminobutyric acid (GABA), abnormalities of the 5-HT receptor are associated with psychiatric diseases such as depression, schizophrenia, drug abuse, and anxiety. Up to date, three kinds of 5-HT PET radiotracers such as [C]N-methylated arylazepine (1), [C]WAY-163909 (2), and [F]fluorophenylcyclopropane (3) have been developed, but they may not be suitable for in vivo 5-HT imaging study due to their modest specific binding.

Identification of the first in silico-designed TREK1 antagonists that block channel currents dose dependently.

TREK1 (Twik-RElated Potassium (K ) channel 1), although a well-characterized target for several neuropsychiatric disorders, underwent very few explorations for prototypic inhibitors. This study aimed to find diverse chemotypes by an in silico means. Homology-built TREK1 on docking with high-affinity quaternary ammonium compounds (QAs) corroborated the previous findings by recreating the binding mode with proximally positioned key residues: Thr157, Thr266, Ile182, Leu189, and Leu304.

Synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as mGluR5 (metabotropic glutamate receptor 5) antagonists.

We described here the synthesis and biological evaluation of picolinamides and thiazole-2-carboxamides as potential mGluR5 antagonists. We found that a series of thiazole derivatives 6 showed better inhibitory activity against mGluR5. Compounds 6bc and 6bj have been identified as potent antagonists (IC50=274 and 159nM) showing excellent in vitro stability profile.

Novel Scaffold Identification of mGlu1 Receptor Negative Allosteric Modulators Using a Hierarchical Virtual Screening Approach.

Metabotropic glutamate receptor 1 (mGluR1) is considered as an attractive drug target for neuropathic pain treatments. The hierarchical virtual screening approach for identifying novel scaffolds of mGluR1 allosteric modulators was performed using a homology model built with the dopamine D3 crystal structure as template. The mGluR1 mutagenesis data, conserved amino acid sequences across class A and class C GPCRs, and previously reported multiple sequence alignments of class C GPCRs to the rhodopsin template, were employed for the sequence alignment to overcome difficulties of model generation with low sequence identity of mGluR1 and dopamine D3.

Crystal structure of (E)-5,5-dimethyl-2-[3-(4-nitro-phen-yl)allyl-idene]cyclo-hexane-1,3-dione.

In the title compound, C17H17NO4, the cylohexane-1,3-dione ring adopts an envelope conformation with the dimethyl-subsituted C atom as the flap. Its mean plane is inclined to the benzene ring by 7.99 (19)°.

Synthesis of the Tricyclic Ring Structure of Daphnanes via Intramolecular [4 + 3] Cycloaddition/SmI2-Pinacol Coupling.

A synthetic approach toward the tricyclic 5,7,6-membered ring structure of daphnane-family natural products is described. An intramolecular [4 + 3] cycloaddition reaction of furan with an oxypentadienyl cation constructed the oxa-bridged bicyclic structure in a stereoselective fashion. Structural analysis revealed that the desired exo isomer was predominantly acquired through epimerization.

Discovery and biological evaluation of tetrahydrothieno[2,3-c]pyridine derivatives as selective metabotropic glutamate receptor 1 antagonists for the potential treatment of neuropathic pain.

Metabotropic glutamate receptor 1 (mGluR1) has been a prime target for drug discovery due to its heavy involvement in various brain disorders. Recent studies suggested that mGluR1 is associated with chronic pain and can serve as a promising target for the treatment of neuropathic pain. In an effort to develop a novel mGluR1 antagonist, we designed and synthesized a library of compounds with tetrahydrothieno[2,3-c]pyridine scaffold.

Tubulin inhibitor identification by bioactive conformation alignment pharmacophore-guided virtual screening.

Microtubules are important cellular component that are critical for proper cellular function. Microtubules are synthesized by polymerization of αβ tubulin heterodimers called protofilaments. Microtubule dynamics facilitate proper cell division during mitosis.

Synthesis and biological evaluation of aryl isoxazole derivatives as metabotropic glutamate receptor 1 antagonists: a potential treatment for neuropathic pain.

Glutamate is the major excitatory neurotransmitter and known to activate the metabotropic and ionotropic glutamate receptors in the brain. Among these glutamate receptors, metabotropic glutamate receptor 1 (mGluR1) has been implicated in various brain disorders including anxiety, schizophrenia and chronic pain. Several studies demonstrated that the blockade of mGluR1 signaling reduced pain responses in animal models, suggesting that mGluR1 is a promising target for the treatment of neuropathic pain.

Crystal structure of (E)-N-[(E)-3-(4-meth-oxy-phen-yl)allyl-idene]naphthalen-1-amine.

In the title compound, C20H17NO, the dihedral angle between the mean planes of the 4-meth-oxy-phenyl ring and the naphthalene ring is 69.50 (7)°. The meth-oxy group is almost coplanar with the benzene ring to which it is connected [Cb-Cb-Om-Cm torsion angle of -7.

Facile diverted synthesis of pyrrolidinyl triazoles using organotrifluoroborate: discovery of potential mPTP blockers.

This article describes the rapid and diversified synthesis of pyrrolidinyl triazoles for the discovery of mitochondrial permeability transition pore (mPTP) blockers. The 1,3-dipolar cycloaddition of ethynyl trifluoroborate with azidopyrrolidine produced a key intermediate, triazolyl trifluoroborate 4, which subsequently underwent a Suzuki-Miyaura coupling reaction to afford a series of 1,4-disubstituted triazoles 2. Subsequent biological evaluation of these derivatives indicated 2ag and 2aj as the most potent mPTP blockers exhibiting excellent cytochrome P450 (CYP) stability when compared to the previously reported oxime analogue 1.

Efficient synthesis of mibefradil analogues: an insight into in vitro stability.

This article describes the synthesis and biological evaluation of a chemical library of mibefradil analogues to investigate the effect of structural modification on in vitro stability. The construction of the dihydrobenzopyran structure in mibefradil derivatives 2 was achieved through two efficient approaches based on a diastereoselective intermolecular Reformatsky reaction and an intramolecular carbonyl-ene cyclization. In particular, the second strategy through the intramolecular carbonyl-ene reaction led to the formation of a key intermediate 3 in a short and highly stereoselective way, which has allowed for practical and convenient preparation of analogues 2.

Synthesis and biological evaluation of 2-substituted quinoline 6-carboxamides as potential mGluR1 antagonists for the treatment of neuropathic pain.

A series of 2-amino and 2-methoxy quinoline-6-carboxamide derivatives have been synthesized and their metabotropic glutamate receptor type 1 (mGluR1) antagonistic activities were evaluated in a functional cell-based assay. The compound 13c showed the highest potency with IC50 value of 2.16 µM against mGluR1.

(E)-2,2'-[3-(4-Chloro-phen-yl)prop-2-ene-1,1-di-yl]bis-(3-hy-droxy-5,5-di-methyl-cyclo-hex-2-en-1-one).

The title compound, C25H29ClO4, adopts a trans conformation about the C=C double bond and the di-methyl-cyclo-hexenone rings both show an envelope conformation with the dimethyl-substituted C atom as the flap. In the mol-ecule, the hy-droxy and carbonyl groups form two intra-molecular O-H⋯O hydrogen bonds typical for xanthene derivatives. In the crystal, weak C-H⋯O hydrogen bonds link the mol-ecules into chains running parallel to the a-axis direction.

9-[(E)-2-(4-Chloro-phen-yl)ethen-yl]-3,3,6,6-tetra-methyl-2,3,4,5,6,7,8,9-octa-hydro-1H-xanthene-1,8-dione.

In the title compound, C25H27ClO3, each of the cyclo-hexenone rings adopts an envelope conformation, whereas the six-membered pyran ring adopts a flattened boat conformation, with the O and methine C atoms deviating from the plane of the other four atoms. The C=C double bond is in the trans conformation. In the crystal, weak C-H⋯O hydrogen bonds link the mol-ecules into chains running parallel to the b axis.

(E)-N-(3,3-Di-phenyl-allyl-idene)naph-thal-en-1-amine.

The title compound, C25H19N, adopts an E conformation about the C=N bond. The naphthalene ring system and the phenyl rings form dihedral angles 38.1 (1), 46.

(E)-9-(4-Fluoro-styr-yl)-3,3,6,6-tetra-methyl-3,4,5,6,7,9-hexa-hydro-2H-xanthene-1,8-dione.

In the title compound, C25H27FO3, each of the cyclo-hexenone rings adopts a half-chair conformation, whereas the six-membered pyran ring adopts a flattened boat conformation, with the O and methine C atoms deviating by 0.0769 (15) and 0.196 (2) Å, respectively, from the plane of the other four atoms (r.

(E)-N-(3,3-Di-phenyl-allyl-idene)-2-(tri-fluoro-meth-yl)aniline.

In the title compound, C22H16F3N, the C=N bond of the central imine group adopts an E conformation. The dihedral angles between the 2-(tri-fluoro-meth-yl)phenyl ring and the benzene rings are 9.34 (1) and 68.

(E)-N-[(E)-3-(4-Nitro-phen-yl)allyl-idene]naphthalen-1-amine.

In the title compound, C19H14N2O2, the dihedral angle between the mean planes of the 4-nitro-phenyl ring and the naphthalene ring system is 12.79 (2)°. The imine group displays a C-C-N=C torsion angle of 41.

Novel pyrimidoazepine analogs as serotonin 5-HT(2A) and 5-HT(2C) receptor ligands for the treatment of obesity.

Obesity is one of the most serious public health problems worldwide in the 21st century. Current therapeutic treatment for obesity is mostly focused on preventive measures involving dietary control and physical exercises in combination with anti-obesity medications. However, most of these anti-obesity medications have little or no effect on weight loss, and some cases have demonstrated fatal side effects.

(E)-2,2'-[3-(4-Fluoro-phen-yl)prop-2-ene-1,1-di-yl]bis-(3-hy-droxy-5,5-dimethyl-cyclo-hex-2-en-1-one).

In the title compound, C25H29FO4, each cyclo-hexenone ring has an envelope conformation with the dimethyl-substituted atom as the flap. The hy-droxy and carbonyl groups form two intra-molecular O-H⋯O hydrogen bonds, as is typical for xanthene derivatives. In the crystal, very weak C-H⋯O hydrogen bonds link mol-ecules into dimers.