Elghareeb E. Elboray

M₂-polarized, tumor-associated macrophages (TAMs) produce pro-tumorigenic and angiogenic mediators, such as interleukin-8 (IL-8) and IL-10. Leucine-rich repeat-containing protein 8 members (LRRC8s) form volume-regulated anion channels and play an important role in macrophage functions by regulating cytokine and chemokine production. We herein examined the role of LRRC8A in IL-8 and IL-10 expression in THP-1-differentiated M₂-like macrophages (M₂-MACs), which are a useful tool for investigating TAMs. In M₂-MACs, the pharmacological inhibition of LRRC8A led to hyperpolarizing responses after a transient depolarization phase, followed by a slight elevation in the intracellular concentration of Ca²⁺. Both the small interfering RNA-mediated and pharmacological inhibition of LRRC8A repressed the transcriptional expression of IL-8 and IL-10, resulting in a significant reduction in their secretion. The inhibition of LRRC8A decreased the nuclear translocation of phosphorylated nuclear factor-erythroid 2-related factor 2 (Nrf2), while the activation of Nrf2 reversed the LRRC8A inhibition-induced transcriptional repression of IL-8 and IL-10 in M₂-MACs. We identified the CCAAT/enhancer-binding protein isoform B, CEBPB, as a downstream target of Nrf2 signaling in M₂-MACs. Moreover, among several upstream candidates, the inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) suppressed the Nrf2–CEBPB transcriptional axis in M₂-MACs. Collectively, the present results indicate that the inhibition of LRRC8A repressed IL-8 and IL-10 transcription in M₂-MACs through the NOX2–Nrf2–CEBPB axis and suggest that LRRC8A inhibitors suppress the IL-10-mediated evasion of tumor immune surveillance and IL-8-mediated metastasis and neovascularization in TAMs.

Diaryliodonium(III) salts are versatile reagents that exhibit a range of reactions, both in the presence and absence of metal catalysts. In this study, we developed efficient synthetic methods for the preparation of aryl(TMP)iodonium(III) carboxylates, by reaction of (diacetoxyiodo)arenes or iodosoarenes with 1,3,5-trimethoxybenzene in the presence of a diverse range of organocarboxylic acids. These reactions were conducted under mild conditions using the trimethoxyphenyl (TMP) group as an auxiliary, without the need for additives, excess reagents, or counterion exchange in further steps. These protocols are compatible with a wide range of substituents on (hetero)aryl iodine(III) compounds, including electron-rich, electron-poor, sterically congested, and acid-labile groups, as well as a broad range of aliphatic and aromatic carboxylic acids for the synthesis of diverse aryl(TMP)iodonium(III) carboxylates in high yields. This method allows for the hybridization of complex bioactive and fluorescent-labeled carboxylic acids with diaryliodonium(III) salts.

1,3‐Dipolar cycloaddition through in situ generation of azomethine ylide provides a straightforward and critically important sustainable approach for access to diverse pyrrolidine chemical space. Herein, we developed a metal‐free AcOH‐activated 1,3‐dipolar cycloaddition protocol that permits the synthesis of uncommon pyrrolidine cycloadducts with excellent diastereoselectivity. The challenging substrates of 3‐formylchromone, glycine ester.HCl and arylidene dipolarophile were reacted in the presence of AcONa, which played a dual role as a base and AcOH source, to deliver firstly endo‐cycloadduct. Under prolonged reaction time at room temperature or heating; the endo‐adduct underwent diastereodivergent via a sequence of retro‐cycloaddition, stereomutation of the generated syn‐dipole into anti‐dipole and recycloaddition; to furnish the scarcely known exo′‐cycloadduct with high diastereodivergency. The reaction worked well with a broad range of substrates and the stereochemistry of the obtained cycloadducts was determined without ambiguity using NMR‐ and X‐ray analysis. Experimental and theoretical DFT calculation studies were performed to support the proposed reaction mechanism and elucidate the key role of AcOH in the process which seems more beneficial than other transition metal‐catalyzed processes.

A one-pot transformation of biaryl dicarboxylic acids to (NH)-phenanthridinone derivatives based on a Curtius rearrangement and subsequent basic hydrolysis was developed. This method is also applicable for the preparation of optically active amide-functionalized [7]helicene-like molecules. Furthermore, aza[5]helicene derivatives with a phosphate moiety were isolated as a product of the Curtius rearrangement step in the case of substrates that bear chalcogen atoms. The stereostructures of these products, revealed by X-ray diffraction analysis, suggested that chalcogen-bonding and pnictogen-bonding interactions might contribute to their stabilization. The configurational stability of the helicene-like molecules and their chiroptical properties were further investigated.

1,3-Dipolar cycloaddition of 2- and 3-nitrobenzaldehydes with 2-aminomethylpyridine and ethyl (2E)-2-cyano-3-(4-nitrophenyl)prop-2-enoate yielded endo-cycloadducts as the sole products under various reaction conditions. Fortuitously, 4-nitrobenzaldehyde behaved differently in three- and four-component cascades to produce a mixture of endo- and exo′-cycloadducts. This reaction is solvent- and temperature-dependent, and consequently, both the endo- and exo′-cycloadducts were synthesized in an excellent regio-, stereo-, and chemoselective fashion. Retro-1,3-dipolar cycloadditions of the endo-cycloadducts were conducted under mild reaction conditions, and the generated syn-dipoles were stereomutated into anti-dipoles which recycloadded with the dipolarophiles to provide the exo′-cycloadducts. Mechanistic studies were carried out to support the proposed mechanisms. Unprecedentedly, particular arylidene scaffolds participated as aldehyde or activated methylene precursors. Density functional theory calculations were performed to shed light on the importance of AcOH in the generation and isomerization of dipoles and to explain the high selectivity and the possibility of retro-cycloaddition.

The oxidation of p-methoxy benzyl (PMB) ethers was achieved using nitroxyl radical catalyst 1, which contains electron-withdrawing ester groups adjacent to the nitroxyl group. The oxidative deprotection of the PMB moieties on the hydroxy groups was observed upon treatment of 1 with 1 equiv of the co-oxidant phenyl iodonium bis(trifluoroacetate) (PIFA). The corresponding carbonyl compounds were obtained by treating the PMB-protected alcohols with 1 and an excess of PIFA.

Axial chirality in N,N‐dimethylaminopyridines as well as N,N‐dipropylaminopyridines bearing an internal carboxy group were evaluated based on their racemization barriers and circular dichroism spectra. The half‐life of racemization of N,N‐dipropylaminopyridine derivative 2 was estimated to be 19.7 days at 20°C. Its enantiomers isolated as optically active forms showed positive‐negative and negative‐positive Cotton effects for (+)‐2 and (−)‐2, respectively, from 310 to 210 nm. Furthermore, (−)‐2 was applied as a chiral nucleophilic catalyst and exhibited asymmetric induction in acylative kinetic resolution of 1‐(1‐naphthyl)ethane‐1‐ol.

Previous studies have reported the up-regulation of the two-pore domain K⁺ channel K_2P5.1 in the CD4⁺ T cells of patients with multiple sclerosis (MS) and rheumatoid arthritis (RA), as well as in a mouse model of inflammatory bowel disease (IBD). However, the mechanisms underlying this up-regulation remain unclear. Inflammation-associated hypoxia is involved in the pathogenesis of autoimmune diseases, such as IBD, MS, and RA, and T cells are exposed to a hypoxic environment during their recruitment from inflamed tissues to secondary lymphoid tissues. We herein investigated whether inflammation-associated hypoxia is attributable to the increased expression and activity of K_2P5.1 in the splenic CD4⁺ T cells of chemically-induced IBD model mice. Significant increases in hypoxia-inducible factor (HIF)-1α transcripts and proteins were found in the splenic CD4⁺ T cells of the IBD model. In the activated splenic CD4⁺ T cells, hypoxia (1.5% O₂) increased K_2P5.1 expression and activity, whereas a treatment with the HIF inhibitor FM19G11 but not the selective HIF-2 inhibitor exerted the opposite effect. Hypoxia-exposed K_2P5.1 up-regulation was also detected in stimulated thymocytes and the mouse T-cell line. The class III histone deacetylase sirtuin-1 (SIRT1) is a downstream molecule of HIF-1α signaling. We examined the effects of the SIRT1 inhibitor NCO-01 on K_2P5.1 transcription in activated CD4⁺ T cells, and we found no significant effects on the K_2P5.1 transcription. No acute compensatory responses of K_2P3.1–K_2P5.1 up-regulation were found in the CD4⁺ T cells of the IBD model and the hypoxia-exposed T cells. Collectively, these results suggest a mechanism for K_2P5.1 up-regulation via HIF-1 in the CD4⁺ T cells of the IBD model.