Nucleophilic Amination of Methoxy Arenes Promoted by a Sodium Hydride/Iodide Composite.

A method for the nucleophilic amination of methoxy arenes was established by using sodium hydride (NaH) in the presence of lithium iodide (LiI). This method offers an efficient route to benzannulated nitrogen heterocycles. Mechanistic studies showed that the reaction proceeds through an unusual concerted nucleophilic aromatic substitution.

Nanomedicine Targeting Cuproplasia in Cancer: Labile Copper Sequestration Using Polydopamine Particles Blocks Tumor Growth In Vivo through Altering Metabolism and Redox Homeostasis.

Copper plays critical roles as a metal active site cofactor and metalloallosteric signal for enzymes involved in cell proliferation and metabolism, making it an attractive target for cancer therapy. In this study, we investigated the efficacy of polydopamine nanoparticles (PDA NPs), classically applied for metal removal from water, as a therapeutic strategy for depleting intracellular labile copper pools in triple-negative breast cancer models through the metal-chelating groups present on the PDA surface. By using the activity-based sensing probe FCP-1, we could track the PDA-induced labile copper depletion while leaving total copper levels unchanged and link it to the selective MDA-MB-231 cell death. Further mechanistic investigations revealed that PDA NPs increased reactive oxygen species (ROS) levels, potentially through the inactivation of superoxide dismutase 1 (SOD1), a copper-dependent antioxidant enzyme. Additionally, PDA NPs were found to interact with the mitochondrial membrane, resulting in an increase in the mitochondrial membrane potential, which may contribute to enhanced ROS production. We employed an in vivo tumor model to validate the therapeutic efficacy of PDA NPs. Remarkably, in the absence of any additional treatment, the presence of PDA NPs alone led to a significant reduction in tumor volume by a factor of 1.66 after 22 days of tumor growth. Our findings highlight the potential of PDA NPs as a promising therapeutic approach for selectively targeting cancer by modulating copper levels and inducing oxidative stress, leading to tumor growth inhibition as shown in these triple-negative breast cancer models.

Catalytic photooxygenation degrades brain Aß in vivo.

Protein degradation induced by small molecules by recruiting endogenous protein degradation systems, such as ubiquitin-proteasome systems, to disease-related proteins is an emerging concept to inhibit the function of undruggable proteins. Protein targets without reliable ligands and/or existing outside the cells where ubiquitin-proteasome systems do not exist, however, are beyond the scope of currently available protein degradation strategies. Here, we disclose photooxygenation catalyst 7 that permeates the blood-brain barrier and selectively and directly degrades an extracellular Alzheimer's disease-related undruggable protein, amyloid-ß protein (Aß). Key was the identification of a compact but orange color visible light-activatable chemical catalyst whose activity can be switched on/off according to its molecular mobility, thereby ensuring high selectivity for aggregated Aß. Chemical catalyst-promoted protein degradation can be applied universally for attenuating extracellular amyloids and various pathogenic proteins and is thus a new entry to induced protein degradation strategies.

Synthetic hyperacetylation of nucleosomal histones.

We report combinations of a DMAP-based catalyst and phenyl acetate with optimal electron density as a new chemical system for high-yield, selective synthetic acetylation of histone lysine residues. The utility of this chemical system as a unique biologic tool is demonstrated by applying it to Xenopus laevis sperm chromatin.

Organocopper cross-coupling reaction for C-C bond formation on highly sterically hindered structures.

We describe a powerful, broadly applicable cross-coupling protocol that enables carbon-carbon bond formation at highly sterically hindered carbon centers (both sp2 and sp3) by employing organocopper reagents under palladium catalysis. Experimental studies and theoretical calculations indicated that the key to the unique reactivity of copper is the relatively low activation energy of the compact transmetalation transition state, due to Cu(i)-Pd(ii) interaction, which is associated with small values of deformation energy of the reactants. This reaction is applicable to a variety of bulky substrates, including compounds inert to previous cross-coupling chemistry and has high functional group tolerance.

Dearylation of arylphosphine oxides using a sodium hydride-iodide composite.

A new protocol for the dearylation of arylphosphine oxides was developed using sodium hydride (NaH) in the presence of lithium iodide (LiI). The transient sodium phosphinite could be functionalized with a range of electrophiles in a one-pot fashion.