Regioselective Amidomethylation of 4-Chloro-3-fluoropyridine by Metalation and Minisci-Type Reactions.

The synthesis of a series of 2-amidomethylated pyridines (-) was investigated, starting from 4-chloro-3-fluoropyridine. Kinetic deprotonation at -75 °C followed by reaction with DMF gave 2-formyl-4-chloro-3-fluoropyridine regioselectively, which was converted to 2-aminomethyl analogue via sulfinamide . Alternatively, Minisci-type amidomethylation under Ag/persulfate or photoredox-mediated conditions using a series of amino acid derivatives gave (-, , and ) in 30-74% yield and isomer ratios in the range 6.

Absolute proteomic quantification reveals design principles of sperm flagellar chemosensation.

Cilia serve as cellular antennae that translate sensory information into physiological responses. In the sperm flagellum, a single chemoattractant molecule can trigger a Ca rise that controls motility. The mechanisms underlying such ultra-sensitivity are ill-defined.

A novel cross-species inhibitor to study the function of CatSper Ca channels in sperm.

Background And Purpose: Sperm from many species share the sperm-specific Ca channel CatSper that controls the intracellular Ca concentration and, thereby, the swimming behaviour. A growing body of evidence suggests that the mechanisms controlling the activity of CatSper and its role during fertilization differ among species. A lack of suitable pharmacological tools has hampered the elucidation of the function of CatSper.

Photocontrol of the Hv1 Proton Channel.

The voltage-gated proton channel Hv1 is expressed in various human cell types, including macrophages, epithelial cells, and sperm. Hv1 opening leads to proton efflux that alkalizes the cytosol. Here, we describe light-activated Hv1 inhibitors (photoswitches) that allow controlling its activity with high spatiotemporal precision.

Identification of a feedback loop involving β-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease.

The lysosomal acid β-glucosidase GBA1 and the non-lysosomal β-glucosidase GBA2 degrade glucosylceramide (GlcCer) to glucose and ceramide in different cellular compartments. Loss of GBA2 activity and the resulting accumulation of GlcCer results in male infertility, whereas mutations in the gene and loss of GBA1 activity cause the lipid-storage disorder Gaucher disease. However, the role of GBA2 in Gaucher disease pathology and its relationship to GBA1 is not well understood.

Downregulation of Spermine Augments Dendritic Persistent Sodium Currents and Synaptic Integration after Status Epilepticus.

Unlabelled: Dendritic voltage-gated ion channels profoundly shape the integrative properties of neuronal dendrites. In epilepsy, numerous changes in dendritic ion channels have been described, all of them due to either their altered transcription or phosphorylation. In pilocarpine-treated chronically epileptic rats, we describe a novel mechanism that causes an increased proximal dendritic persistent Na(+) current (INaP).

Sperm navigation along helical paths in 3D chemoattractant landscapes.

Sperm require a sense of direction to locate the egg for fertilization. They follow gradients of chemical and physical cues provided by the egg or the oviduct. However, the principles underlying three-dimensional (3D) navigation in chemical landscapes are unknown.

Synthesis of a potent photoreactive acidic γ-secretase modulator for target identification in cells.

Supramolecular self-assembly of amyloidogenic peptides is closely associated with numerous pathological conditions. For instance, Alzheimer´s disease (AD) is characterized by abundant amyloid plaques originating from the proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Compounds named γ-secretase modulators (GSMs) can shift the substrate cleavage specificity of γ-secretase toward the production of non-amyloidogenic, shorter Aβ fragments.

Chemical Biology, Molecular Mechanism and Clinical Perspective of γ-Secretase Modulators in Alzheimer's Disease.

Comprehensive evidence supports that oligomerization and accumulation of amyloidogenic Aβ42 peptides in brain is crucial in the pathogenesis of both familial and sporadic forms of Alzheimer's disease. Imaging studies indicate that the buildup of Aβ begins many years before the onset of clinical symptoms, and that subsequent neurodegeneration and cognitive decline may proceed independently of Aβ. This implies the necessity for early intervention in cognitively normal individuals with therapeutic strategies that prioritize safety.

Presenilin is the molecular target of acidic γ-secretase modulators in living cells.

The intramembrane-cleaving protease γ-secretase catalyzes the last step in the generation of toxic amyloid-β (Aβ) peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of γ-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are γ-secretase modulators (GSMs), which are small molecules that selectively lower generation of the highly amyloidogenic Aβ42 peptides but spare Notch processing.