ABSTRACT The first Pt II ···Au III metallophilic interaction is reported in K 4 [Pt(CN) 4 ][Au(CN) 4 ]Cl·6H 2 O, which consists of a 1D chain of stacking [Pt(CN) 4 ] 2− and [Au(CN) 4 ] − units bridged by potassium cations, with extremely short Pt II ···Au III distances of 3.0024(4) and 3.0057(4) Å at 80 K. The chloride ions and water molecules are bound to the potassium cation. Addition of KCl to the reaction mixture is necessary for the metallophilic Pt II ···Au III chain to assemble. The isostructural [Pd(CN) 4 ] 2− and [Ni(CN) 4 ] 2− analogs can be rationally synthesized in a similar manner, which feature the first Pd II ···Au III and Ni II ···Au III interactions, with the Ni II analog having the shortest metal‐metal distances of 2.968(3) and 2.978(3) Å. The bromide versions of all compounds were also synthesized by substituting KBr for KCl in the reaction mixture. 195 Pt solid‐state NMR of the title compound revealed highly anisotropic, axially symmetric magnetic shielding which resembles that found in systems with Pt II ···Pt II interactions, such as K 2 [Pt(CN) 4 ]·H 2 O. The Pd II and Pt II analogs are emissive, with λ max of 555 and 570 nm. Theoretical calculations indicate that the positive charge of the K + ions effectively neutralizes the electrostatic repulsion between the cyanometallates, resulting in significant metal‐based donor‐acceptor interactions. These novel d 8 ··· d 8 interactions provide a conceptual framework for the rational design of future metallophilic compounds.

Substitution of perfluoropyridine (PFP) in the 4-position through an SNAr reaction is facile through mechanochemical methods, with yields in excess of 99% and short reaction times on a multigram scale. Glycol materials can be end-capped with PFP to create bis-PFP ethers, which are capable of further activation in the 2- and 6-positions by sonochemical means. A bis-PFP ether was substituted sonochemically with eugenol in the 2- and 6-positions to produce a prepolymer utilizing a bio-based feedstock as a polymerizable motif; however, it was ultimately found to perform identically to a traditional thermal reaction. The resulting material was polymerized with a commercially available dithiol to yield crosslinked, insoluble, sponge-like elastomers. The sponges display similar thermal stability (T onset = 311 degrees C-355 degrees C), but highly variant glass transition temperatures (T g = -35 degrees C to 8 degrees C), indicating that this is a viable methodology to create elastomers with tunable T g's dependent on the nature of the central linker in the 4-position.

High-valent transition-metal nitrides have recently emerged as versatile platforms for N-atom transfer, and their reactivity remains sensitive to subtle electronic perturbations. Cr salen (where "salen" represents N2O2 bis-phenolate bis-Schiff-base ligands) nitrides offer a rare platform in which both the metal center and the redox-active salen ligand are both susceptible to one-electron oxidation, enabling systematic evaluation of how salen ligand substituent effects can change the electronic structure, and ultimately nitride reactivity. Herein, we evaluate a series of CrNSalR complexes to better understand how changing the ancillary ligand donating ability via the para-phenolate substituent (R = NO2, CF3, H, tBu, OMe, OiPr, NMe2) dictates overall electronic structure. For electron-donating R = OMe and R = OiPr, designed to probe the threshold for switching the oxidation locus from metal to ligand, one-electron oxidation results in a metal-centered Cr(VI) nitride, extending the window for metal-based oxidation beyond the previously established R = tBu derivative. In contrast, the R = NO2-substituted analogue, while not promoting bimolecular nitride coupling as observed in Mn congeners, nonetheless renders the CrN unit more electrophilic than previously reported R = CF3-substituted systems. Together, these results expand the electronic landscape of Cr-salen-nitrides and demonstrate how fine-tuning the donating ability of the ancillary salen ligand can be used to systematically manipulate the electronic structure at the nitride.

This work presents a novel, promising, and efficient strategy to develop potential Pt(IV) prodrugs for cancer chemotherapy while to simultaneously overcome the ″undruggability″ of CDC25A. New series of Pt(IV) complexes (Pt5-Pt13) bearing 1,4-naphthoquinone (NQ, a natural active skeleton) derivatives (c1-c3) as potential dual CDC25A/NF-κB inhibitory ligands were synthesized and characterized. Their in vitro and in vivo anticancer activities were subsequently evaluated. Mechanistic investigations revealed that Pt6, the most potent candidate with ligand c2, effectively depleted CDC25A levels in A2780 cancer cells through a synergistic effect mediated by DNA damage. Thus, Pt6 triggered multimodal anticancer mechanisms, which included reactive oxygen species/endoplasmic reticulum stress-mediated mitochondrial apoptotic pathway, DNA damage coupled with S-phase cell cycle arrest, and autophagy-dependent ferroptosis. In A2780 xenograft models, Pt6 administrated with a dosage of 8 mg/kg manifested superior tumor growth inhibition than both cisplatin and "cisplatin + c2" combination, along with satisfying low toxicity.

A new nonsymmetric anthrahydrazone ligand (AAIH) was designed and synthesized, affording novel manganese(II) and cobalt(II) complexes, AAIH-Mn and AAIH-Co. Both complexes crystallized in the same centrosymmetric dinuclear coordination mode, however, AAIH-Mn exhibited much higher in vitro cytotoxicity (IC50 = 1.64 μM against MGC-803 cells) than AAIH-Co (IC50 = 10.05 μM) and AAIH (IC50 = 18.82 μM), signifying the importance of the Mn(II) center. Furthermore, AAIH-Mn exerted anticancer activity via multiple pathways: S-phase cell cycle arrest, cell apoptosis, autophagy and notably, the emerging process of ferroptosis. AAIH-Mn also effectively inhibited 56% of tumor growth in vivo on MGC-803 xenografts at 16 mg/kg, without causing obvious toxicity. Low toxicity was further supported by zebrafish models, along with its anti-inflammatory activity and low cardiotoxicity. As the first Mn(II) complex inducing ferroptosis, AAIH-Mn provides a valuable example of a low-toxicity metal center to generate highly cytotoxic nonplatinum anticancer complex.

Perfluoropyridine (PFP) is a fluorinated small molecule heterocycle which can undergo a variety of substitutions in the 2-, 4-, and 6-position to afford rationally designed prepolymers. PFP is known to undergo mechanochemical substitutions, however ball mills have a large start-up cost and are bulky, creating a barrier of entry for researchers. We sought to provide a low tech, affordable, reproducible, and space-saving methodology towards general mechanochemistry while retaining the ability to work on gram scale. Herein we report the successful application of tin can milling (TCM) towards the gram scale synthesis of 4-tetrafluoropyridines (24 examples, up to ≥99% conversion) using a tomato paste can, aluminum beads, a rubber stopper, and agitation with a Burrell Wrist Action™ shaker unit. This approach eliminates problems of scalability with a mortar and pestle and provides a clean method to do benchtop-scale mechanochemistry without additional equipment. We further apply this technique towards making natural product-based prepolymers for polymerization by inverse vulcanization as a proof-of-concept for the use of TCM in monomer synthesis.

Perfluoropyridine (PFP) is a heavily fluorinated heterocycle which readily undergoes nucleophilic aromatic substitution (SNAr) reactions at low temperatures. Herein, we report a facile synthesis of 2-hydroxyethyl methacrylate derivatives of PFP through solvothermal and mechanochemical means. The resulting monomers were polymerized to form hard, insoluble materials which offer an improvement in thermal stability compared to the starting alcohol. Most unusually the 4-substituted PFP-methacrylate derivative displays superior thermal properties in air compared to nitrogen and generally superior thermal properties compared to the starting alcohol. Additionally, di-substitution of the PFP to form the di-methacrylate appears to initiate decomposition of the monomer into ethylene glycol dimethacrylate through an acyl fluoride-mediated transesterification.

Six sets of tetracyanoaurate(III) salts were synthesized and structurally characterized using the metal‐ligand complex cations [RE(bipyO 2 ) 4 ] 3+ (RE = Sc, Y, La; bipyO 2 = 2,2′‐bipyridine‐ N , N ’‐dioxide), [Fe(bipyO 2 ) 3 ] 3+ , [Ln(dmbipyO 2 ) 4 ] 3+ (Ln = Ce, Eu, Yb; dmbipyO 2 = 4,4′‐dimethyl‐2,2′‐bipyridine‐ N , N ’‐dioxide), [Ca(tcmc)] 2+ (tcmc = 1,4,7,10‐tetrakis‐(carbamoylmethyl)‐1,4,7,10‐tetraazacyclododecane), and [Ca(12‐crown‐4) 2 ] 2+ . Noncovalent assembly of the [Au(CN) 4 ] − anions tended to occur via Au···N cyano interactions; however, rare Au(III)···Au(III) contacts between the [Au(CN) 4 ] − groups — suggesting aurophilicity — could be induced when certain cation shape requirements were met. Specifically, cations with shape, size, and symmetry that allowed for packing in a complementary fashion with Au(III)···Au(III) aligned [Au(CN) 4 ] − dimers or trimers — providing efficiently close‐packed layers — were found to be sufficient for manifesting Au(III)···Au(III) contacts. Modifying the [RE(bipyO 2 ) 4 ] 3+ cation with peripheral methyl groups (the [Ln(dmbipyO 2 ) 4 ] 3+ cation) caused isoreticular replacement of a {[Au(CN) 4 ] 3 } 3− trimer with a dumbbell‐shaped {[Au(CN) 4 ] 2 Cl} 3− tri‐anion featuring an unusual Au···Cl···Au bridge — illustrating that the assembly of the anionic groups will adapt to conserve the same close packing. Au(III) aurophilicity between the [Au(CN) 4 ] − groups was studied using computational methods, crystal packing of the structures was probed using Hirshfeld surface analysis, and the emission properties of compounds containing the [Eu(dmbipyO 2 ) 4 ] 3+ luminophore were investigated, showing high quantum yields of ca . 50%.

We report the thermal and photoactivation of a solution-stable Mn nitride ligand radical complex [MnV(SalNMe2•)N]+, which facilitates N-N bond homocoupling to generate N2, a reaction commonly observed in MnVI nitrides. Theoretical calculations suggest that the nitride is ambiphilic, facilitating the N-N bond formation. Notably, photoactivation of the MnV ligand radical at room temperature enables rapid C-H bond activation, leading to the formation of C-N insertion products, excluding dihydroanthracene where a desaturation product is observed. This study presents a rare example of photochemically driven intermolecular N atom transfer to a C-H bond mediated by a first-row Mn terminal nitride complex, made possible by the unique stability and turn-on reactivity of the oxidized ligand radical electronic structure.

Controlling the aggregation of amyloid-β (Aβ) peptides offers a promising strategy to mitigate Alzheimer's disease (AD). Herein, we introduce a series of photoactivatable Ru(II) complexes (Ru1-8) designed to efficiently generate singlet oxygen (1O2) and subsequently oxidatively modify the Aβ peptide. Upon light activation, these complexes rapidly direct Aβ1-42 aggregation toward high molecular weight amorphous species, with Ru1 demonstrating the most pronounced effect. Transmission electron microscopy (TEM) revealed that the amorphous aggregates formed immediately and persist over time. Complementary assays, including bicinchoninic acid (BCA) quantification and Western blotting, demonstrated rapid photoinduced aggregation and a decrease of soluble peptide upon photoactivation, while proteinase-K digestion showed that the resulting amorphous species are more susceptible to proteolysis in comparison to canonical fibrils. Control experiments under anaerobic conditions and in the presence of an 1O2 scavenger suggest that these effects are oxygen-dependent. Notably, photoactivation of Ru1 in the presence of preformed fibrils results in a morphology change to degradable amorphous aggregates, providing both preventive and disruptive activity. Together, these findings establish photoactivatable Ru1 as a light-controlled chemical tool capable of redirecting Aβ aggregation, enhancing aggregate protease degradation, and offering a versatile platform for therapeutic exploration.

The synthesis of MnV and CrV nitride complexes of a pro-radical tetradentate bis-phenol bis-N-heterocyclic carbene ligand H2LC2O2 was investigated. Employing either azide photolysis of the MnIII precursor complex MnLC2O2(N3) or a nitride exchange reaction between MnLC2O2(Br) and the nitride exchange reagent Mnsalen(N) failed to provide a useful route to the target nitride MnLC2O2(N). Experimental results support initial formation of the target nitride MnLC2O2(N), however, the nitride rapidly inserts into a Mn-CNHC bond. A second insertion reaction results in the isolation of the doubly inserted ligand product [H2LC2O2(N)]+ in good yield. In contrast, the Cr analogue CrLC2O2(N) was readily prepared and characterized by a number of experimental methods, including X-ray crystallography. Theoretical calculations predict a lower transition state energy for nitride insertion into the M-CNHC bond for Mn in comparison to Cr, and in addition the N-inserted product is stabilized for Mn while destabilized for Cr. Natural bond order (NBO) analysis predicts that the major bonding interaction (π MN → σ* M-CNHC) promotes nucleophilic attack of the nitride on the carbene as the major reaction pathway. Finally, one-electron oxidation of CrLC2O2(N) affords a relatively stable cation that is characterized by experimental and theoretical analysis to be a metal-oxidized d0 CrVI species.

The p53 protein plays an important role in preventing cancer and is critical in inducing an antiproliferative response. Unfortunately, the p53 pathway is compromised in almost all cancers, and mutations to p53 lead to loss of function due to protein unfolding, compromised Zn2+ binding, aggregation and amyloid formation. Herein, two new multidentate N,O donor ligands LI-A and LH-A were tested to potentially restore Zn2+ binding to mutant p53, while also inhibiting protein aggregation. The design of these ligands centered on combining an iminodiacetate (IDA) metal binding moiety which was previously determined to exhibit favourable Zn2+ binding affinity and Cu2+/Zn2+ selectivity ratio, with a benzothiazole unit that has been demonstrated to limit mutant p53 protein aggregation. The new ligands were shown to exhibit Zn2+ Kd values in the low nM range based on a fluorophore competition assay, while also inhibiting mutant p53 aggregation via a Thioflavin-T (ThT) assay. In cell-based assays and NCI-60 screening, neither of the new ligands displayed significant cytotoxicity. A reactive oxygen species (ROS) assay showed that neither of the new ligands increased intracellular ROS, however, the previously studied LI compound did show an increase in ROS, providing further information on the mechanism of action of this class of compounds. The current results highlight that the dipicolylamine (DPA) unit is important for anticancer activity, and that phenolate substitution has an important role in dictating the mechanism of cytotoxicity.

Alternative energy sources have become critical to address climate change and global warming. Ammonia activation has been proposed as a solution to reduce CO 2 emissions, given ammonia's high hydrogen content and energy density, using transition metal electrocatalysis to oxidize ammonia as a hydrogen carrier, forming dinitrogen. Accordingly, a series of transition metal phthalocyanine complexes were selected as potential electrocatalysts for ammonia activation due to their wide range of metal (and ligand) oxidation states, rendering them excellent redox-active catalysts. Despite the inherent insolubility of phthalocyanine complexes, the addition of peripheral substituents can enhance their solubility, transforming them into effective homogeneous catalysts. In this research, we are investigating a series of octa-butoxy transition metal phthalocyanine complexes as electrocatalysts for ammonia activation. Initial studies have focused on interaction with NH 3 via UV-Vis spectroscopy and Electron Spray Ionisation-Mass Spectrometry, and electrochemically using cyclic voltammetry and differential pulse voltammetry. We will detail our results and research plans in this presentation.

The misfolding and aggregation of the amyloid-β (Aβ) peptide is a major hallmark of Alzheimer's disease (AD), yet therapeutic strategies targeting this process have faced long-standing challenges related to efficacy and specificity. Here, we investigate two photoactivatable Ru(ii) polypyridyl complexes (RuP) that operate as dual-action modulators of AD pathology by addressing both Aβ aggregation and Cu-Aβ associated ROS generation. The RuP contain an extended planar imidazo[4,5-f] [1,10]phenanthroline ligand, which is important for pre-association with the Aβ peptide via hydrophobic and π-π interactions, as well as sterically hindered ligands 6,6'-dimethyl-2,2'-bipyridyl (6,6'-dmb) for RuP1 and 2,9-dimethyl-1,10-phenanthroline (2,9-dmp) for RuP2, which cause steric strain at the metal center. Photoactivation of the RuP results in loss of either a 6,6'-dmb or 2,9-dmp ligand exposing cis-exchangeable coordination sites for binding to the Aβ peptide, which immediately redirects the Aβ peptide away from its β-sheet-rich fibrillization pathway, promoting the formation of amorphous, off-pathway aggregates that exhibit increased sensitivity to proteolytic degradation. We find that the photoactivated RuP are closely associated with the amorphous aggregates, and that this is a common endpoint regardless of Aβ peptide aggregation state (monomer, oligomer, or fibril). Importantly, we show that the ejected ligands also inhibit the redox cycling and ROS generation of Cu-Aβ species. Together, these results highlight the potential of photoactivatable RuP as multifunctional therapeutic candidates, offering a rational approach to intercepting Aβ aggregation and Cu-mediated oxidative stress, and advancing the design of light-responsive treatments for neurodegenerative diseases.

A series of [Au(CN)4]− salts with lanthanide 2,2′-bipyridine dioxide cations feature Au(iii) aurophilicity between [Au(CN)4]− groups; the 3.3603(4) Å distance represents the shortest unsupported Au(iii)–Au(iii) interaction reported to date.

N-Monosubstituted ethylenediamine derivatives with three methylene-tethered aromatic groups ((ArCH2)(2)NCH2CH2N(R)CH2Ar (R-ArArAr), where Ar = 2-pyridyl, 2-quinolyl, 1- and 3-isoquinolyl and 2-quinoxalyl; R = methyl, benzyl and phenyl) were utilized as pentadentate ligands for copper(II) complexation. Fifteen mononuclear copper(II) complexes were synthesized and exhibit differences in cyclic voltammetry, absorption spectroscopy and solid state geometries, depending on the aromatic group (Ar) and the substituent on the aliphatic nitrogen atom (R) of the ligand. Compared with the pyridine and isoquinoline complexes, the quinoline and quinoxaline derivatives exhibit distinct Cu(II)/Cu(I) redox potentials and d-d transition absorption wavelengths. Similarly, the phenyl derivatives are different from their methyl and benzyl counterparts. These characteristic trends are discussed in relation to the square-pyramidal/trigonal-bipyramidal structure of the complexes which is perturbed by the location of quinoline moieties in the penta- or hexacoordinate complexes with Jahn-Teller distortion. In addition, the results are compared to the copper(II) complexes with pyridine/quinoline mixed ligands, Ph-(ArArAr3)-Ar-1-Ar-2 (((ArCH2)-C-1)((ArCH2)-C-2)NCH2CH2N(Ph)CH2Ar3).

We detail the relative role of ancillary ligand electron-donating ability in comparison to the locus of oxidation (either metal or ligand) on the electrophilic reactivity of a series of oxidized Mn salen nitride complexes.

We highlight recent advances in the development of multifunctional molecules designed to limit misfolding and aggregation of intrinsically disordered biomolecules, with a focus on the amyloid-beta peptide in AD and the mutant p53 protein in cancer.