SIKs Regulate HDAC7 Stabilization and Cytokine Recall in Late-Stage T Cell Effector Differentiation.

Understanding the mechanisms underlying the acquisition and maintenance of effector function during T cell differentiation is important to unraveling how these processes can be dysregulated in the context of disease and manipulated for therapeutic intervention. In this study, we report the identification of a previously unappreciated regulator of murine T cell differentiation through the evaluation of a previously unreported activity of the kinase inhibitor, BioE-1197. Specifically, we demonstrate that liver kinase B1 (LKB1)-mediated activation of salt-inducible kinases epigenetically regulates cytokine recall potential in effector CD8+ and Th1 cells.

Synthesis and Pharmacological Characterization of a Difluorinated Analogue of Reduced Haloperidol as a Sigma-1 Receptor Ligand.

Reduced haloperidol () was previously reported to act as a potent sigma-1 receptor (S1R) ligand with substantially lower affinity to the dopamine D2 receptor (D2R) compared to haloperidol. It was also found to facilitate brain-derived neurotrophic factor (BDNF) secretion from astrocytic glial cell lines in a sigma-1 receptor (S1R)-dependent manner. Although an increase in BDNF secretion may have beneficial effects in some neurological conditions, the therapeutic utility of reduced haloperidol () is limited because it can be oxidized back to haloperidol in the body, a potent dopamine D2 receptor antagonist associated with well-documented adverse effects.

Effects of 6-Aminonicotinic Acid Esters on the Reprogrammed Epigenetic State of Distant Metastatic Pancreatic Carcinoma.

In the search for alternatives to 6-aminonicotinamide (6AN), a series of 6-aminonicotinic acid esters were designed and synthesized as precursors of 6-amino-NADP, a potent inhibitor of 6-phosphogluconate dehydrogenase (6PGD). Like 6AN, some of these esters were found to reverse the loss of histone 3 lysine 9 trimethylation (H3K9me3) in patient-derived pancreatic ductal adenocarcinoma (PDAC) distant metastasis (A38-5). Among them, 1-(((cyclohexyloxy)carbonyl)oxy)ethyl 6-aminonicotinate () showed more potent antiproliferative activity than 6AN.

D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II.

Glutamate carboxypeptidase-II (GCPII) is a zinc-dependent metalloenzyme implicated in numerous neurological disorders. The pharmacophoric requirements of active-site GCPII inhibitors makes them highly charged, manifesting poor pharmacokinetic (PK) properties. Herein, we describe the discovery and characterization of catechol-based inhibitors including L-DOPA, D-DOPA, and caffeic acid, with sub-micromolar potencies.

Tandem aza-Heck Suzuki and carbonylation reactions of -phenyl hydroxamic ethers: complex lactams carboamination.

The palladium-catalysed tandem aza-Heck-Suzuki and aza-Heck-carbonylation reactions of -phenyl hydroxamic ethers are reported. These formal alkene carboamination reactions provide highly versatile access to wide range complex, stereogenic secondary lactams and exhibit outstanding functional group tolerance and high diastereoselectivity.

Allosteric kidney-type glutaminase (GLS) inhibitors with a mercaptoethyl linker.

A series of allosteric kidney-type glutaminase (GLS) inhibitors possessing a mercaptoethyl (SCHCH) linker were synthesized in an effort to further expand the structural diversity of chemotypes derived from bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a prototype allosteric inhibitor of GLS. BPTES analog 3a with a mercaptoethyl linker between the two thiadiazole rings was found to potently inhibit GLS with an IC value of 50 nM. Interestingly, the corresponding derivative with an n-propyl (CHCHCH) linker showed substantially lower inhibitory potency (IC = 2.

Palladium(0)-Catalyzed Intermolecular Asymmetric Cascade Dearomatization Reaction of Indoles with Propargyl Carbonate.

An intermolecular asymmetric cascade dearomatization reaction of indole derivatives with propargyl carbonate was developed. The challenges associated with both the chemoselectivity between the carbon and nitrogen nucleophile and the enantioselective control during the formation of an all-carbon quaternary stereogenic center were well addressed by a Pd catalytic system derived from the Feringa ligand. A series of enantioenriched multiply substituted fused indolenines were provided in good yields (71-86 %) with excellent enantioselectivity (91-96 % ee) and chemoselectivity (3/4>19:1 in most cases).

Palladium(0)-Catalyzed Intermolecular Asymmetric Allylic Dearomatization of Polycyclic Indoles.

An intermolecular Pd-catalyzed allylic dearomatization reaction of polycyclic indoles with substituted allylic carbonates was realized in the presence of a newly synthesized chiral phosphoramidite ligand. Various polycyclic indoline and indolenine derivatives were successfully synthesized in excellent yields (up to 99%) with excellent enantioselectivity (up to 98% ee). The obtained products could undergo versatile transformations, increasing the application potential of the method in organic synthesis.

Pd-catalyzed cascade allylic alkylation and dearomatization reactions of indoles with vinyloxirane.

We have developed Pd-catalyzed intermolecular Friedel-Crafts-type allylic alkylation and allylic dearomatization reactions of substituted indoles bearing a nucleophilic group with vinyloxirane, providing an efficient method to synthesize structurally diverse tetrahydrocarboline and spiroindolenine derivatives under mild conditions.

Palladium(0)-Catalyzed Intermolecular Allylic Dearomatization of Indoles by a Formal [4+2] Cycloaddition Reaction.

Bridged indoline derivatives were synthesized by an intermolecular Pd-catalyzed allylic dearomatization reaction of substituted indoles. The reaction between indoles and allyl carbonates bearing a nucleophilic alcohol side-chain proceeds in a cascade fashion, providing bridged indolines in excellent enantioselectivity.

Reaction of trisubstituted alkenes with iron porphyrin carbenes: facile synthesis of tetrasubstituted dienes and cyclopentadienes.

The unprecedented reaction of trisubstituted alkenes with iron porphyrin carbenes has been successfully developed. Both multiply substituted 1,3-butadiene and cyclopentadiene products are readily accessible with high efficiency and selectivity in good yields.