Monomeric Complexes Research Articles

“ATAD3C regulates ATAD3A assembly and function in the mitochondrial membrane”

Mitochondrial ATAD3A is an ATPase Associated with diverse cellular Activities (AAA) domain containing enzyme, involved in the structural organization of the inner mitochondrial membrane and of increasing importance in childhood disease. In humans, two ATAD3A paralogs arose by gene duplication during evolution: ATAD3B and ATAD3C. Here we investigate the cellular activities of the ATAD3C paralog that has been considered a pseudogene. We detected unique ATAD3C peptides in HEK 293T cells, with expression similar to that in human tissues, and showed that it is an integral membrane protein that exposes its carboxy-terminus to the intermembrane space. Overexpression of ATAD3C, but not of ATAD3A, in fibroblasts caused a decrease in cell proliferation and oxygen consumption rate, and an increase of cellular ROS. This was due to the incorporation of ATAD3C monomers in ATAD3A complex in the mitochondrial membrane reducing its size. Consistent with a negative regulation of ATAD3A function in mitochondrial membrane organization, ATAD3C expression led to increased accumulation of respiratory chain dimeric CIII in the inner membrane, to the detriment to that assembled in respiratory supercomplexes. Our results demonstrate a negative dominant role of the ATAD3C paralog with implications for mitochondrial OXPHOS function and suggest that its expression regulates ATAD3A in the cell.

Electrocatalytic Water Oxidation by Mononuclear Copper Complexes of Bis-amide Ligands with N4 Donor: Experimental and Theoretical Investigation.

The present work describes electrocatalytic water oxidation of three monomeric copper complexes [CuII(L1)] (1), [CuII(L2)(H2O)] (2), and [CuII(L3)] (3) with bis-amide tetradentate ligands: L1 = N,N'-(1,2-phenylene)dipicolinamide, L2 = N,N'-(4,5-dimethyl-1,2-phenylene)bis(pyrazine-2-carboxamide), L3 = N,N'-(1,2-phenylene)bis(pyrazine-2-carboxamide), for the production of molecular oxygen by the oxidation of water at pH 13.0. Ligands and all complexes have been synthesized and characterized by single crystal XRD, analytical, and spectroscopic techniques. X-ray crystallographic data show that the ligand coordinates to copper in a dianionic fashion through deprotonation of two -NH protons. Cyclic voltammetry study shows a reversible copper-centered redox couple with one ligand-based oxidation event. The electrocatalytic water oxidation occurs at an onset potential of 1.16 (overpotential, η ≈ 697 mV), 1.2 (η ≈ 737 mV), and 1.23 V (η ≈ 767 mV) for 1, 2, and 3 respectively. A systematic variation of the ligand scaffold has been found to display a profound effect on the rate of electrocatalytic oxygen evolution. The results of the theoretical (density functional theory) studies show the stepwise ligand-centered oxidation process and the formation of the O-O bond during water oxidation passes through the water nucleophilic attack for all the copper complexes. At pH = 13, the turnover frequencies have been experimentally obtained as 88, 1462, and 10 s-1 (peak current measurements) for complexes 1, 2, and 3, respectively. Production of oxygen gas during controlled potential electrolysis was detected by gas chromatography.

Silyl‐Substituted ortho‐Terphenoxide Group 3–5 Complexes: Synthesis, Structure and Applications in Catalysis

AbstractThe complexation behavior of 3,3’‐silyl‐substituted ortho‐terphenoxide ligands o‐C6H4(C6H2‐2‐OH‐3‐SiR3‐5‐Me)2 (SiR3= SiPh3, SiMePh2, SiMe3, Sit‐BuMe2) with a range of yttrium, titanium, niobium and tantalum precursors was examined. The complexation of the ligands with [Y(N(SiHMe2)2)3(THF)2] yielded monomeric complexes, as confirmed by NMR spectroscopy and X‐ray crystallography for the methyldiphenylsilyl‐ and tert‐butyldimethylsilyl‐substituted complex. The triphenylsilyl‐substituted yttrium bis(dimethylsilyl)amido complex showed good activity in the intramolecular hydroamination reaction of aminoalkenes. Complexation with Ti(NMe2)4 yielded a mixture of products, depending on the silyl substituents and the solvent used for complexation. A mono‐ligated bimetallic titanium complex and a bisligated titanium complex were analyzed by X‐ray crystallography. Complexation with M(NMe2)5 (M=Nb, Ta) produced the corresponding monomeric ortho‐terphenoxide complexes as confirmed by NMR spectroscopy and X‐ray structure analysis of a niobium complex and 3 tantalum complexes.

Blood coagulation system in experimental acute lung injury and its treatment with dexamethasone

The effects of short- and long-term administrations of dexamethasone on survival, severity of pulmonary edema, and hemostasis on experimental lipopolysaccharide-induced acute lung injury in rats were analyzed. Acute lung injury in rats was modeled by the intratracheal injection of lipopolysaccharide from the Salmonella enterica cell wall. White male rats were randomly divided into nine groups: the intact group consisted of 10 animals; two control groups of 20 animals each, in which acute lung injury was simulated without further treatment and removed from the experiment on day 3 or 7; six comparison groups of 20 animals each, in which, 3 h after modeling of acute lung injury and then once a day for 3 days (short mode of administration) or 7 days (long mode of administration), dexamethasone solution was administered intraperitoneally in the following doses: 0. 52 (equivalent to 6 mg/day for humans), 1. 71 (20 mg/day for humans), and 8 mg/kg/day (94 mg/day, pulse therapy for humans). On days 3 and 7, the survival rate, coagulogram values (active partial thromboplastin time, prothrombin time, activity of antithrombin, and soluble fibrin monomer complexes), and low-frequency piezotromboelastography data were assessed in the surviving animals. The results revealed that dexamethasone reduces mortality in acute lung injury and has a dose-dependent effect on the hemostasis system: with an increase in the dose administered, blood clotting processes increase and fibrinolysis is inhibited. Low-frequency piezothromboelastography with a conventional coagulogram allows for a comprehensive assessment of the hemostasis system, identifying violations, and timely drug correction.

CO2 to Cyclic Carbonate: A Mechanistic Insight of a Benign Route Using Zinc(II) Salophen Complexes

AbstractZinc(II) Schiff base complexes with different substituents at 5, 5’ positions have been synthesized to study the effect of the electronic environment of the metal towards the cycloaddition reaction between CO2 and epoxide. The complexes have been characterized by FT‐IR, XPS, NMR, electronic spectroscopy, LC–MS, and TGA. We have used density functional theory to study the electronic structure of the Zn(II) complexes and modelled the electronic spectra and the mechanism of catalysis. Results obtained from DFT and LC–MS indicate the dimeric structures for all the complexes except ZnL4. The monomeric ZnL4 has the strongest electron withdrawing group, i. e., −NO2 at 5, 5’ positions along with two labile water molecules attached to the Zn center. The dimeric complexes exhibit good to moderate yield for cycloaddition reaction to styrene carbonate under solvent‐free conditions and a relatively low reaction temperature of 80 °C, with CO2 pressure of ~1 atm. The best yield has been achieved by ZnL4. Different rate‐determining steps are captured by the DFT studies for dimeric and monomeric complexes. Without taking any preventing measure of dimerization by attaching the bulky tBu groups, relatively lesser catalytic amounts of all the complexes have shown yields of cyclic carbonate between 53–74 %, depending on the nature of the substituent present.

Supramolecular assemblies of citalopram and escitalopram in β-cyclodextrin dimeric cavity: Crystallographic and theoretical insights

Cyclodextrin (CD) encapsulation improves physicochemical and pharmacological properties of selective serotonin reuptake inhibitors (SSRIs), which are efficacious in treating depression, a global mental health problem. Here, we scrutinize β-CD inclusion complexes with racemate citalopram (rac-CTP; 1) and escitalopram ((S)-CTP; 2) by combined single-crystal X-ray diffraction and DFT full-geometry optimization. X-ray analysis unveiled that the 2:2 inclusion complexes of 1 and 2 with similar inclusion modes and topologies are stabilized by various intermolecular interactions of host–guest CH···π, host–host OH···O H-bonds, and guest–guest F···F in the tail-to-tail dimeric asymmetric unit. In the crystals, these dimers are stacked on top of each other, yielding similar channel structures of distinct crystal symmetries, triclinic, P1 (1) and monoclinic, P21 (2), which are further maintained by guest–guest π···π and CN···π interactions. The thermodynamic stabilities evaluated by DFT calculation indicate the vital role of weak intermolecular interactions in the formation and stabilization of the β-CD monomeric and dimeric inclusion complexes. This study provides crystallographic and theoretical evidence for the improved stability and the masked bitterness of CTP through β-CD encapsulation as patented previously and suggests the pharmaceutical implications in the drug delivery and enantioseparation.

Metamagnetism and canted antiferromagnetic ordering in two monomeric CoII complexes with 1-(2-pyrimidyl)piperazine. Hirshfeld surface analysis and theoretical studies.

Here we present the magnetic properties of two cobalt complexes formulated as: [Co(SCN)2(L)2] (1) and (H2L)2[Co(SCN)4]·H2O (2) (L = 1-(2-pyrimidyl)piperazine). The two compounds contain isolated tetrahedral CoII complexes with important intermolecular interactions that lead to the presence of a canted antiferromagnetic order below 11.5 and 10.0 K, with coercive fields at 2 K of 38 and 68 mT, respectively. Theoretical calculations have been used to explain this behaviour. Hirshfeld surface analysis shows the presence of strong intermolecular interactions in both compounds. The crystal geometries were used for geometry optimization using the DFT method. From the topological properties, electrostatic potential maps and molecular orbital analysis, information about the noncovalent interaction and chemical reactivity was obtained.

CO reduction by calcium and ytterbium hydride complexes with a bulky monodentate carbazolyl ligand.

The bulky monodentate carbazolyl ligand 1,8-bis(3,5-ditertbutylphenyl)-3,6-ditertbutylcarbazole (dtbpCbz) was employed in the synthesis of monomeric heteroleptic amido carbazolyl complexes of Ca and Yb. For both central metal atoms, dimeric hydride complexes [(dtbpCbz)Ca(benzene)H]2, [(dtbpCbz)Ca(THF)H]2, [(dtbpCbz)Yb(benzene)H]2 and [(dtbpCbz)Yb(THF)H]2 were obtained, which show remarkably poor solubility in organic solvents. The characteristic hydride 1H NMR resonance of [(dtbpCbz)Ca(benzene)H]2 was observed at 2.07 ppm, and for the first time, characteristic vibrational modes of the Ca2H2 and Yb2H2 moiety are discussed. Despite their poor solubility, the hydride complexes could be reacted with CO to yield the corresponding ethenediolate complexes.

Temperature induced single-crystal to single-crystal transformation of uranium azide complexes.

The monomeric and dimeric uranium azide complexes {[(CH3)2NCH2CH2NPiPr2]2U(N3)2} (2) and {[(CH3)2NCH2CH2NPiPr2]2U(N3)2}2 (3) were synthesized by treating complex 1 with NaN3 at 60 and -20 °C, respectively. A temperature-induced single-crystal to single-crystal transformation of 3 to 2 was observed. The reduction of either 2 or 3 with KC8 yields a uranium nitride complex {[(CH3)2NCH2CH2NPiPr2]4U2(μ-N)2} (4).

Activation and functionalisation of carbon dioxide by bis-tris(pyrazolyl)borate-supported divalent samarium and trivalent lanthanide silylamide complexes.

Synthesis and reactivity with carbon dioxide (CO2) of divalent samarium in the bis-tris(pyrazolyl)borate ligand environment has been reported. In addition, CO2 activation and functionalisation by lanthanide silylamides in the bis-tris(pyrazolyl)borate ligand environment was demonstrated. Reduction of the Sm(III) precursor [Sm(Tp)2(OTf)] (Tp = hydrotris(1-pyrazolyl)borate; OTf = triflate) with KC8 yielded the insoluble Sm(II) multi-metallic coordination polymer [{Sm(Tp)2}n] 1-Sm. Addition of 1,2-dimethoxyethane (DME) to 1-Sm enabled isolation of the monomeric complex [Sm(Tp)2(DME)] 1-Sm(DME). Complex 1-Sm(DME) reduced CO2 to yield the oxalate-bridged dimeric Sm(III) complex [{Sm(Tp)2}2(μ-η2:η2-O2CCO2)] 2-Sm. The reactions of heteroleptic Ln(III) silylamide complexes [Ln(Tp)2(N'')] (Ln = Y, Sm; N'' = N(SiMe3)2) with CO2 yielded monomeric Ln(III) silyloxides [Ln(Tp)2(OSiMe3)] 3-Ln and trimethylsilyl isocyanate (OCNSiMe3). Complexes 3-Ln are the first crystallographically characterised examples of Ln(III)-OSiMe3 bonds accessed via CO2 activation and functionalisation. Full characterisation data are presented for all complexes, including solid-state molecular structure determination by single-crystal X-ray diffraction.

Photosystem I complexes form remarkably stable self-assembled tunneling junctions.

This paper describes large-area molecular tunneling junctions comprising self-assembled monolayers (SAMs) of light-harvesting protein complexes using eutectic Ga-In (EGaIn) as a top contact. The complexes, which are readily isolable in large quantities from spinach leaves, self-assemble on top of SAMs of [6,6]-phenyl-C61-butyric acid (PCBA) on gold (Au) supported by mica substrates (AuMica), which induces them to adopt a preferred orientation with respect to the electron transport chain that runs across the short axis of each complex, leading to temperature-independent rectification. We compared trimeric protein complexes isolated from thermophilic cyanobacteria to monomeric complexes extracted from spinach leaves by measuring charge-transport at variable temperatures and over the course of at least three months. Transport is independent of temperature in the range of 130 to 310 K for both protein complexes, affirming that the likely mechanism is non-resonant tunneling. The junctions rectified current and were stable for at least three months when stored at room temperature in ambient conditions, with the yield of working junctions falling from 100% to 97% over that time. These results demonstrate a straightforward strategy for forming remarkably robust molecular junctions, avoiding the fragility that is common in molecular electronics.

Volatile lanthanide complexes with fluorinated heptadentate ligands.

Understanding factors that influence the volatility of lanthanide complexes remains an important goal for applications such as gas-phase f-metal separations and the synthesis of lanthanide-containing thin films. Lanthanide complexes often exhibit volatility differences that depend on the ability of ligands to saturate the lanthanide coordination sphere and attenuate intermolecular bonding in the solid state. This can make it difficult to assess how electronic factors associated with differing ligand substituents influence volatility. Here we describe the synthesis, structures, and thermal properties of a series of volatile lanthanide complexes (Ln = Nd, Er, and Yb) containing N4O3 ligands decorated with different alkyl and fluoroalkyl substituents (CF3, CF2CF2CF3, Me, and tBu). These ligands completely enveloped the tested lanthanides to form monomeric complexes with 7-coordinate distorted capped octahedral coordination geometries, as determined using single-crystal X-ray diffraction. Thermogravimetric analysis and bulk sublimation studies show how metal encapsulation affords complexes with the same volatility regardless of metal size, even with lanthanide ions with significantly different radii such as Nd3+ and Yb3+. Most notably, the results show that increasing ligand fluorination, a strategy often used to increase the volatility of metal complexes, is not always beneficial and can significantly attenuate the volatility of lanthanide complexes depending on location with respect to other substituents in the ligand framework. A pair-wise model based on density functional theory shows that the net intermolecular interactions in the unit cell can still be stronger when fluorination is present. In other words, even if individual interactions between neighboring molecules are weaker, the total number of interactions in the solid arising from the nature of crystal packing is equally important to consider.

Association Between Coagulation Fibrinolysis Markers and Severity in Patients with COVID-19.

Thrombosis is a major complication of COVID-19. D-dimer (DD) is an important coagulation fibrinolysis marker in COVID-19 and has been extensively studied. However, very little is known about the role of other fibrinolysis markers, plasmin-plasmin inhibitor complex (PIC), and fibrin monomer complex (FMC) in COVID-19. This study investigated and compared the associations of DD, PIC, and FMC with COVID-19 severity. Archived plasma samples from patients with COVID-19 (n = 50) were assessed for DD, FMC, and PIC levels. We compared the levels between patients with mild (n = 36) and moderate (n = 14) COVID-19 and evaluated their correlation with other COVID-19 severity markers, including lactate dehydrogenase (LD), serum albumin (Alb), C-reactive protein (CRP), and neutrophil-lymphocyte ratio (NLR). Patients with moderate COVID-19 had significantly higher DD and PIC levels than those with mild disease, while FMC levels were comparable. DD and PIC levels significantly correlated with LD, Alb, and NLR. Additionally, PIC levels significantly correlated with CRP levels. However, FMC levels correlated only with Alb but not with LD, NLR, or CRP. COVID-19 severity was significantly associated with PIC and DD levels but not with FMC levels. PIC was the variable with the most clearly significant difference between patients with moderate disease and those with mild disease, highlighting its potential as an indicator of coagulation and fibrinolysis imbalance in patients with COVID-19. Further studies with larger sample sizes and more diverse severity groups are required to confirm these findings.

Benzene-fused porphyrin(2.1.2.1) array: synthesis, structure, and electrocatalytic hydrogen evolution.

The development of efficient molecular catalysts for the electrocatalytic hydrogen evolution reaction (HER) is very necessary and important for fuel cells. In this work, we report a new benzene-fused porphyrin(2.1.2.1) array, BPD, with a unique S-shaped molecular conformation. The electrochemistry of BPD displays multielectron donating and accepting properties owing to the two porphyrin(2.1.2.1) blocks and degenerate molecular orbitals. The electrocatalytic HER activity of BPD is remarkably higher-that is, BPD exhibited lower overpotential, faster HER kinetics, faster charge transfer kinetics, and extended catalytic stability-than that of the porphyrin(2.1.2.1) copper complex monomer.

Repeat Structure in Salmonella genomes

Salmonella is a genus of gram-negative, facultative and non-spore-forming anaerobic bacteria. The genus includes two species: S. bongori and S. enterica. All Salmonella, which are pathogenic to humans and animals, belong to the species S. enterica. It includes seven subspecies, which includes more than 2500 serotypes. According to global statistics, they cause about 2.8 billion cases of diarrheal diseases annually, and the mortality rate reaches more than 300000 cases. S. enterica spp strains that have acquired multidrug resistance to antibiotics have become especially dangerous. Against the backdrop of this global problem, a detailed study of the complete genomes of various representatives of the genus Salmonella becomes relevant. Repeats play an important role in the regulation of basic genetic processes during the life cycle and evolution. The work examines various manifestations of repetition in the genomes of S. enterica. Taking into account common fragments of different genomes serves as the basis for the formation of a matrix of pairwise relative complexity, which is used in constructing a phylogenetic tree. Long repeats within individual genomes typically correspond to large individual duplications. The main attention is paid to local structural regularities, most of which are represented by tandem repeats. Of significant interest are multivalued repeats, such as tandem repeats forming a palindrome, repeats with regular substitutions or complex monomer structure.

Synthesis, structures and optical properties of mononuclear La, Eu and Tb complexes supported by calix[4]arene ligands bearing three pendant salicylaldiminato arms

AbstractThe synthesis and complexation behaviour of a new calix[4]arene ligand H4L3 bearing three pendant salicylaldimine arms towards selected lanthanide ions has been investigated. Reaction of H4L3 with Ln(NO3)3⋅6H2O in MeOH in the presence of NEt3 provides monomeric complexes of composition [Ln(HL3)] (Ln=La3+ (4), Eu3+ (5), Tb3+ (6)). An X‐ray crystallographic analysis for 4 reveals that only two of the three ligand arms are involved in the coordination of the lanthanide ions, to give eight‐coordinated Ln3+ ions in a distorted square‐antiprismatic N2O6 environment. UV‐vis spectrophotometric titrations show that such monomeric species prevail in CH2Cl2/MeOH (1/1 v/v) solution. The apparent stability constants determined by UV‐vis spectrophotometric titration are log K=6.8(2) for 5 and log K=5.8(1) for 6. The Eu and Tb complexes luminesce only weakly at 77 K with luminescence lifetimes of 0.469 and 0.306 s.

Aluminum and titanium complexes bearing 2,6-Bis(2-hydroxyphenyl)pyridines for ring-opening polymerization of lactide, ε-caprolactone and their copolymerization: Effect of a ligand on coordination chemistry and reactivity

In ring-opening polymerization (ROP) of cyclic esters, the rational design of the catalyst is generally applied to solve the task of providing polyester biocompatibility (non-toxicity) and the problem of copolymer homogeneity when using comonomers of different nature (e. g. lactones and lactides). In the present work, we report the synthesis of aluminum and titanium complexes, based on substituted 2,6-bis(2-hydroxyphenyl)pyridine pro-ligands 1 and 2. It was found that the structure of the pro-ligand drastically affect the structure of the reaction product. Pro-ligand 2 with a bulky tert‑butyl group leads to the monomeric complexes 6 (LAlMe) and 7 (LTi(OiPr)2), while the ligands with less bulky groups lead to the oligomeric Al-containing compounds 3 and 4, and in the case of Ti bis-ligand complex 5 is formed. Complexes 6 (in presence of BnOH) and 7 turned out to be active in the ROP of ε-caprolactone and l-lactide and gave PCL and PLA with high molecular masses. Compound 6 was an effective initiator of copolymerization of ε-caprolactone and l-lactide which led to statistical copolymer poly(LA-stat-CL) with comonomer subunits ratio of 1:1.

Exploring a Mitochondria Targeting, Dinuclear Cyclometalated Iridium (III) Complex for Image-Guided Photodynamic Therapy in Triple-Negative Breast Cancer Cells.

Photodynamic therapy (PDT) has emerged as an efficient and noninvasive treatment approach utilizing laser-triggered photosensitizers for combating cancer. Within this rapidly advancing field, iridium-based photosensitizers with their dual functionality as both imaging probes and PDT agents exhibit a potential for precise and targeted therapeutic interventions. However, most reported classes of Ir(III)-based photosensitizers comprise mononuclear iridium(III), with very few examples of dinuclear systems. Exploring the full potential of iridium-based dinuclear systems for PDT applications remains a challenge. Herein, we report a dinuclear Ir(III) complex (IRDI) along with a structurally similar monomer complex (IRMO) having 2-(2,4-difluorophenyl)pyridine and 4'-methyl-2,2'-bipyridine ligands. The comparative investigation of the mononuclear and dinuclear Ir(III) complexes showed similar absorption profiles, but the dinuclear derivative IRDI exhibited a higher photoluminescence quantum yield (Φp) of 0.70 compared to that of IRMO (Φp = 0.47). Further, IRDI showed a higher singlet oxygen generation quantum yield (Φs) of 0.49 compared to IRMO (Φs = 0.28), signifying the enhanced potential of the dinuclear derivative for image-guided photodynamic therapy. In vitro assessments indicate that IRDI shows efficient cellular uptake and significant photocytotoxicity in the triple-negative breast cancer cell line MDA-MB-231. In addition, the presence of a dual positive charge on the dinuclear system facilitates the inherent mitochondria-targeting ability without the need for a specific targeting group. Subcellular singlet oxygen generation by IRDI was confirmed using Si-DMA, and light-activated cellular apoptosis via ROS-mediated PDT was verified through various live-dead assays performed in the presence and absence of the singlet oxygen scavenger NaN3. Further, the mechanism of cell death was elucidated by an annexin V-FITC/PI flow cytometric assay and by investigating the cytochrome c release from mitochondria using Western blot analysis. Thus, the dinuclear complex designed to enhance spin-orbit coupling with minimal excitonic coupling represents a promising strategy for efficient image-guided PDT using iridium complexes.

Abstract A086: NST-628 is a novel molecular glue that inhibits signaling and pathway reactivation in oncogenic RAS-MAPK cancers

Abstract Alterations in the RAS-MAPK pathway are identified in nearly 30% of cancers and are associated with poor patient prognosis. Although available therapies target various nodes of the RAS-MAPK pathway, clinical anti-tumor activity is limited by paradoxical bypass mechanisms, feedback signaling and pathway reactivation, and genetic resistance mechanisms. NST-628 aims to overcome the limitations of traditional RAS-MAPK pathway inhibitors by stabilizing all RAF-MEK complexes in a conformation that blocks MEK phosphorylation, to sequester these nodes from dynamic signaling processes that promote RAF-mediated bypass signaling. In comparison with clinically approved RAS-MAPK pathway inhibitors, only NST-628 robustly and durably decreases pathway reactivation, as measured by MEK phosphorylation, in KRAS-G13D tumor models in vitro and in vivo. Immunoprecipitation of endogenous ternary complexes demonstrates that NST-628 promotes potent stabilization of CRAF-MEK, BRAF-MEK, and ARAF-MEK complexes with complete shutdown of MEK, ERK, and RSK phosphorylation. Moreover, NST-628 treatment completely prevents RAF paralog heterodimerization in RAS-driven cells. Dose-dependent panRAF-MEK complex stabilization was confirmed using recombinant pre-formed CRAF-MEK, BRAF-MEK, and ARAF-MEK complexes, and MEK and RAF paralog affinity increases in the presence of NST-628 were quantified via surface plasmon resonance (SPR). In this assay, NST-628 significantly increased the affinity of MEK with both inactive monomeric and active dimeric RAF complexes. In parallel, we structurally characterized NST-628 bound to CRAF-MEK, BRAF-MEK, ARAF-MEK complexes using x-ray crystallography and cryogenic electron microscopy (cryo-EM). NST-628 binds the interfacial allosteric pocket along the MEK activation loop, thereby preventing RAF-mediated activation of MEK. We also demonstrate RAF paralog-specific pocket features that NST-628 can engage, helping us rationalize the large increase in affinity observed for MEK and CRAF in the presence of NST-628. The increased stabilization of CRAF-MEK complex by NST-628 may contribute to the decreased pathway reactivation in specific biomarker-driven tumors. Through our robust biophysical and cellular characterization coupled with novel structural insights, we have defined the unique mechanism of action for NST-628 and provide insight into its best-in-class potential in RAS-MAPK activated cancers. Citation Format: Bradley Quade, Meagan Ryan, Brooke Swalm, Steven Cohen, Zhong Fang, Aysegul Ozen, Xin Huang, Arvin C Dar, Yongxin Han, Klaus P Hoeflich, Margit Hagel, Michael Hale. NST-628 is a novel molecular glue that inhibits signaling and pathway reactivation in oncogenic RAS-MAPK cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A086.

An efficient one-pot synthesis of pyrazole complexes formed in situ: synthesis, crystal structure, Hirshfeld surface analysis and in vitro biological properties.

The molecular crystals of monomeric and dimeric pyrazole complexes were prepared via one-pot syntheses. These are dichloridobis(3,5-dimethyl-1H-pyrazole-κN1)cobalt/zinc(0.2/0.8), [Co0.20Zn0.80Cl2(C5H8N2)2] or [Co0.2Zn0.8Cl2(3,5-dmp)2] (1), and bis(μ-3,5-dimethyl-1H-pyrazole)-κ2N1:N2;κ2N2:N1-bis[bromido/chlorido(0.7/0.3)bis(3,5-dimethyl-1H-pyrazole-κN1)cobalt/zinc(0.1/0.9)], [Co0.20Zn1.80Br1.40Cl0.60(C5H7N2)2(C5H8N2)2] or [Co0.1Zn0.9Br0.7Cl0.3(μ-3,5-dmp)(3,5-dmp)]2 (2). The isolated complexes contain 3,5-dimethylpyrazole (3,5-dmp) ligands formed in situ from the decomposition of 1-hydroxymethyl-3,5-dimethylpyrazole. In both isolated complexes, some positional disorder is observed at the metal ions and halogen ligands. The molecular crystals of 1 and 2 are centrosymmetric, with the space groups C2/c and P-1, respectively. Additionally, in the dinuclear complex, the pyrazole ring has a bridging coordination function with respect to the metal ions. Both complexes have good biological activities against cancer cells. The results of an in vitro cytotoxicity study indicated that compounds 1 and 2 showed significant cytotoxicity for cancer cell lines, including hepatic (HepG2 cells), lung (A549 cells) and colon cancer cells (SW 480 and SW 620). Based on the calculated IC50 values against human cancer cell lines, it was found that both complexes demonstrated potent antiproliferative activity combined with great selectivity towards cancer cells. Complex 2 was a more effective cytotoxic agent which, at the same time, exhibited high cytocompatibility. The obtained data are very encouraging and could be useful for anticancer drug discovery.