Destabilizing Effect of Organo Ru(II) Salts on the Intermolecular Parallel CGG Repeat DNA Quadruplex Associated with Neurodegenerative/Neuromuscular Diseases.

The cationic organo ruthenium(II) salts ([Ru(p-cymene)(ipit)(Cl)](Cl) (RuS), 1-isopropyl-3-(pyridin-2-yl)-imidazol-2-thione (ipit) and [Ru(p-cymene)(ipis)(Cl)](Cl) (RuSe), 1-isopropyl-3-(pyridin-2-yl)-imidazol-2-selenone (ipis)) are isolated, and their binding efficacy with d(CGG)15 quadruplex is investigated. Circular dichroism (CD) wavelength scan titration experiments of RuS and RuSe compounds with the intermolecular parallel quadruplex formed by d(CGG)15 (associated with neurodegenerative/neuromuscular/neuronal intranuclear inclusion disorders like FXTAS, OPMD, OPDM types 1-4, and OPML as well as FXPOI) and with the control d(CGG)15·d(CCG)15 duplex indicate their specificity toward the former. Electrophoretic mobility shift titration experiments also confirm the binding of the ligands with d(CGG)15. CD thermal denaturation experiments indicate that both RuS and RuSe destabilize the quadruplex, specifically at 10 mM concentration of the ligands. This is further confirmed by 1D 1H NMR experiments. Such a destabilizing effect of these ligands on the d(CGG)15 quadruplex indicates that RuS and RuSe chalcogen complexes can act as a template for the design of novel molecules for the diagnostics and/or therapeutics of CGG repeat expansion-associated diseases.

Introducing an orthogonally polarized electron-rich alkene: synthesis of a zwitterionic boron-containing π-conjugated system.

The synthesis of an alkene is reported which is concurrently twisted (twist angle = 86.6(8)°), push-pull (dipole moment = 7.48 D), and electron-rich (E1/2 = -1.45 V and -0.52 V vs. Fc/Fc+) in nature, comprising a unique trinity combination for the alkene class of compounds. Subsequently, this newly synthesized alkene-motif was used as a donor for the synthesis of a zwitterionic boron-containing π-conjugated compound (dipole moment = 12.17 D) through an intramolecular charge transfer process exploiting the π-conjugated donor-acceptor system.

Bis-Olefin Based Crystalline Schlenk Hydrocarbon Diradicals with a Triplet Ground State.

A modular approach for the synthesis of isolable crystalline Schlenk hydrocarbon diradicals from m-phenylene bridged electron-rich bis-triazaalkenes as synthons is reported. EPR spectroscopy confirms their diradical nature and triplet electronic structure by revealing a half-field signal. A computational analysis confirms the triplet state to be the ground state. As a proof-of-principle for the modular methodology, the 4,6-dimethyl-m-phenylene was further utilized as a coupling unit between two alkene motifs. The steric conjunction of the 4,6-dimethyl groups substantially twists the substituents at the nonbonding electron bearing centers relative to the central coupling m-phenylene motif. As a result, the spin delocalization is decreased and the exchange coupling between the two unpaired spins, hence, significantly reduced. Notably, 108 years after Schlenk's m-phenylene-bis(diphenylmethyl) synthesis as a diradical, for the first time we were able to isolate its derivative with the same spacer, i.e. m-phenylene, between two radical centers in a crystalline form.

A Simple and Fast Access to Phosphine-Substituted Copper(I)-Carbene Complexes via C=Se Bond Cleavage Reaction.

Phosphine coordinated copper(I)-N-heterocyclic carbene complexes have emerged as an efficient material in catalysis and light-emitting applications. In this study, a gentle and sustainable approach to the copper(I)-carbene phosphine complexes is reported through an efficient C=Se activation protocol. The complexes [(Py^NHC)Cu(PPh3 )2 ]X, X=BF4 (1), ClO4 (2), PF6 (3) and OTf (4); Py^NHC=3-isopropyl-1-(pyridin-2-yl)-imidazol-2-ylidene, and [(Py^NHC)Cu(PPh3 )(X)], X=Br (5) and I (6) have been synthesized by treating 1-isopropyl-3-(pyridin-2-yl)-imidazole-2-selone with corresponding copper(I) precursors and triphenylphosphine. In this synthetic strategy, N-heterocyclic carbene gets transferred from N-heterocyclic selone through a C=Se bond cleavage reaction to form copper(I) complexes within five minutes at room temperature. In addition, the mechanism responsible for the C=Se bond cleavage reaction has been fully investigated. These reactions are not sensitive to moisture and oxygen.

A Sustainable Approach for Graphene Oxide-supported Metal N-Heterocyclic Carbenes Catalysts.

Sustainable noble metal-N-heterocyclic carbenes (NHC's) are a topic of arising concern in both the chemical industry and the academic community due to a growing consciousness of environmental pollution and scarcity. Recovering and reusing homogeneous catalysts from the reaction mixture requires a tremendous amount of capital investment in the chemical manufacturing industry. Heterogeneous catalysts are proved to have better functional groups tolerance; however, catalysts support largely influences the active catalyst sites to affect catalyst efficiency and selectivity. Thus the, choice of catalyst supports plays an almost decisive role in this emerging area of catalysis research. Graphene oxide (GO)/reduced graphene oxide (rGO) support has a potential growth in heterogeneous catalysis owing to their commercial availability, considerably larger surface area, inert towards chemical transformations, and easy surface functionalization to attached metal complexes via covalent and non-covalent aromatic π-conjugates. To take advantage of two independently well-established research areas of noble metal-N-heterocyclic carbenes and GO/rGO support via covalent or non-covalent interactions approach would offer novel heterogeneous complexes with improved catalytic efficiency without sacrificing product selectivity. This unique concept of marrying metal-N-heterocyclic carbenes with GO/rGO support has potential growth in the chemical and pharmaceutical industry, however, limited examples are reported in the literature. In this perspective, a comprehensive summary of metal-NHC synthesis on GO/rGO support and synthetic strategies to graft M-NHC onto GO/rGO surface, catalytic efficiency, for the catalytic transformation are critically reviewed. Furthermore, a plausible mechanism for non-covalent grafting methodology is summarized to direct readers to give a better understanding of M-NHC@rGO complexes. This would also allow the designing of engineered catalysts for unexplored catalytic applications.

In Vitro Interaction of a C-Terminal Fragment of TDP-43 Protein with Human Serum Albumin Modulates Its Aggregation.

An increased level of naturally occurring anti-TDP-43 antibodies was observed in the serum and cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis patients. Human serum albumin (HSA), the most abundant protein in blood plasma and CSF, is found to interact with pathological proteins like Aß and α-synuclein. Therefore, we examined the effect on the in vitro aggregation of a C-terminal fragment of TDP-43 in the presence of HSA. We found that the lag phase in TDP-432C aggregation is abrogated in the presence of HSA, but there is an overall decreased aggregation as examined by thioflavin-T fluorescence spectroscopy and microscopy. An early onset of TDP-432C oligomer formation in the presence of HSA was observed using atomic force microscopy and transmission electron microscopy. Also, a known chemical inhibitor of TDP-432Caggregation, AIM4, abolishes the HSA-induced early formation of TDP-432C oligomers. Notably, the aggregates of TDP-432C formed in the presence of HSA are more stable against sarkosyl detergent. Using affinity copurification, we observed that HSA can bind to TDP-432C, and biolayer interferometry further supported their physical interaction and suggested the binding affinity to be in sub-micromolar range. Taken together, the data support that HSA can interact with TDP-432C in vitro and affect its aggregation.

Highly Active Cyclic Zinc(II) Thione Catalyst for C-C and C-N Bond Formation Reactions.

The first discrete seven-membered cyclic zinc(II) complex catalyzed room temperature Knoevenagel condensation reactions, and the synthesis of perimidine derivatives has been reported under mild reaction conditions. The cyclic zinc(II) complex [(L)ZnBr2 ] (1) was isolated from the reaction between 1-(2-hydroxyethyl)-3-isopropyl-benzimidazol-2-thione (L) and ZnBr2 . Complex 1 was characterized by different analytic techniques such as FT-IR, CHNS, TGA, NMR, and SCXRD. The mononuclear zinc(II) complex 1 was utilized as a catalyst for Knoevenagel condensation reactions to isolate twenty different substituted methylene malononitriles with excellent yield. Besides, the zinc(II) thione complex 1 was utilized for the synthesis of 2,4-dihydroperimidine derivatives in a highly efficient manner. Catalyst 1 depicted wide substrate scopes. Overall, twenty different substituted methylene malononitriles and nine different perimidine derivatives were synthesized using catalyst 1 at room temperature. The present investigation features a mild and fast synthetic approach along with excellent functional group tolerance.

Mechanically tunable photo-cross-linkable bioinks for osteogenic differentiation of MSCs in 3D bioprinted constructs.

3D bioprinting technique renders a plausible solution to tissue engineering applications, mainly bone tissue regeneration, which could provide the microenvironment with desired physical, chemical, and mechanical properties. However, the mechanical and structural stability of current natural polymers is a critical issue in the fabrication of bone tissue-engineered scaffolds. To overcome these issues, we have developed 3D bioprintable semi-synthetic polymers derived from natural (sodium alginate, A) and synthetic (polyethylene glycol, PEG) biopolymers. In order to enhance the cross-linking properties and biocompatibility, we have functionalized these polymers with acrylate and methacrylate chemical moieties. These selected combination of natural and synthetic polymers improved the mechanical strength due to the synergistic effect of covalent as well as ionic bond formation in the hydrogel system, which is evident from the tested tensile data. Further, the feasibility of 3D bioprinting of acrylate and methacrylate functionalized PEG and hydrogels have been tested for the biocompatibility of the fabricated structures with human umbilical cord mesenchymal stem cells (UMSCs). Further, these bioprinted scaffolds were investigated for osteogenic differentiation of UMSCs in two types of culture conditions: namely, i) with osteoinduction media (with OIM), ii) without osteoinduction media (w/o OIM). We have examined the osteoinductivity of scaffolds with the activity of alkaline phosphatase (ALP) content, and significant changes in the ALP activity was observed with the stiffness of developed materials. The extent osteogenic differentiation was observed by alizarin red staining and reverse transcription PCR analysis. Elevated levels of ALP, RUNX2 and COL1 gene expression has been observed in without OIM samples on week 1 and week 3. Further, our study showed that the synthesized alginate methacrylate (AMA) without osteoinduction supplement with young's modulus of 0.34 MPa has a significant difference in ALP quantity and gene expression over the other reported literature. Thus, this work plays a pivotal role in the development of 3D bioprintable and photo-cross-linkable hydrogels in osteogenic differentiation of mesenchymal stem cells.

A gold(I) 1,2,3-triazolylidene complex featuring the interaction between gold and methine hydrogen.

A mesoionic N-heterocyclic carbene-gold(I) complex with a unique Au⋯H-C(methine) intramolecular hydrogen bonding interaction has been investigated in the solid state. The structure of this new neutral gold(I)-carbene was characterized by FT-IR and NMR spectroscopy, TGA, and X-ray diffraction techniques. Density functional theory (DFT) and atoms-in-molecule (AIM) analysis revealed that the gold-hydrogen bonding situation is more favored. Besides, the photophysical properties of the gold(I) complex were also investigated.

Antimony(III) Halide-Assisted Stereospecific Coordination of Thione.

The antimony halide-aided stereospecific coordination of a cyclic thiourea-type of ligand is observed for the first time. The antimony(III) imidazole thione complexes syn-[(L1 )SbCl3 ] (syn-1) and anti-[(L1 )SbBr3 ] (anti-2) have been synthesized in very good yield by the reaction between the spatially defined steric impact ligand [(IPaul)S] (L1 ) ([(IPaul)S]=1,3-bis(2,4-methyl-6-diphenyl phenyl)imidazole thione) and corresponding antimony halide. The stereoselective formation of complexes syn-1 and anti-2 has been confirmed by both NMR and single-crystal X-ray diffraction studies. Interestingly the stereospecific nature of syn-1 and anti-2 remains intact in solution. Furthermore, the thermal stability of antimony(III) imidazole thione complexes were examined by TGA analysis.

Acridine N-Heterocyclic Carbene Gold(I) Compounds: Tuning from Yellow to Blue Luminescence.

The synthesis and the luminescence features of three gold(I)-N-heterocyclic carbene (NHC) complexes are presented to study how the n-alkyl group can influence the luminescence properties in the crystalline state. The mononuclear gold(I)-NHC complexes, [(L1 )Au(Cl)] (1), [(L2 )Au(Cl)] (2), and [(L3 )Au(Cl)] (3) were isolated from the reactions between [(tht)AuCl] and corresponding NHC ligand precursors, [N-(9-acridinyl)-N'-(n-butyl)-imidazolium chloride, (L1 .HCl)], [N-(9-acridinyl)-N'-(n-pentyl)-imidazolium chloride, (L2 .HCl)] and [N-(9-acridinyl)-N'-(n-hexyl)-imidazolium chloride, (L3 .HCl)]. Their single-crystal X-ray analysis reveals the influence of the n-alkyl groups on solid-state packing. A comparison of the luminescence features of 1-3 with n-alkyl substituents is explored. The molecules 1-3 depicted blue emission in the solution state, while the yellow emission (for 1), greenish-yellow emission (for 2), and blue emission (for 3) in the crystalline phase. This paradigm emission shift arises from n-butyl to n-pentyl and n-hexyl in the crystalline state due to the carbon-carbon rotation of the n-alkyl group, which tends to promote unusual solid packing. Hence n-alkyl group adds a novel emission property in the crystalline state. Density Functional Theory and Time-Dependent Density Functional Theory calculations were carried out for monomeric complex, N-(9-acridinyl)-N'-(n-heptyl)imidazole-2-ylidene gold(I) chloride and dimeric complex, N-(9-acridinyl)-N'-(n-heptyl)imidazole-2-ylidene gold(I) chloride to understand the structural and electronic properties.

Rare antimony(III) imidazole selone complexes: steric controlled structural and bonding aspects.

Novel antimony(iii) imidazole selone complexes in a super crowded environment are reported for the first time. The super bulky selone antimony complexes, [{IPr*Se}(SbCl3)2] (1) and [{IPr*Se}(SbBr3)2] (2), were isolated from the reactions between IPr*Se (IPr*Se = [1,3-bis(2,6-diphenylmethylphenyl)imidazole selone]) and suitable antimony(iii) halides. 1 and 2 are dinuclear complexes with a Sb : Se ratio of 1 : 0.5 with an unusual coordination mode of selone. The molecules 1 and 2 consist of both Menshutkin-type Sbπaryl interactions and a Sb-Se coordination bond. However, the reaction between antimony(iii) halides and [(IPaul)Se] ([(IPaul)Se] = [1,3-bis(2,4-methyl-6-diphenyl phenyl)imidazole selone]) with a spatially defined steric impact gave the dinuclear complex [{(IPaul)Se}(SbCl3)]2 (3) and the mononuclear complex [{(IPaul)Se}(SbBr3)] (4) without Menshutkin-type interactions. The Sb : Se ratio in 3 and 4 is 1 : 1. Interestingly, the Menshutkin-type interaction was absent in 3 and 4 due to the efficient coordinating ability of the ligand [(IPaul)Se] with the Sb(iii) center compared to that of the super bulky ligand IPr*Se. The thermal property of these antimony selone complexes was also investigated. Density functional theory (DFT) calculations were carried out on the model systems [L(SbCl3)2] (1A), [L(SbCl3)] (1B), [L'(SbCl3)2] (1C), and [L'(SbCl3)] (1D), where L = [1,3-bis(2,6-diisopropyl-4-methyl phenyl)imidazole selone] and L' = [1,3-bis(phenyl)imidazole selone], to understand the nature of orbitals and bonding situations. The computed metrical parameters of 1A are in good agreement with the experimental values. Natural population analysis of the model system reveals that the natural charge and total population of antimony(iii) are comparable. The unequal interaction between selenium and antimony obtained using Wiberg bond indices (WBIs) is fully consistent with the findings of the single-crystal X-ray studies.

Computational insights into mechanism of AIM4-mediated inhibition of aggregation of TDP-43 protein implicated in ALS and evidence for in vitro inhibition of liquid-liquid phase separation (LLPS) of TDP-432C-A315T by AIM4.

TDP-43 is an RNA/DNA-binding protein which is also implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) disease. TDP-43's cytoplasmic mis-localization, liquid-liquid phase separation (LLPS) due to RNA depletion and aggregation, are proposedly important TDP-43-toxicity causing mechanisms. So far, therapeutic options for ALS are extremely ineffective hence, multi-faceted approaches such as targeting the oxidative stress and inhibiting the TDP-43's aggregation, are being actively pursued. Recently, we have identified an acridine derivative, AIM4, as an anti-TDP-43 aggregation molecule however, its mechanism is not deciphered. Here, we have utilized computational tools to examine binding site(s) of AIM4 in the TDP-43 structure and compared with other relevant compounds. We find that AIM4 has a binding site in the C-terminal amyloidogenic region (aa: 288-319), with Gly-288 & Phe-289 residues which are also important for TDP-43's LLPS. Importantly, alike to previously reported effects of RNA, AIM4 could also inhibit the in vitro LLPS of a C-terminal fragment TDP-432C bearing an A315T familial mutation. Furthermore, isothermal titration calorimetry (ITC) data also support the binding of AIM4 to TDP-432C-A315T. This antagonism of AIM4 towards TDP-43's LLPS and presence of binding site of AIM4 on TDP-43 support AIM4's potential to be an important molecule towards ALS therapeutic research.

Catalytically active coordination polymer with a tiny Zn2Se2 ring bridged by bis-selone.

The unprecedented architecture of a one-dimensional coordination polymer with a tiny Zn2Se2 ring system incorporated in the hydrogen-bonded array has been prepared, where the di-selone ligand functions as a unique neutral bridging ligand. The coordination polymer shows excellent catalytic activity in substituted 8-hydroxy-2-quinolinyl synthesis through Knoevenagel condensation reaction.

Luminescent zinc(ii) selone macrocyclic ring.

The synthesis and photophysical properties of macrocyclic Zn(ii) selone molecule have been reported. The structural property of Zn(ii) selone was elucidated using single crystal X-ray diffraction study. The solid-state structure of zinc(ii) selone molecule exhibits a perfect zinc(ii) selone 28 membered ring system with tetra coordination geometry around zinc(ii) center. The zinc(ii) selone ring system can be considered as the largest zinc(ii) ring system known without any non-interacting centered guest moiety. Detailed trends in photophysical as well as thermal properties were probed. In photoluminescence study, the solid-state sample of zinc(ii) selone ring system emits the bluish-yellow color with considerable quantum yields, while the solution state sample of zinc(ii) selone ring system in DMSO emits bluish-yellow. The luminescence lifetime of zinc(ii) selone was measured using standard time-correlated single photon counting (TCSPC) technique.

Blue-emitting acridine-tagged silver(i)-bis-N-heterocyclic carbene.

Herein, the photophysical properties of an acridine derivative of a bis-N-heterocyclic carbene silver complex were investigated. The HOMO and LUMO energy differences between 9-[(N-methyl imidazol-2-ylidene)]acridine and 4,5-bis[(N-methyl-imidazol-2-ylidene)methyl]acridine were theoretically compared. Based on the calculation, the 4,5-bis N-heterocyclic carbene-tethered acridine type of ligand was found to be a potential source for tuning the fluorescent nature of the resultant metal derivatives. Thus, a 4,5-bis N-heterocyclic carbene (NHC)-tethered acridine silver(i) salt was synthesized, and its photophysical properties were investigated. The 4,5-bis[(N-isopropylimidazol-2-ylidene)methyl]acridine silver(i) hexafluorophosphate complex was obtained from the reaction between [4,5-bis{(N-isopropylimidazolium)methyl}acridine] hexafluorophosphate and Ag2O in very good yield; this molecule was characterized by elemental analysis and FTIR, multinuclear (1H and 13C) NMR, UV-Vis, and fluorescence spectroscopic techniques. The molecular structure has been confirmed by single-crystal X-ray diffraction analysis, which has revealed that the complex is a homoleptic mononuclear silver(i) cationic solid. The charge of the Ag(i)-NHC cation is balanced by the hexafluorophosphate anion. The cationic moieties are closely packed in the chair and inverted chair forms where silver(i) possesses a quasi-linear geometry. Moreover, the silver complex provided blue emission from all the three excitations with good fluorescence quantum yield. The fluorescence lifetime of the silver(i) complex has been determined using the time-correlated single photon counting technique. Interestingly, the fluorescence decay pattern and the fluorescence lifetimes of the silver complex are largely different from those of the parent ligand acridine imidazolium salt. Moreover, the theoretical predictions have been found to be in good agreement with the experimental results.

Role of C, S, Se and P donor ligands in copper(i) mediated C-N and C-Si bond formation reactions.

The first comparative study of C, S, Se and P donor ligands-supported copper(i) complexes for C-N and C-Si bond formation reactions are described. The syntheses and characterization of eight mononuclear copper(i) chalcogenone complexes, two polynuclear copper(i) chalcogenone complexes and one tetranuclear copper(i) phosphine complex are reported. All these new complexes were characterized by CHN analysis, FT-IR, UV-vis, multinuclear NMR and single crystal X-ray diffraction techniques. The single crystal X-ray structures of these complexes depict the existence of a wide range of coordination environments for the copper(i) center. This is the first comparative study of metal-phosphine, metal-NHC and metal-imidazolin-2-chalcogenones in C-N and C-Si bond formation reactions. Among all the catalysts, mononuclear copper(i) thione, mononuclear copper(i) N-heterocyclic carbene and tetranuclear copper(i) phosphine are exceedingly active towards the synthesis of 1,2,3-triazoles as well as for the cross-dehydrogenative coupling of alkynes with silanes. The cross-dehydrogenative coupling of terminal alkynes with silanes represents the first report of a catalytic process mediated by metal-imidazolin-2-chalcogenones.

An acridine derivative, [4,5-bis{(N-carboxy methyl imidazolium)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with aggregation of TAR DNA-binding protein-43 (TDP-43) in neuronal cells and manifests as motor neuron dysfunction &muscle atrophy. The carboxyl-terminal prion-like domain of TDP-43 can aggregate in vitro into toxic ß-sheet rich amyloid-like structures. So far, treatment options for ALS are very limited and Riluzole, which targets glutamate receptors, is the only but highly ineffective drug. Therefore, great interest exists in developing molecules for ALS treatment. Here, we have examined certain derivatives of acridine containing same side chains at position 4 &5, for inhibitory potential against TDP-43 aggregation. Among several acridine derivatives examined, AIM4, which contains polar carboxyl groups in the side arms, significantly reduces TDP-43-YFP aggregation in the powerful yeast model cell and also abolishes in vitro amyloid-like aggregation of carboxyl terminal domain of TDP-43, as observed by AFM imaging. Thus, AIM4 can be a lead molecule potentiating further therapeutic research for ALS.

Catalytically active lead(ii)-imidazolium coordination assemblies with diversified lead(ii) coordination geometries.

Five Pb(ii)-imidazolium carboxylate coordination assemblies with novel structural motifs were derived from the reaction between the corresponding flexible, semi flexible or rigid imidazolium carboxylic acid ligands and lead nitrate. The imidazolium linker present in these molecules likely plays a triple role such as the counter ion to balance the metal charge, the ligand being an integral part of the final product and the catalyst facilitating carbon-carbon bond formation reaction. These lead-imidazolium coordination assemblies exhibit, variable chemical and thermal stabilities, as well as catalytic activity. These newly prepared catalysts are highly active towards benzoin condensation reactions with good functional group tolerance.

Facile access to zinc and cadmium selones: highly active catalysts for Barbier reactions in aqueous media.

The syntheses and structures of five mononuclear zinc and cadmium selone complexes along with a polynuclear cadmium selone 1D chain were described. The mononuclear homoleptic zinc selone complexes were the first examples of structurally characterized zinc(ii) selone complexes. The spectral properties of the zinc and cadmium selone derivatives were investigated. Interesting structural diversity, coordination geometry, and variable chemical and thermal stability were observed for these zinc and cadmium selone compounds. Besides this, the first metal selone mediated Barbier coupling was reported. These catalysts were highly active for Barbier coupling reactions in aqueous alcohol media. In addition, the scope of the catalytic reactions was further explored with eleven different aldehydes.