Halogen Moieties Research Articles

Modulation of aryl hydrocarbon receptor activity by halogenated indoles

The aryl hydrocarbon receptor (AhR) is a cytosolic ligand-activated transcription factor integral to various physiological and pathological processes. Among its diverse ligands, indole-based compounds have garnered attention due to their significant biological activity and potential therapeutic applications. This study explores the activation of AhR by structurally diverse halogenated indoles. We evaluated the transcriptional activity of AhR and cell viability in the human LS174T-AhR-luc reporter cell line. Among the tested compounds, 4-FI, 7-FI, 6-BrI, 7-BrI, 6-Cl-2-ox, 5-Br-2-ox, and 6-Br-2-ox activated AhR in a concentration-dependent manner, displaying high efficacy and potency. Molecular docking analysis revealed moderate binding affinities of these compounds to the PAS-B domain of AhR, corroborated by competitive radioligand binding assays. Functional assays showed that halogenated indoles induce the formation of AhR-ARNT heterodimer and enhance the binding of the AhR to the CYP1A1 promoter. Additionally, 4-FI and 7-FI exhibited anti-inflammatory properties in Caco-2 cell models, highlighting their potential for therapeutic applications. This study underscores the significance of the type and position of halogen moiety in indole scaffold, suggesting their potential as candidates for developing therapeutics drugs to treat conditions such as inflammatory bowel disease via AhR activation.

Chemoselective oxidative N-debenzylation of aryl halogenated amines using the Laccase LAC97/TEMPO system

The N-debenzylation of aryl-halogenated amines using the Laccase LAC97/TEMPO system is reported, demonstrating selective N-debenzylation with no dehalogenation of the phenyl ring, which is observed with conventional debenzylation methods such as palladium-catalysed hydrogenation. This reaction was performed under ambient conditions in acidic buffer with 5 % DMSO as co-solvent in an open-to-air vessel. The versatility and robustness of the system was demonstrated on substrates harbouring different halogen moieties. The limitations of the Laccase LAC97/TEMPO system were also studied, highlighting the formation of by-products due to overoxidation on selected substrates. A series of substrates with various halogens were studied. High conversion (78–90 %) in 6 h and full conversion was achieved within 24 h using HPLC to monitor the reaction. Overall, this system is presented as a chemoselective N-debenzylation alternative for aryl-halogenated substrates.

Computational Design and Experimental Validation of an Orthogonal X-bond/H-bond System to Improve the Binding Affinity and Recognition Specificity between Anesthetic Protein Kinase Cι and its Pseudosubstrate Peptide

Protein kinase C isoform [Formula: see text] (PKC[Formula: see text]) is an essential regulator of diverse neurobiological signaling pathways, which has been implicated in general anesthetic action and a variety of nervous neoplasms. Traditional efforts have been primarily addressed on the development of small-molecule inhibitors to target the catalytic or regulatory domain of this kinase. Instead, we herein reported a rational chemical modification of Par3 pseudosubstrate peptide to target the kinase domain with improved affinity and specificity. Structural and energetic analysis suggested that the Par3 peptide can be divided into two binding-independent sections; they are separately anchored to the substrate-binding pocket of PKC[Formula: see text] with two aromatic anchor residues Phe818 and Phe823. The side-chain phenyl group of these two aromatic residues was systematically substituted by different halogen moieties at [Formula: see text]-, [Formula: see text]- and [Formula: see text]-positions of the phenyl group. It is revealed that the [Formula: see text]-bromination of Par3 Phe818 and the [Formula: see text]-iodinization of Par3 Phe823 residue can separately form two geometrically and energetically satisfactory orthogonal halogen (X)-bond/hydrogen (H)-bond [ortX/H] motifs across Par3 complex interface with PKC[Formula: see text]; they co-define a so-called ortX/H system and were demonstrated to improve both the binding affinity and recognition specificity of the kinase–peptide interaction by integrating in silico analysis and in vitro assay. The peptide affinity promotes 23.5-fold and 6.6-fold upon the formation of ortX/H motif-I and motif-II, respectively, which further increases to 43.5-fold by forming the complete ortX/H system, indicating cooperativity between the two motifs in the system. In addition, we also demonstrated that the ortX/H system can considerably enhance the peptide selectivity for its cognate PKC[Formula: see text] and noncogante isoforms PKC[Formula: see text] and PKC[Formula: see text].

Selective Hydrogenation of Aldehydes under Syngas Using CeO2-Supported Au Nanoparticle Catalyst.

Chemoselective hydrogenation of aldehydes to alcohols is of importance in synthetic chemistry. Here, we report a reusable CeO2-supported Au nanoparticle catalyst for the selective hydrogenation of aldehydes using syngas as the hydrogen source for which CO in syngas works as a site blocker to prevent side reactions. In particular, the hydrogenation of aldehydes with an easily reducible alkene, alkyne, or halogen moiety under syngas gave the corresponding alcohols with high selectivity, while the hydrogenation under pure hydrogen resulted in overreduction or dehalogenation. Of particular interest is that CO works as a site blocker but does not affect the hydrogenation rate significantly. A potential application of the present catalyst system was demonstrated by the conversion of terminal alkenes to alcohols via a one-pot hydroformylation/hydrogenation sequence.

Simultaneous Degradation, Dehalogenation, and Detoxification of Halogenated Antibiotics by Carbon Dioxide Radical Anions

Despite the extensive application of advanced oxidation processes (AOPs) in water treatment, the efficiency of AOPs in eliminating various emerging contaminants such as halogenated antibiotics is constrained by a number of factors. Halogen moieties exhibit strong resistance to oxidative radicals, affecting the dehalogenation and detoxification efficiencies. To address these limitations of AOPs, advanced reduction processes (ARPs) have been proposed. Herein, a novel nucleophilic reductant—namely, the carbon dioxide radical anion (CO2−)—is introduced for the simultaneous degradation, dehalogenation, and detoxification of florfenicol (FF), a typical halogenated antibiotic. The results demonstrate that FF is completely eliminated by CO2−, with approximately 100% of Cl− and 46% of F− released after 120 min of treatment. Simultaneous detoxification is observed, which exhibits a linear response to the release of free inorganic halogen ions (R2 = 0.97, p < 0.01). The formation of halogen-free products is the primary reason for the superior detoxification performance of this method, in comparison with conventional hydroxyl-radical-based AOPs. Products identification and density functional theory (DFT) calculations reveal the underlying dehalogenation mechanism, in which the chlorine moiety of FF is more susceptible than other moieties to nucleophilic attack by CO2−. Moreover, CO2−-based ARPs exhibit superior dehalogenation efficiencies (> 75%) in degrading a series of halogenated antibiotics, including chloramphenicol (CAP), thiamphenicol (THA), diclofenac (DLF), triclosan (TCS), and ciprofloxacin (CIP). The system shows high tolerance to the pH of the solution and the presence of natural water constituents, and demonstrates an excellent degradation performance in actual groundwater, indicating the strong application potential of CO2−-based ARPs in real life. Overall, this study elucidates the feasibility of CO2− for the simultaneous degradation, dehalogenation, and detoxification of halogenated antibiotics and provides a promising method for their regulation during water or wastewater treatment.

Electrochemical oxidative selective halogenation of pyrazolones for the synthesis of 4-halopyrazolones.

An efficient and environmentally friendly electrochemical oxidative selective halogenation of pyrazolones has been developed under conditions free of metals, external oxidants, and external supporting electrolytes. The reaction demonstrates good functional group tolerance and maintains high efficiency in large-scale synthesis, yielding moderate to excellent yields of the desired 4-halopyrazolones. This method provides a green and convenient route for the direct installation of a halogen moiety into bioactive pyrazolone derivatives, which can be utilized in a myriad of applications.

Ultrahigh Capacity from Complexation-Enabled Aluminum-Ion Batteries with C70 as the Cathode.

Restricted by the available energy storage modes, currently rechargeable aluminum-ion batteries (RABs) can only provide a very limited experimental capacity, regardless of the very high gravimetric capacity of Al (2980mAhg-1 ). Here, a novel complexation mechanism is reported for energy storage in RABs by utilizing 0D fullerene C70 as the cathode. This mechanism enables remarkable discharge voltage (≈1.65V) and especially a record-high reversible specific capacity (750mAhg-1 at 200mAg-1 ) of RABs. By means of in situ Raman monitoring, mass spectrometry, and density functional theory (DFT) calculations, it is found that this elevated capacity is attributed to the direct complexation of one C70 molecule with 23.5 (super)halogen moieties (superhalogen AlCl4 and/or halogen Cl) in average, forming (super)halogenated C70 ·(AlCl4 )m Cln-m complexes. Upon discharging, decomplexation of C70 ·(AlCl4 )m Cln-m releases AlCl4 - /Cl- ions while preserving the intact fullerene cage. This work provides a new route to realize high-capacity and long-life batteries following the complexation mechanism.

Computational insights into the spontaneity of epoxide formation from halohydrins and other mechanistic details of Williamson’s ether synthesis

The reaction mechanism of several Williamson‟s ether syntheses have been studied using density functional theory with triple-ζ basis sets. These computations show that the synthesis of geometrically-strained epoxide from deprotonated halohydrins is due to the combined effects of favourable solvation of the products, higher bond enthalpy of C-O bonds vs. C-Cl bonds and increased vibrational entropy of the epoxide vs. the original halohydrin. Examination of the pathways leading to the formation of larger cyclic ethers revealed that the experimentally-observed preference for the formation of five-atom rings over six-atom-rings is due to the preference of the intervening methylene groups for staggered conformations, which entails that the alkyl carbon in the reactant state leading to the six-atom cyclic ether is initially not properly aligned with the attacking alkoxide. Study of the competing elimination reactions further shows that during the synthesis of five-atom cyclic ethers the competing elimination reaction is strongly disfavoured due to steric effects. The temperature dependence of both reactions favours elimination over SN2 as temperature rises, though only when the alkoxide and the halogen moieties are not part of the same carbon chain.

Catalytic Potential of [B12X11]2- (X = F, Cl, Br, I, CN) Dianions.

Dodecaborate anions ([B12H12]2-) and their derivatives where hydrogen atoms are replaced by halogen, pseudohalogen, or superhalogen moieties belong to a class of very stable species, even in the gas phase. Their stability is attributed to Wade's electron counting rule that requires n + 1 pairs of skeletal electrons, n being the number of boron atoms. Consequently, [B12X11]2- (X = H, F, Cl, Br, I, CN) dianions that carry one more electron than needed to satisfy Wade's rule should not be stable, assuming that the rule applies to fragments as well. While this is the case for X = H, we show that [B12X11]2- (X = F, Cl, Br, I, CN) dianions are stable with the second electron in [B12(CN)11]2- bound by as much as 3.17 eV. More importantly, the stability of these dianions is found to have a significant effect on the activation of gas molecules such as CO2 and N2, providing a path toward the development of new catalysts.

Diflunisal and Analogue Pharmacophores Mediating Suppression of Virulence Phenotypes in Staphylococcus aureus.

Invasive methicillin-resistant Staphylococcus aureus (MRSA) infections are leading causes of morbidity and mortality that are complicated by increasing resistance to conventional antibiotics. Thus, minimizing virulence and enhancing antibiotic efficacy against MRSA is a public health imperative. We originally demonstrated that diflunisal (DIF; [2-hydroxy-5-(2,4-difluorophenyl) benzoic acid]) inhibits S. aureus virulence factor expression. To investigate pharmacophores that are active in this function, we evaluated a library of structural analogues for their efficacy to modulate virulence phenotypes in a panel of clinically relevant S. aureus isolates in vitro. Overall, the positions of the phenyl, hydroxyl, and carboxylic moieties and the presence or type of halogen (F vs. Cl) influenced the efficacy of compounds in suppressing hemolysis, proteolysis, and biofilm virulence phenotypes. Analogues lacking halogens inhibited proteolysis to an extent similar to DIF but were ineffective at reducing hemolysis or biofilm production. In contrast, most analogues lacking the hydroxyl or carboxylic acid groups did not suppress proteolysis but did mitigate hemolysis and biofilm production to an extent similar to DIF. Interestingly, chirality and the substitution of fluorine with chlorine resulted in a differential reduction in virulence phenotypes. Together, this pattern of data suggests virulence-suppressing pharmacophores of DIF and structural analogues integrate halogen, hydroxyl, and carboxylic acid moiety stereochemistry. The anti-virulence effects of DIF were achieved using concentrations that are safe in humans, do not impair platelet antimicrobial functions, do not affect S. aureus growth, and do not alter the efficacy of conventional antibiotics. These results offer proof of concept for using novel anti-virulence strategies as adjuvants to antibiotic therapy to address the challenge of MRSA infection.

11C-, 12C-, and 13C-cyanation of electron-rich arenes via organic photoredox catalysis

As a non-invasive imaging technology, positron emission tomography (PET) plays a crucial role in personalized medicine, including early diagnosis, patient screening, and treatment monitoring. The advancement of PET research depends on the discovery of new PET agents, which requires the development of simple and efficient radiolabeling methods in many cases. As bioisosteres for halogen and carbonyl moieties, nitriles are important functional groups in pharmaceutical and agrochemical compounds. Here, we disclose a mild organophotoredox-catalyzed method for efficient cyanation of a broad spectrum of electron-rich arenes, including abundant and readily available veratroles and pyrogallol trimethyl ethers. Notably, the transformations not only are compatible with various affordable 12C and 13C-cyanide sources, but also could be applied to carbon-11 synthons to incorporate [11C]nitriles into arenes. The aryl [11C]nitriles can be further derivatized to [11C]carboxylic acids, [11C]amides, and [11C]alkyl amines. The newly developed reaction can serve as a powerful tool for generating new PET agents.

A new class of 5-HT2A /5-HT2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2-aminotetralins.

The 5-HT receptor subtypes 5-HT2A and 5-HT2C are important neurotherapeutic targets, though, obtaining selectivity over 5-HT2B and H1 receptors is challenging. Here, we delineated molecular determinants of selective binding to 5-HT2A and 5-HT2C receptors for novel 4-phenyl-2-dimethylaminotetralins (4-PATs). We synthesized 42 novel 4-PATs with halogen or aryl moieties at the C(4)-phenyl meta-position. Affinity, function, molecular modeling and 5-HT2A receptor mutagenesis studies were performed to understand structure-activity relationships at 5-HT2 -type and H1 receptors. Lead 4-PAT-type 5-HT2A /5-HT2C receptor inverse agonists were compared with pimavanserin, a selective 5-HT2A /5-HT2C receptor inverse agonist approved to treat Parkinson's disease-related psychosis, in the mouse head twitch response and locomotor activity assays, models relevant to antipsychotic drug development. Most 4-PAT diastereomers in the (2S,4R)-configuration bound non-selectively to 5-HT2A , 5-HT2C and H1 receptors, with >100-fold selectivity over 5-HT2B receptors, whereas diastereomers in the (2R,4R)-configuration bound preferentially to 5-HT2A over 5-HT2C receptors and had >100-fold selectivity over 5-HT2B and H1 receptors. Results suggest that G2385.42 and V2355.39 in 5-HT2A receptors (conserved in 5-HT2C receptors) are important for high affinity binding, whereas interactions with T1945.42 and W1584.56 determine H1 receptor affinity. The 4-PAT analog (2S,4R)-4-(4'-(dimethylamino)-[1,1'-biphenyl]-3-yl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine, (2S,4R)-2k, a potent and selective 5-HT2A /5-HT2C receptor inverse agonist, had activity like pimavanserin in the mouse head twitch response assay but was distinct in not suppressing locomotor activity. The novel 4-PAT chemotype can yield selective 5-HT2A /5-HT2C receptor inverse agonists for antipsychotic drug development by optimizing ligand-receptor interactions in transmembrane domain 5. Chirality can be exploited to attain selectivity over H1 receptors, which may circumvent sedative effects.

Flexible Alkali-Halogen Bonding in Two Dimensional Alkali-Metal Organic Frameworks.

On-surface fabrication of two-dimensional (2D) metal organic frameworks (MOFs) has been continuously attracting attentions for years. However, the synthesis of 2D MOFs with large-amplitude flexibility was rarely carried out since the bonding configurations in the coordination nodes are typically highly directional. Here we demonstrate that single alkali ions, which are fully isotropic in ionic bonding, can act as pivot joints for constructing tunable 2D MOFs by bonding to dihalogen groups in organic molecules. We take 2,3,6,7,10,11-hexabromotriphenylene, a 3-fold polycyclic molecule with three ortho-dibromo groups, and sodium (Na) atoms as a model system and successfully construct Na-based MOFs on Au(111) surface. The deflection angle of the Na coordination nodes is variable in an unprecedentedly large range between ±36° that allows the construction of multiple 2D MOF architectures. Such a flexible alkali-halogen bonding may provide a unique toolbox for designing and constructing more tunable MOFs by choosing various alkali atoms and halogen moieties.

Identification of new halogen-containing 2,4-diphenyl indenopyridin-5-one derivative as a boosting agent for the anticancer responses of clinically available topoisomerase inhibitors

Based on previous reports on the significance of halogen moieties and the indenopyridin-5-one skeleton, we designed and synthesized a novel series of halogen (F−, Cl−, Br−, CF3− and OCF3−)-containing 2,4-diphenyl indenopyridin-5-ones and their corresponding -5-ols. Unlike indenopyridin-5-ols, most of the prepared indenopyridin-5-ones with Cl−, Br−, and CF3− groups at the 2-phenyl ring conferred a strong dual topoisomerase I/IIα inhibitory effect. Among the series, para-bromophenyl substituted compound 9 exhibited the most potent topoisomerase inhibition and antiproliferative effects, which showed dependency upon the topoisomerase gene expression level of diverse cancer cells. In particular, as a DNA minor groove-binding non-intercalative topoisomerase I/IIα catalytic inhibitor, compound 9 synergistically promoted the anticancer efficacy of clinically applied topoisomerase I/IIα poisons both in vitro and in vivo, having the great advantage of alleviating poison-related toxicities.

Luminescent halogen clusters

Halogen···halogen (X···X) short contacts, especially halogen bonds (XBs), have been widely used in multifarious fields because of their bridging function among luminophores, as well as their well-known heavy atom effect. Little attention, however, has been paid to the luminescent ability of halogen clusters. It remains unknown whether they could be emissive. Herein, to our knowledge, we report the first examples of emissive halogen clusters with fluorescence-phosphorescence dual emission in an aggregated state and even under ambient conditions, which should be attributed to the extended delocalization through effective intra- and intermolecular X···X contacts. Additionally, multi-tunable luminescence in response to excitation wavelength, temperature, and compression is noticed. These results unveil the potential of halogen clusters as novel chromophores and may inspire further exploration of nonconventional luminophores involving halogen moieties. Pure, organic halogen clusters are found to be emissive Varieties of halogen-halogen short contacts promote through-space conjugation Multi-tunable emission relies on excitation wavelength, temperature, and compression Insights into emission mechanism of nonconventional luminophores are provided By forming multitudinous halogen-halogen short contacts, Zhao et al. demonstrate that halogen clusters can exhibit fluorescent-phosphorescence dual emission, which is multi-tunable in response to excitation wavelength, temperature, and compression. These results offer opportunities for halogen-involved luminophores and provide strong implications for the emission mechanism of nonconventional luminophores.

Orthogonal cross-coupling through intermolecular metathesis of unstrained C(aryl)-C(aryl) single bonds.

While metathesis reactions involving carbon-carbon double bonds, namely olefin metathesis, have been well established with broad utility in organic synthesis and materials science, direct metathesis of kinetically less accessible C-C single bonds is extremely rare. Here we report a ruthenium-catalysed reversible C-C single-bond metathesis reaction that allows redox- and pH-neutral biaryl synthesis. Assisted by directing groups, unstrained homo-biaryl compounds undergo aryl exchanges to generate cross-biaryl products, catalysed by a well-defined air-stable ruthenium(II) complex. Functional groups reactive under typical cross-coupling reactions, such as halogen, silyl and boronate moieties, are compatible under the metathesis conditions. Mechanistic studies disclose an intriguing 'olefin-metathesis-like' pathway that involves an unexpected heptacoordinated, 18-electron closed-shell intermediate. The distinct reaction mode discovered here is expected to inspire the development of more general C-C single-bond metathesis and orthogonal cross-coupling reactions.

Stepwise Nucleophilic Substitution to Access Saturated N-heterocyclic Carbene Haloboranes with Boron–Methyl Bonds

Compounds of boranes with N-heterocyclic carbenes are known, yet little attention has been paid to NHC compounds of boron bearing methyl and halogen moieties together. The reason can be attributed ...

Di-tert-butyl Peroxide (DTBP)-Mediated Oxysilylation of Unsaturated Carboxylic Acids for the Synthesis of Silyl Lactones.

Herein, we describe the first oxysilylation of unsaturated carboxylic acids mediated by di-tert-butyl peroxide (DTBP), which enables the rapid and efficient preparation of silyl lactone compounds. This process tolerates functional groups, such as methyl, methoxy, halogen (fluoride and chloride), and cyano moieties. Furthermore, the strategy allows the application of a wide range of primary, secondary, and tertiary hydrosilanes for functionalization.

Mechanism and dynamics of [formula omitted] + CCl4 halophilic reaction

In halophilic reactions, the nucleophile attacks the halogen moiety of the substrate instead of the carbon atom and displaces a carbanion as the leaving group. We report here a detailed ab initio and DFT study of the mechanism and dynamics of the reaction between CCl4 and CH2NO2− in the gas phase. The potential energy profiles for the reaction were mapped using DFT, MP2, and CCSD(T) methods considering the bimolecular halophilic (SN2X), SN2, and H/Cl exchange pathways. The SN2X pathway results in the products CCl3− + CH2ClNO2, while the H/Cl exchange pathway gives CHCl3 + CHClNO2−. The H/Cl exchange products were also possible by a sequential pathway that involved the SN2X reaction followed by a proton transfer from CH2ClNO2 to CCl3−. The SN2X and the sequential H/Cl exchange pathways were found to be barrierless and energetically feasible. The atomic-level mechanisms followed in the reaction was investigated by on-the-fly classical trajectory simulations at the B3LYP/6-311++G∗∗ level of theory. The trajectory simulations support the formation of both the halophilic and H/Cl exchange products. The halophilic reaction was found to largely follow non-IRC dynamical pathway that avoids the pre-transition state complex. In addition, the dynamics of the reaction was found to be nonstatistical with the trajectories showing recrossing behavior and nonexponential lifetimes for the post-transition state complex that leads to the halophilic products.

4-Halo-N-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)benzamide and Benzothioamide Derivatives: Synthesis and in vitro Anticancer Assessment

Cancer is a lethal disorder that has caused a serious threat to human health and nowadays there is a crucial need for the development of novel anticancer agents. A new series of 1,3,4-thiadiazole-based compounds were synthesized and evaluated for anti-cancer properties in vitro. The synthesis of 5-(Trifluoromethyl)-1,3,4-thiadiazol-2-amine (3) was carried out via solvent-free conditions and consequently, benzamide (4a-4f) and benzothioamide (5a-5f) derivatives bearing halogen moieties (Cl, F) were synthesized. MTT assay was applied for in vitro cytotoxicity assessment against three cancerous cell lines consist of PC3 (Prostate cancer), HT-29 (Colon cancer), and SKNMC (Neuroblastoma). All tested derivatives exhibited equal or more (IC50 = 3-7 µM) cytotoxic activity than doxorubicin (IC50 = 7 µM) as a reference drug against PC3 cell line. Chlorine containing benzamideas well as benzothioamide derivatives (IC50 = 14-36 µM) were also exerted a higher cytotoxic activity against SKNMC cell line compared to doxorubicin (IC50 = 40 µM).