Data set associated with hydrogen bond cross-linkers in curly hair. Wet and dry tests.

Intramolecular halogen bonds between aryl halide donors and suitable acceptors, such as carbonyl or quinolinyl groups, held in proximity by 1,2-aryldiyne linkers, provide triangular structures in the solid state. Aryldiyne linkers provide a nearly ideal template for intramolecular halogen bonding as minor deviations from alkyne linearity can accommodate a variety of halogen bonding interactions, including O···Cl, O···Br, O···I, N···Br, and N···I. Halogen bond lengths for these units, observed by single crystal X-ray crystallography, range from 2.75 to 2.97 Å. Internal bond angles of the semirigid bridge between halogen bond donor and acceptor are responsive to changes in the identity of the halogen, the identity of the acceptor, and the electronic environment around the halogen, with the triangles retaining almost perfect co-planarity in even the most strained systems. Consistency between experimental results and structures predicted by M06-2X/6-31G* calculations demonstrates the efficacy of this computational method for modeling halogen-bonded structures of this type.

To address the challenges of rapid enzyme inactivation, poor tumor targeting, and acquired drug resistance in gemcitabine (GEM) application, we report two groups of maleimide-functionalized GEM prodrugs conjugating covalently in situ with Cys-34 of blood-circulating albumin and then resulting in macromolecular prodrugs after intravenous administration. Tailored and accurate controlled release was achieved through different combinations of linkage bonds, relatively stable and labile (carbamate and carbonate, respectively), and linkers with or without insertion of a disulfide bond. Interestingly, we found that the overall advantages or disadvantages brought by a disulfide bond varied with the stability of the linkage bond. Finally, the carbonate linkage bond-bearing group, especially the one with a linker lacking a disulfide bond, stood out with remarkably increased bioavailability (21-fold greater than GEM) and efficient tumor free-GEM accumulation (8-fold of GEM), which consequently contributed to excellent in vivo antitumor efficacy.

An emerging strategy for exploring the application of polyoxometalates (POMs) is to assemble POM clusters into open-framework materials, especially inorganic–organic hybrid three-dimensional (3D) open-framework materials, via the introduction of different organic linkers between the POM clusters. This strategy has yielded a few 3D crystalline POMs of which a typical class is the group of polyoxometalate metal–organic frameworks (POMMOFs). However, for reported POMMOFs, only coordination bonds are involved between the linkers and POM clusters, and it has not yet produced any covalently bonded polyoxometalate frameworks. Here, the concept of “covalently bonded POMs (CPOMs)” is developed. By using vanadoborates as an example, we showed that the 3D CPOMs can be obtained by a condensation reaction through the oxolation mechanism of polymer chemistry. In particular, suitable single crystals were harvested and characterized by single-crystal X-ray diffraction. This work forges a link among polymer science, POM chemistry, and open-framework materials by demonstrating that it is possible to use covalent bonds according to polymer chemistry principles to construct crystalline 3D open-framework POM materials.

Activatable cell-penetrating peptides (ACPPs) are known to be able to decrease the cytotoxicity of cell-penetrating peptide (CPP)-based drug delivery systems. Furthermore, they can improve the targeting of CPPs when specifically recognized and hydrolyzed by characteristic proteases. A comprehensive and profound understanding of the recognition and hydrolysis process will provide a better design of the ACPP-based drug delivery system. Previous studies have clearly described how ACPPs are recognized and bound by MMPs. However, the hydrolysis mechanism of ACPPs is still unsolved. This work focuses on a proteinase-sensitive cleavable linker of ACPPs (PLGLAG), the key structure for recognition and hydrolysis, trying to determine the mechanism by which MMP-9 hydrolyzes its substrate PLGLAG. The quantum mechanics/molecular mechanics (QM/MM) calculations herein show that MMP-9 proteolysis is a water-mediated four-step reaction. More specifically, it consists of (i) nucleophilic attack, (ii) hydrogen-bond rearrangement, (iii) proton transfer, and finally (iv) amide bond rupture. Considering the reversibility of multistep reaction, the second step (i.e., hydrogen-bond rearrangement) has the highest barrier and is the rate-limiting step in the hydrolysis of PLGLAG. The possible design and improvement of the key P1 and P1′ sites are also explored through mutations. The present results indicate that, while the mutations affect the reaction energy barriers and the rate-limiting steps, all mutants considered could be hydrolyzed by MMP-9. To provide further insights, the hydrolysis mechanism of MMP-2, which has a similar hydrolysis process to that of MMP-9 but with different reaction barriers, is also studied and compared. As a result, this work provides detailed insights into the hydrolysis mechanism of ACPPs by MMP-9 and, thus, also possible insights for the development of new strategies for ACPP-based delivery systems.

Metal–organic framework (MOF) UiO-66 and its variants have been used for applications ranging from gas adsorption to catalyzing chemical warfare agent degradation. Intrinsic point defects, most commonly missing linkers, are usually present in UiO-66. At high concentrations, defects may significantly impact the material’s properties, such as adsorption, transport, and catalytic activity. A quantitative description of how intrinsic defects affect adsorption and transport of guest molecules is required to design tailored materials. In this work, we identify how different arrangements of missing linker defects impact adsorption and diffusion of isopropyl alcohol (IPA). IPA is an ideal test molecule to quantify the impact of missing linker defects on adsorption and diffusion of polar molecules because it forms hydrogen bonds with other IPA molecules and the framework atoms, similar to some classes of chemical warfare agents and their simulants. We have generated 25% missing linker defect structures having ordered and nonordered arrangements of defects. We found that adsorption isotherms are fairly insensitive to the specific arrangement of defects. In contrast, diffusivities can depend strongly on ordering of the defects. Specifically, we found that structures that contain percolating defects, which allow diffusion through the material traversing only defective windows, exhibit faster diffusivities and lower diffusion barriers compared with structures having nonpercolating defects. All defective structures exhibited faster diffusivities at low to moderate IPA loadings than pristine UiO-66. At high IPA loading, diffusivity values in nonpercolating defective structures are less than in pristine UiO-66. This decrease at high loadings is due to IPA forming hydrogen-bonding ring-like structures facilitated by the larger defective pores. We show that an experimentally synthesized defective UiO-66 having a bcu net topology has percolating diffusion pathways, which serves as a proof-of-concept that it is possible to synthesize of MOFs having percolating diffusion pathways.

Over the last decade, there has been a lot of interest in incorporating dynamic covalent bonds (DCBs) into epoxy resins. Because diselenide and disulfide bonds have similar properties, they are frequently used as DCBs in self-healing epoxy networks. In this paper, we present diselenide and disulfide dynamic linkers containing epoxy networks by analyzing the effects of mechanical properties, thermal stability, activation energies, and self-healing properties. The glass transition temperature (Tg) values, mechanical properties, crosslinking density (ve), and thermal stability of disulfide linkers networks were higher than those of diselenide linkers networks, according to our research. The activation energies of disulfide linkers were higher than those of diselenide linkers (up to 14 kJ/mol), but their healing efficiency was lower than that of the diselenide network. These findings demonstrate the advantages of diselenide and disulfide dynamic linkers in epoxy networks systems, as well as a method for designing and preparing the appropriate diselenide dynamic linkers or disulfide dynamic linkers incorporated into epoxy networks for the appropriate application and processing technology.

Complete NMR data sets for compounds reported in 'A broadly applicable cross-linker for aliphatic polymers containing C–H bonds', Science 2019. Acquired on a Bruker AVANCE 300 spectrometer or a Bruker AVANCE Neo 500 spectrometer.

For optimized performance as effective drug-delivery vehicles, it is hypothesized that polymer-drug conjugates need to adopt a compact conformation during circulation in the blood-stream, such that the pendant drug molecules are screened from interaction with the body by an encapsulating polymer layer. Conversely, to optimize the release of the covalently bound drug molecule at the site of delivery within (e.g.) tumour cell, requires a more open conformation to facilitate access to the linking groups between polymer and drug by the appropriate peptide-cleaving enzymes. We have proposed that this can be achieved by inclusion of hydrophobic moieties to induce aggregation that are linked by pH degradable bonds such that at the low pH environment at the site of drug-delivery a change in conformation occurs as these groups are released from the conjugate. In this SANS experiment the solution conformation observed will be followed over time to investigate the kinetics of the change, and correlate the conformation changes with the drug-release kinetics study to be carried out in parallel.

Insertion of a tricoordinate phosphorus ligand into late metal–carbon bonds is reported. Metalation of a P^P-chelating ligand (L1), composed of a nontrigonal phosphorous (i.e., P(III)) triamide moiety, P(N(o-N(Ar)C6H4)2, tethered by a phenylene linker to a −PiPr2 anchor, with group 10 complexes L2M(Me)Cl (M = Ni, Pd) results in insertion of the nontrigonal phosphorus site into the metal–methyl bond. The stable methylmetallophosphorane compounds thus formed are characterized spectroscopically and crystallographically. Metalation of L1 with (cod)PtII(Me)(Cl) does not lead to a metallophosphorane but rather to the standard bisphosphine chelate (κ2-L1)Pt(Me)(Cl). These divergent reactivities within group 10 are rationalized by reference to periodic variation in M–C bond enthalpies.

Reported is the synthesis and characterization of guest-free and guest-included frameworks assembled from the anionic metal complex [Fe(ox)3]3‑ and the cationic diprotonated 4,4′-bipyridinium2+ (H2bpy) or 1,2-bis(4-pyridinium)ethylene2+ (H2bpye) linkers, where the complex and linkers are bonded by multiple charge-assisted hydrogen bonds. In some of the compounds additional barium cations serve as bridges between the anionic metal complexes forming −{[Fe(ox)33‑]2[Ba2+]}∞– anionic infinite chains. Aromatic guest molecules of 4-methoxyphenol (mp), 1,6-dimethoxynaphtalene (dmn), and 1,5-dihydroxynaphthalene (dhn) were successfully incorporated in the cavities of the frameworks. The π–π interactions between the pillars and the guests in the resulting guest-included frameworks were confirmed spectroscopically. The magnetic properties of the frameworks were measured as well.

The last decade has witnessed significant advances in the scale-up synthesis of metal–organic frameworks (MOFs) using commercially available and affordable organic linkers. However, the synthesis of MOFs using elongated and/or multitopic linkers to access MOFs with large pore volume and/or various topologies can often be challenging due to multistep organic syntheses involved for linker preparation. In this report, a modular MOF synthesis strategy is developed by utilizing the coordination and covalent bonds formation in one-pot strategy where monoacid-based ligands reacted to form ditopic ligands, which then assembled into a three-dimensional MOF with Zr6 clusters. Chemical stability of the resulting materials was significantly enhanced through converting the imine bond into robust linkage via cycloaddition with phenylacetylene. Oxygen storage capacities of the MOFs were measured, and enhanced volumetric O2 uptake was observed for the stabilized MOF, NU-401-Q.

The metal-linker coordination bond in metal–organic frameworks (MOFs) can be unstable in humid and acid gas environments, leading to loss of crystallinity and porosity. This degradation is not necessarily irreversible; solvent-assisted crystal redemption (“SACRed”) has been shown to recover the physical and chemical properties of ZIF-8 exposed to humid SO2. This approach can also be useful in creating mixed-linker materials that might be challenging to produce via de novo synthesis. Here, we expand more generally the concept of controlled degradation of a MOF with acid gas, followed by treatment with a fresh linker solution, to the use of different template MOFs (ZIFs, UiO-66, and UiO-67) and acid gases (SO2 and NO2 in dry and humid conditions). Significant losses in porosity and crystallinity along with structural changes (acid gas-linker complexes and linker functionalizations) are observed in the acid gas-exposed MOF templates, and SACRed is shown to reconstruct these partially demolished MOFs with a high degree of structural recovery. Detailed structural and spectroscopic characterizations of the controlled degradation and subsequent recovery are presented and analyzed. These findings indicate the generality of controlled degradation and reconstruction as a means for linker replacement in a wider variety of MOFs and also create the potential for linker substitutions (with non-native linkers) to obtain new hybrid MOFs.

Objective: This study aimed to evaluate the role of collagen cross-linkers in the bonding performance of the resin-dentin interface through a systematic review and a network meta-analysis.Sources: The literature search was conducted in several databases like PubMed, EMBASE, Cochrane, Scopus and Web of Science from their inception till 30 April 2022.Study selection: The inclusion criteria consisted of in vitro studies evaluating the micro-tensile and micro-shear bond strengths of different cross-linkers acting on dentin. Bayesian network meta-analysis was conducted using RStudio.Data: Out of the 294 studies evaluated in the full-text analysis, 40 were included in the systematic review and meta-analysis. Most studies have used cross-linkers as primer (65.1%), followed by incorporating them into in adhesives and acid etching agents. The application methods of the adhesive system were classified as “etch-and-rinse (ER) adhesives” (77%) and “self-etching (SE) adhesives”. Moreover, there were six types of cross-linkers in this presented review, of which the most numerous were polyphenols.Conclusion: Different application methods of cross-linkers, the long-term results showed that were only effective when used for longer durations, the immediate results were not statistically different. According to immediate and long-term results, etch-and-rinse (ER) adhesives showed a greater bonding performance than the control groups (p ≤ 0.05), whereas self-etching (SE) adhesives showed similar bond strength values (p ≥ 0.05). The result of network meta-analysis (NMA) showed that Dope like compound showed higher long-term bonding performance than other cross-linkers.Clinical significance: Long-term clinical studies may be needed to determine the effect of the cross-linkers on the bonding properties.

Anthrax lethal factor (LF) is a critical virulence factor in the pathogenesis of anthrax. A structure−activity relationship (SAR) of potential lethal factor inhibitors (LFi) is presented in which the zinc-binding group (ZBG), linker, and backbone moieties for a series of hydroxypyrone-based compounds were systematically varied. It was found that hydroxypyrothione ZBGs generate more potent inhibitors than hydroxypyrone ZBGs. Furthermore, coupling the hydroxypyrothione to a backbone group via a thioamide bond improves potency when compared to an amide linker. QM/MM studies show that the thioamide bond in these inhibitors allows for the formation of two additional hydrogen bonds with the protein active site. In both types of hydroxypyrothione compounds, ligand efficiencies of 0.29−0.54 kcal mol−1 per heavy atom were achieved. The results highlight the need for a better understanding to optimize the interplay between the ZBG, linker, and backbone to get improved LFi.

Proteolysis-targeting chimeras (PROTACs) must be cell permeable to reach their target proteins. This is challenging as the bivalent structure of PROTACs puts them in chemical space at, or beyond, the outer limits of oral druggable space. We used NMR spectroscopy and molecular dynamics (MD) simulations independently to gain insights into the origin of the differences in cell permeability displayed by three flexible cereblon PROTACs having closely related structures. Both methods revealed that the propensity of the PROTACs to adopt folded conformations with a low solvent-accessible 3D polar surface area in an apolar environment is correlated to high cell permeability. The chemical nature and the flexibility of the linker were essential for the PROTACs to populate folded conformations stabilized by intramolecular hydrogen bonds, π–π interactions, and van der Waals interactions. We conclude that MD simulations may be used for the prospective ranking of cell permeability in the design of cereblon PROTACs.

Linker structures are a crucial component of proteolysis-targeting chimeras (PROTACs) and have traditionally been designed based on empirical methods, which presents significant challenges in the development of PROTACs. Current optimization strategies typically focus on reducing the number of rotatable bonds in the linker to limit conformational freedom. However, this approach overlooks the complexity of the target protein degradation process. Retrospective analyses suggest that merely adjusting the rotatable bonds in the linker is insufficient to control the conformational freedom of the PROTACs, indicating the need for new optimization strategies. By integration of computational methods such as molecular dynamics simulations, this study investigates the role of the linker throughout the induction process, particularly its impact on the formation and stability of the ternary complex. This approach offers potential for overcoming the limitations of traditional strategies, reducing reliance on empirical methods, and enhancing the overall efficiency and effectiveness of PROTAC design.

N,C-Chelate boron compounds such as B(ppy)Mes2 (ppy = 2-phenylpyridyl, Mes = mesityl) have been recently shown to undergo a facile and reversible C−C/C−B bond rearrangement upon irradiation with UV-light, quenching the emission of the sample and limiting their use in optoelectronic devices. To address this problem, four molecules have been synthesized in which the π-conjugation is extended using either vinyl or acetylene linkers. These compounds, (ph-CC-ppy)BMes2 (B1A), (ph-CHCH-ppy)BMes2 (B1), p-bis(ppy-CHCH)benzene2 (B2), and 1,3,5-tris(ppy-CHCH)benzene3 (B3) have been fully characterized by NMR and single-crystal X-ray diffraction analyses. All four compounds are light yellow and emit blue or blue-green light upon UV irradiation. The acetylene compound B1A has been found to exhibit photochemical instability the same as that of the parent chromophore B(ppy)Mes2. In contrast, all of the olefin-substituted compounds are photochemically stable, instead undergoing cis−trans isomerization exclusively upon exposure to UV light. Experimental and TD-DFT computational results establish that the presence of the olefinic bond in B1−B3 provides an alternate energy dissipation pathway for the B(ppy)Mes2 chromophore, stabilizing the molecule toward photochromic switching via cis−trans isomerization. Furthermore, the incorporation of a cis−trans isomerization pathway may prove to be a useful strategy for the stabilization of photochemically unstable chromophores in other π-systems as well.

A dimer of dimers containing two quadruply bonded [Mo2(DAniF)3]+ units (DAniF = N,N′-di(p-anisyl)formamidinate) linked by the S-donor linker, dimethyldithiooxamidate was synthesized, structurally characterized, and electronic communication was probed. The core of [Mo2(DAniF)3]2(C2S2N2Me2), 1, formed by the Mo2NSC2SNMo2 atoms shows two fused but non planar six-membered rings, which differs from that of the β form of dimethyloxamidate analogue that has a heteronaphthalene-type structure (Cotton, F. A.; Liu, C. Y.; Murillo, C. A.; Villagrán, D.; Wang, X. J. Am. Chem. Soc. 2004, 126, 14822). For these two analogous compounds electronic coupling between the two [Mo2] units, as determined by electrochemical measurements, diminishes considerably upon replacement of O-donor by S-donor atoms (ΔE1/2 = 531 mV and 440 mV, respectively). This suggests that the non planar conformation of the linker in 1 hampers a pathway leading to π conjugation. Density functional theory (DFT) calculations show that the highest occupied molecular orbitals HOMO−HOMO-1 energy gap of 0.12 eV for 1 is much smaller than that of 0.61 eV for the O-donor analogue, which is consistent with the electrochemical data.

The present work reports the identification of a robust and reproducible metal-carboxylate noncluster-based secondary building unit (SBU) using flexible ligands, methylenebis(3,5-dimethylpyrazole), and homologous alkanedicarboxylic acids (HOOC-(CH2)n-COOH). We have successfully synthesized a series of zinc(II) coordination polymers using a tailor-made SBU, designed with the proper utilization of the hydrogen bonds of a pyrazole-based ligand. We have identified a clear correlation between the type of auxiliary linker used and the vertex geometry that is present in the resultant network. This, in effect, can pave the way for the strategic control of the vertex geometry, which should enable us to design and predict the topology and dimensionality of a metal−organic framework.