Insight into Binding of Phosphodiesterase-9A Selective Inhibitors by Crystal Structures and Mutagenesis

PDE9 inhibitors have been studied as therapeutics for treatment of cardiovascular diseases, diabetes, and neurodegenerative disorders. To illustrate the inhibitor selectivity, the crystal structures of the PDE9A catalytic domain in complex with the enantiomers of PDE9 inhibitor 1-(2-chlorophenyl)-6-(3,3,3-trifluoro-2-methylpropyl)-1H-pyrazolo[3,4-d]pyrimidine-4(5H)-one ((R)-BAY73-6691 or (S)-BAY73-6691, 1r or 1s) were determined and mutagenesis was performed. The structures showed that the fluoromethyl groups of 1r and 1s had different orientations while the other parts of the inhibitors commonly interacted with PDE9A. These differences may explain the slightly different affinity of 1r (IC50 = 22 nM) and 1s (IC50 = 88 nM). The mutagenesis experiments revealed that contribution of the binding residues to the inhibitor sensitivity varies dramatically, from a few of folds to three orders of magnitude. On the basis of the crystal structures, a hypothesized compound that simulates the recently published PDE9 inhibitors was modeled to provide insight into the inhibitor selectivity

Phosphine Oxide-Promoted Rh(I)-Catalyzed C–H Cyclization of Benzimidazoles with Alkenes

Ligands play a critical role in promoting transition-metal-catalyzed C–H activation reactions. However, owing to high sensitivity of the reactivity of C–H activation to metal catalysts, the development of effective ligands has been a formidable challenge in the field. Rh(I)-catalyzed C–H cyclization of benzimidazoles with alkenes has been faced with low reactivity, often requiring very harsh conditions. To address this challenge, a phosphine oxide-enabled Rh(I)–Al bimetallic catalyst was developed for the reaction, significantly promoting the reactivity and allowing the reaction to run at 120 °C with up to 97% yield

A Directive Ni Catalyst Overrides Conventional Site-Selectivity in Pyridine C–H Alkenylation

A remote C3–H activation of pyridine-containing substrates can be achieved with a directive Ni catalyst. The bifunctional NHC ligand incorporates an Al-binding side-arm that recruits and orients the substrate leading to the assembly of the requisite macrocyclophane transition state through reversible coordination. This assembly not only induces the reactivity of the otherwise unreactive Ni catalyst, but also overrides the intrinsic C2/C4 electronic bias of the Al-bound pyridine substrate, allowing for the first time, the C3 alkenylation of a variety of pyridine and heteroarene substrates as the limiting reagent

Artificial Intelligence Supports Research Progress in the Diagnosis and Treatment of Rare Diseases

It is noteworthy that only 5% of more than 7000 described rare diseases are treated. In the era of big data, there is ever-increasing data for understanding biomedicine. The need for efficient and rapid data collection, analyses and characterization methods is pressing. Rare diseases can particularly benefit from artificial intelligence (AI) application. AI, with an emphasis on machine learning, creates a path for such efforts and is being applied to diagnosis and treatment. AI has demonstrated its potential to learn and analyze data from different sources with results in prediction。Presently, there are AI-driven technologies applied for rare diseases and this review aims to summarize these advances. Moreover, this review scrutinizes the limitation and identifies the pitfalls of AI applications in the diagnosis and treatment of rare diseases

Double Ligand-Enabled Ni-Catalyzed C-H Alkenylation of Amines with Alkynes

A nickel-catalyzed C−H alkenylation of amines with alkynes was developed, providing a series of allylic amines in up to 94% yield. The use of bulky amino protecting group (triisopropylphenylsulfonyl) and double ligands (IPr and PCy3) proved critical to the reaction efficiency

Amide-Ligand-Controlled Highly <i>para</i>-Selective Arylation of Monosubstituted Simple Arenes with Arylboronic Acids

Pd-catalyzed highly <i>para</i>-selective arylations of monosubstituted simple arenes with arylboronic acids to widely existed biaryls have been developed. Inspired by requisite amide-directing groups in reported selective oxidative couplings, amide ligands, especially DMF, are designed and found to be critical for the selectivity control in current arylations

Ligand-Promoted C3-Selective Arylation of Pyridines with Pd Catalysts: Gram-Scale Synthesis of (±)-Preclamol

The first example of Pd-catalyzed, C3-selective arylation of unprotected pyridines has been developed by employing a catalytic system consisting of Pd(OAc)₂ and 1,10-phenanthroline. This protocol provides an expeditious route to an important class of 3-arylpyridines and 3-arylpiperidines frequently found in bioactive compounds. A brief synthesis of the drug molecule (±)-preclamol is also reported

Enantioselective Ni–Al Bimetallic Catalyzed <i>exo</i>-Selective C–H Cyclization of Imidazoles with Alkenes

A Ni–Al bimetallic catalyzed enantioselective C–H <i>exo</i>-selective cyclization of imidazoles with alkenes has been developed. A series of bi- or polycyclic imidazoles with β-stereocenter were obtained in up to 98% yield and >99% ee. The bifunctional SPO ligand-promoted bimetallic catalysis proved to be critical to this challenging stereocontrol

Enantioselective Ni–Al Bimetallic Catalyzed <i>exo</i>-Selective C–H Cyclization of Imidazoles with Alkenes

A Ni–Al bimetallic catalyzed enantioselective C–H <i>exo</i>-selective cyclization of imidazoles with alkenes has been developed. A series of bi- or polycyclic imidazoles with β-stereocenter were obtained in up to 98% yield and >99% ee. The bifunctional SPO ligand-promoted bimetallic catalysis proved to be critical to this challenging stereocontrol