A highly potent bi-thiazole inhibitor of LOX rewires collagen architecture and enhances chemoresponse in triple-negative breast cancer.

Lysyl oxidase (LOX) is upregulated in highly stiff aggressive tumors, correlating with metastasis, resistance, and worse survival; however, there are currently no potent, safe, and orally bioavailable small molecule LOX inhibitors to treat these aggressive desmoplastic solid tumors in clinics. Here we discovered bi-thiazole derivatives as potent LOX inhibitors by robust screening of drug-like molecules combined with cell/recombinant protein-based assays. Structure-activity relationship analysis identified a potent lead compound (LXG6403) with ∼3.

Intramolecular CH-Hydrogen Bonding During the Dissociation of the Oxaphosphetane Intermediate Facilitates Z/E-Selectivity in Wittig Olefination.

Herein, DFT studies corroborating experimental results revealed that the shortest intramolecular hydrogen bonding distance of cis/trans-oxaphosphetane (OPA) oxygen with the CH-hydrogen of a triphenylphosphine phenyl ring provides good evidence for the attained olefin Z/E-selectivity in Wittig olefination of the studied examples. 2-Nitrobenzaldehyde, 3-nitrobenzaldehyde, 2-nitro-3-bromobenzaldehyde, 2-nitro-5-bromobenzaldehyde and 2-nitro-5-arylbenzaldehydes provided Z-nitrostilbenes with (2-chloro-4-hydroxy-3-methoxy-5-(methoxycarbonyl)benzyl) triphenylphosphonium chloride as the major products. However, 4-nitrobenzaldehyde and 2-nitro-6-bromobenzaldehydes furnished E-nitrostilbenes as the major products in high yields.

Cis- and trans-resveratrol have opposite effects on histone serine-ADP-ribosylation and tyrosine induced neurodegeneration.

Serum tyrosine levels increase during aging, neurocognitive, metabolic, and cardiovascular disorders. However, calorie restriction (CR) and sleep lower serum tyrosine levels. We previously showed that tyrosine inhibits tyrosyl-tRNA synthetase (TyrRS)-mediated activation of poly-ADP-ribose polymerase 1 (PARP1).

Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation.

Unlike widely perceived, resveratrol (RSV) decreased the average lifespan and extended only the replicative lifespan in yeast. Similarly, although not widely discussed, RSV is also known to evoke neurite degeneration, kidney toxicity, atherosclerosis, premature senescence, and genotoxicity through yet unknown mechanisms. Nevertheless, in vivo animal models of diseases and human clinical trials demonstrate inconsistent protective and beneficial effects.

Dopamine Triggers CTCF-Dependent Morphological and Genomic Remodeling of Astrocytes.

Dopamine is critical for processing of reward and etiology of drug addiction. Astrocytes throughout the brain express dopamine receptors, but consequences of astrocytic dopamine receptor signaling are not well established. We found that extracellular dopamine triggered rapid concentration-dependent stellation of astrocytic processes that was not a result of dopamine oxidation but instead relied on both cAMP-dependent and cAMP-independent dopamine receptor signaling.

Lithium Bromide/Water as Additives in Dearomatizing Samarium-Ketyl (Hetero)Arene Cyclizations.

New conditions for dearomatizing samarium-ketyl (hetero)arene cyclizations are reported. In many examples of these samarium diiodide-mediated reactions, lithium bromide and water can be used as additives instead of the carcinogenic and mutagenic hexamethylphosphoramide (HMPA). The best results were obtained for the cyclizations of N-acylated indole derivatives delivering the expected indolines in good yields and excellent diastereoselectivities.

Synthesis of polycyclic tertiary carbinamines by samarium diiodide mediated cyclizations of indolyl sulfinyl imines.

Samarium diiodide mediated cyclizations of N-acylated indole derivatives bearing sulfinyl imine moieties afforded polycyclic tertiary carbinamines with moderate to excellent diastereoselectivities. Lithium bromide and water turned out to be the best additives to achieve these transformations in good yields. Using enantiopure sulfinyl imines the outcome strongly depends on the reactivity of the indole moiety.

BF3-Et2O mediated skeletal rearrangements of norbornyl appended cyclopentanediols.

An unusual cascade rearrangement has been noticed as a competitive reaction during the treatment of norbornyl appended cyclopentanediols with a Lewis acid (LA): a BF3-Et2O mediated pinacol-pinacolone rearrangement. Deketalization and pinacolone rearrangement occur at two different sites in the molecule and are responsible for the observed cascade rearrangement product. However, deketalization appears to be triggering the cascade steps.

Synergism and inhibition in the combination of visible light and HMPA in SmI2 reductions.

The reaction of six substrates (diphenylacetylene, benzonitrile, methyl benzoate, phenylacetylene, naphthalene, and 1-chloro-4-ethylbenzene) with SmI(2) in the presence of MeOH or TFE was studied. The reactions were monitored under three different conditions: (a) irradiation, (b) irradiation in the presence of HMPA, and (c) reactions in the presence of HMPA in the dark. The combination of visible light and HMPA was found in some cases to be synergistic, in others to be additive, and in four cases to be inhibitive.

Photostimulated reduction of nitriles by SmI2.

Despite their high electron-withdrawing strength, nitriles are not good electron acceptors and therefore are hard to reduce. In this work, using photostimulation in the visible region, we examined the reactivity of aliphatic and aromatic, mono- and dicyano compounds in reaction with SmI(2). A proton donor that complexes efficiently with SmI(2) must be used.

The effect of replacing carbon by nitrogen in reductions with SmI2: reduction of azobenzene.

The reduction of azobenzene by SmI(2) in THF to give hydrazobenzene was investigated. The kinetics are first order in the substrate and first order in SmI(2). The kinetic order in MeOH is ca.

Autocatalysis and surface catalysis in the reduction of imines by SmI2.

The reduction of the three imines, N-benzylidene aniline (BAI), N-benzylidenemethylamine (BMI), and benzophenone imine (BPI), with SmI(2) gives the reduced as well as coupled products. The reactions were found to be autocatalytic due to the formation of the trivalent samarium in the course of the reaction. When preprepared SmI(3) was added to the reaction mixture, the reaction rate increased significantly.