Asymmetric Linkers Research Articles

Self-assembled oligomeric structures of an asymmetric molecular linker; 4-isocyanophenyl disulfide on Au(111)

Para-substituted benzenes, such as 1,4-benzene dithiol and 1,4-phenyl diisocyanide, have been observed to oligomerize on the Au(111) surface by incorporating gold adatoms extracted from the substrate. This work investigates if oligomerization occurs for an analogous but asymmetric linker, 4-isocyanophenyl disulfide (ICPD) on Au(111). This molecule is comprised of both disulfide and isocyanide terminal groups attached to the phenyl ring. The resulting surface structures formed on Au(111) following exposure to ICPD are studied using scanning tunneling microscopy (STM). 1,4-isocyanophenyl thiolate (ICPT), formed through scission of ICPD’s disulfide bond, was also found to oligomerize on the surface, and potential oligomer structures and binding geometries are proposed with the aid of density functional theory (DFT) calculations, along with simulated STM images of the resulting structures. It is observed in this work that ICPT forms oligomeric structures that cover large sections of the substrate and appear to create etch pits resulting from gold atom extraction. Numerous potential binding geometries are investigated based on the distances between substrate gold atom adsorption sites compared to the monomer length. Selected structural candidates were optimized using DFT and were used to generate simulated STM images using the Tersoff–Hamann method to compare with experiment. It has been shown previously that the isocyanide- and thiol-connected oligomers conduct electrons, suggesting the possibility that the asymmetric oligomers found here might form the basis for fabricating molecular diodes.

Layer‐By‐Layer Assembly of Asymmetric Linkers into Non‐Centrosymmetric Metal Organic Frameworks: A Thorough Theoretical Treatment

AbstractLayer‐by‐layer synthesis of surface‐coordinated metal–organic frameworks (SURMOF) enables the assembly of asymmetric, dipolar linkers into non‐centrosymmetric pillar‐layered structures. Using appropriate substrate terminations can yield oriented growth with the dipoles aligned perpendicular to the surface. The aligned pillar linkers give rise to a built‐in electrostatic field. In addition, the non‐centrosymmetric structure of the SURMOF gives rise to intriguing nonlinear optical features, such as second harmonic generation. Previous research with methyl‐functionalized bipyridine pillar linkers have demonstrated that this approach works in principle, but so far the total degree of alignment is only very small. Herein, a multiscale modelling approach is presented for in‐silico SURMOF assembly to identify and overcome limitations in the growth of pillar‐layered SURMOFs and to develop a strategy to maximize linker alignment. Using master equation models and kinetic Monte Carlo simulations, it is found that the formation of a highly ordered state corresponding to the thermodynamic equilibrium is often prevented by long‐lasting transient effects. Based on ab initio binding energies for a wide selection of hypothetical pillar linkers, a fast‐binding, slow‐relaxation scheme is able to be identified during the SURMOF growth for a range of different pillar linkers. These observations allow them to derive a rational strategy for the design of novel linkers to yield SURMOF‐based non‐centrosymmetric materials with substantially improved properties.

Synthesis and antimicrobial testing of 5-fluorouracil derivatives.

Antibiotic resistance has increased the demand for novel treatments against multidrug-resistant microorganisms. In the research literature, 5-fluorouracil (5-FU) was proposed as an alternative due to its intrinsic antibacterial property. However, given its toxicity profile at high doses, its use in antibacterial therapy is dubious. In the quest for improving the efficacy of 5-FU, the present study intends to synthesise 5-FU derivatives and assess their susceptibility and mechanism against pathogenic bacteria. It was found that the compounds having tri-hexylphosphonium substitution on both nitrogen groups of 5-FU (6a, 6b and 6c) had considerable activity against both Gram-positive and Gram-negative bacteria. Among the active compounds, those with an asymmetric linker group 6c were found to have higher antibacterial efficacy. However, no conclusive efflux inhibition activity was found. As elucidated by electron microscopy studies, these self-assembling active phosphonium-based 5-FU derivatives caused considerable septal damage and cytosolic alterations in Staphylococcus aureus cells. In Escherichia coli, these compounds triggered plasmolysis. Interestingly, the minimal inhibitory concentration (MIC) of the most potent 5-FU derivative 6c remained constant, regardless of the bacteria's resistance profile. Further analysis revealed that compound 6c generated significant alterations in membrane permeabilization and depolarization in S. aureus and E. coli cells at the MIC. Compound 6c was found to substantially impede bacterial motility, suggesting its importance in regulating bacterial pathogenicity. Additionally, the nonhaemolytic activity of 6c suggested that it could be a potential therapeutic option for treating multidrug-resistant bacterial infections.

Front Cover: Synthesis and Structural Characterization of Macrocyclic Plasmin Inhibitors (ChemMedChem 6/2023)

Graphical Abstract The Front Cover shows new macrocyclic plasmin inhibitors containing a C-terminal P1 benzylamine group. Their N-terminal substitution provided analogues with sub-nanomolar Ki values. Additional inhibitors containing an asymmetric linker possess Ki values close to 2 nM. For the first time, crystal structures of these macrocyclic inhibitors in complex with a Ser195Ala microplasmin mutant were determined, which explain their excellent potency and selectivity. More information can be found in the Research Article by Simon J. A. Wiedemeyer, Guojie Wu, Ruby H. P. Law, Torsten Steinmetzer et al.

Synthesis and Structural Characterization of Macrocyclic Plasmin Inhibitors.

Two series of macrocyclic plasmin inhibitors with a C-terminal benzylamine group were synthesized. The substitution of the N-terminal phenylsulfonyl group of a previously described inhibitor provided two analogues with sub-nanomolar inhibition constants. Both compounds possess a high selectivity against all other tested trypsin-like serine proteases. Furthermore, a new approach was used to selectively introduce asymmetric linker segments. Two of these compounds inhibit plasmin with Ki values close to 2 nM. For the first time, four crystal structures of these macrocyclic inhibitors could be determined in complex with a Ser195Ala microplasmin mutant. The macrocyclic core segment of the inhibitors binds to the open active site of plasmin without any steric hindrance. This binding mode is incompatible with other trypsin-like serine proteases containing a sterically demanding 99-hairpin loop. The crystal structures obtained experimentally explain the excellent selectivity of this inhibitor type as previously hypothesized.

Structure and Magnetic Property of A pcu Cobalt(II) Network Constructed with Mixed-Clusters and V-shaped Ketone Ligand

The V-shaped ketone ligand, benzophenone-2,4′-dicarboxylic acid (H2bpdc), was used as a long ditopic asymmetric linker to bridge mixed cobalt(II) clusters into a three-dimensional pcu network, namely [Co7(μ3–OH)2(bpdc)6(2,2′-bpy)4]·2H2O (1) (2,2′-bpy=2,2′-bipyridine), which was synthesized by methods of hydrothermal reaction and the crystal structure was determined. The linear trinuclear cluster [Co3(COO)6] and planar tetranuclear cluster [Co4(μ3–OH)2(COO)4] simultaneously appeared in the same compound for the first time. IR, elemental analysis and XRPD confirmed the phase purity of the bulk materials. Magnetic properties of 1 in the 300–2 K have been studied, which reveal the occurrence of antiferromagnetic interactions between Co(II) ions.

Self-Assembly and Crystallization of DNA-Coated Colloids via Linker-Encoded Interactions.

Coating colloidal particles with DNA is a promising strategy to make functional nanoscale materials because the particles can be programmed to spontaneously self-assemble into complex, ordered structures. In this Article, we explore the phase behavior and types of structures that can be formed when interactions between DNA-coated colloids are specified by linker DNA strands dispersed in solution. We show that linker-mediated interactions direct the self-assembly of colloids into equilibrium crystal structures. Furthermore, we demonstrate how different linker sequences and concentrations produce different crystal lattices, whose symmetry and compositional order are encoded exclusively by the linker-mediated interactions. These results illustrate how linkers can be used to separate the assembly instructions, encoded in the linkers, from the colloids themselves. We also examine the phase behavior of asymmetric linkers, which bind more strongly to one colloidal species than the other. We find that asymmetry strongly influences the concentration dependence of the colloidal interactions, which we explain using a mean-field model. We also find evidence that asymmetric linkers might help to reduce kinetic bottlenecks to colloidal crystallization. Together, our findings expand the design rules of linker-mediated self-assembly and make connections between the various schemes for programming assembly of DNA-coated colloids reported in the literature.

The Anisotropic Responses of a Flexible Metal-Organic Framework Constructed from Asymmetric Flexible Linkers and Heptanuclear Zinc Carboxylate Secondary Building Units.

A new porous and flexible metal–organic framework (MOF) has been synthesized from the flexible asymmetric linker N-(4-carboxyphenyl)succinamate (CSA) and heptanuclear zinc oxo-clusters of formula [Zn7O2(carboxylate)10DMF2] involving two coordinated terminal DMF ligands. The structural response of this MOF to the removal or exchange of its guest molecules has been probed using a combination of experimental and computational approaches. The topology of the material, involving double linker connections in the a and b directions and single linker connections along the c axis, is shown to be key in the material’s anisotropic response. The a and b directions remain locked during guest removal, whereas the c axis linker undergoes large changes significantly reducing the material’s void space. The changes to the c axis linker involve a combination of a hinge motion on the linker’s rigid side and conformational rearrangements on its flexible end, which were probed in detail during this process despite the presence of crystallographic disorder along this axis, which prevented accurate characterization by experimental methods alone. Although inactive during guest removal, the flexible ends of the a and b axis linkers are observed to play a prominent role during DMF to DMSO solvent exchange, facilitating the exchange reaction arising in the cluster.

Local Electronic Structure of Molecular Heterojunctions in a Single-Layer 2D Covalent Organic Framework.

The synthesis of a single-layer covalent organic framework (COF) with spatially modulated internal potentials provides new opportunities for manipulating the electronic structure of molecularly defined materials. Here, the fabrication and electronic characterization of COF-420: a single-layer porphyrin-based square-lattice COF containing a periodic array of oriented, type II electronic heterojunctions is reported. In contrast to previous donor-acceptor COFs, COF-420 is constructed from building blocks that yield identical cores upon reticulation, but that are bridged by electrically asymmetric linkers supporting oriented electronic dipoles. Scanning tunneling spectroscopy reveals staggered gap (type II) band alignment between adjacent molecular cores in COF-420, in agreement with first-principles calculations. Hirshfeld charge analysis indicates that dipole fields from oriented imine linkages within COF-420 are the main cause of the staggered electronic structure in this square grid of atomically-precise heterojunctions.

Greatly enhanced spin filtering of single ferrocene devices: An ab initio study

First-principles studies of spin-dependent electronic transport are carried out on single ferrocene molecules in two so-called eclipsed and staggered configurations sandwiched between gold electrodes through asymmetric sulfur and amine linkers. These calculations are performed using density functional theory combined with the non-equilibrium Green's function method. Results revealed that the spin-polarized properties of a single ferrocene device can be remarkably enhanced by anchoring atoms so that a nearly perfect spin-filtering effect is observed in both configurations at zero bias. More interestingly, the configurational geometries of the molecule cause the spin current to be varied greatly through the device. Additionally, in the calculated bias region, a large spin-rectifying effect with a ratio larger than 5 and an obvious negative differential resistance behavior can be achieved in the eclipsed and staggered conformations, respectively. Our results suggest that the proposed molecule with the asymmetric linkers may hold potential applications in designing molecular spintronic devices.

Correlated disorder in metal–organic frameworks containing asymmetric linkers

Correlated disorder in metal–organic frameworks containing asymmetric linkers

Methylated conjugated polymers based on diketopyrrolopyrrole and dithienothiophene for high performance field-effect transistors

In this work, a series of conjugated polymers based on diketopyrrolopyrrole (DPP) and dithienothiophene were designed for application in field-effect transistors (FETs). Owing to the synthetic nature of DPP units, the DPP polymers here contain different aromatic linkers with thiophene and methylthiophene, resulting in non-methylated and methylated DPP polymers. Methylated DPP polymers were found to show good crystalline properties and provide high hole mobilties up to 5.32 cm2 V−1 s−1 in FETs, while non-methylated polymer exhibits a hole mobility of 3.16 cm2 V−1 s−1. Especially, the polymer containing asymmetric linkers presents “face-on” orientation in thin films but provides the highest mobility. Our results reveal that the polymers incorporating methyl units as side chains can be used to realize high carrier mobility in FETs.

Optimization of silicon dioxide surface functionalization protocol for designing the receptor layer of a biosensor for detecting explosives

The development of the receptor layer of the biosensor for detecting explosive compounds is described. The covalent modification has been chosen for immobilizing E. coli nitroreductase on the gate oxide of the ion-sensitive field effect transistor (ISFET) that is comprised of silicon dioxide. The self-assembled monolayer technique has been used for immobilization. This method assumes the usage of different silanes and spacer molecules for activating the surface of SiO2. Two different immobilization strategies have been compared, one using asymmetric spacers (3-maleimidobenzoic acid N-hydroxysuccinimide ester (MBS) and 4-(4-maleimidophenyl)butyric acid N-hydroxysuccinimide ester (SMPB)) and another using a symmetric glutaric dialdehyde linker both accompanied by appropriate silanes. For the first method, the dependence of functionalization efficiency on silane concentration has been studied. The sufficient density of enzyme molecules on the surface of SiO2 has been achieved at a concentration of silane of 0.0015%. The type of asymmetric linker has no influence on immobilization efficiency. The method implying glutaric dialdehyde results in higher activity of the immobilized enzyme. For this method, the immobilization procedure has been optimized. The method has been adapted for immobilization of E. coli nitroreductase inside the channel of a microfluidic system on the surface of ISFET. For this purpose, (3-aminopropyl)triethoxysilane (APTES) has been changed to the corresponding silatrane, and the concentration of the enzyme has been increased to 30 μg/mL. The optimized procedure has been successfully used to develop a biosensor for detecting explosives.

Manganese amido-imine bisphenol Hangman complexes

A modular ligand macrocycle is composed from two phenolic groups linked to a cyclohexane bridge through an amide bond and an imine bond. The stability of the asymmetric linkers to metathesis permits a macrocyclic platform to be assembled from the condensation of two different phenolic groups in a single-step, high yield, reaction. The primary coordination sphere may be tuned with functional groups on one phenolic group. The other phenolic group may be modified with a scaffold possessing a proton transfer group. In this way, control over the secondary coordination sphere of the macrocycle is achieved. Manganese complexes of the amido-imine linked macrocycle catalytically epoxidizes 1,2-dihydronapthalene using sodium hypochlorite as the oxidant. The amido-imine macrocycles represent a new metal active site capable of supporting high oxidation states and attendant atom transfer chemistry while at the same time permitting control over the primary and secondary sphere of the metal center.

A novel means of asymmetric linker attachment to DNA molecule by RecA-mediated multistranded DNA formation

We have developed a novel asymmetric linker attachment technology that utilizes multistranded DNA formation mediated by the RecA protein and Exonuclease I. Multistranded DNA can readily be formed at the terminus of double-stranded DNA by a complementary oligonucleotide in the presence of RecA and Exonuclease I. We have explored the possibility of applying this finding to the asymmetric attachment of linkers to specific DNA termini. We show that these unique properties of the terminal triple-stranded structure can be applied to directly clone specific DNA sequences.

The stoichiometry of the four linker subunits of Lumbricus terrestris hemoglobin suggests an asymmetric distribution

The extracellular, giant (∼3.6 MDa) hexagonal bilayer hemoglobin of the earthworm Lumbricus terrestris consists of 12 dodecamers of globin chains tethered to a central complex of 36 non-globin, linker chains (24–32 kDa). Four types of linker chains L1–L4 have been detected by electrospray ionization (ESI) and by matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS) and isolated by reversed phase high pressure liquid chromatography (HPLC). Deconvolution of the HPLC elution profile and of the MS spectra provided the following individual linker contents, expressed as percent of the sum of the four linker peak areas: HPLC-21% L1, 37% L2, 23% L3 and 19% L4, MALDI-47% L1, 29% L2, 16% L3 and 8% L4; ESI-24% L1, 16% L2, 40% L3 and 20% L4; respectively. Comparison with electrophoretic results revealed a surprising lack of overall agreement between all the methods. The calculated mean values of the available linker contents were found to be 32±12% L1, 28±9% L2, 27±10% L3 and 13±7% L4, suggesting the following relative stoichiometry: L1: L2: L3: L4 ≈1: 1: 1: 0.5. With a total of 36 linkers, a hexagonally symmetric distribution of each of the four linker chains is impossible. Thus, the asymmetric linker distribution provides an explanation for the existence of a large dipole moment of Lumbricus terrestris hemoglobin, 17300±2300 Da ( Takashima et al., 1999).

Asymmetric linker histone association directs the asymmetric rearrangement of core histone interactions in a positioned nucleosome containing a thyroid hormone response element.

We describe histone-DNA cross-linking in a positioned nucleosome containing a thyroid hormone response element (TRE) from the Xenopus laevis thyroid hormone receptor betaA gene (TRbetaA). Histones H3 and H4 are cross-linked to DNA in the nucleosome core within 30 base pairs to either side of the dyad axis. Histone H2A cross-links to DNA in the core at the dyad axis, and histones H2A and H2B have extensive interactions with DNA 40-80 bp away from the dyad axis. Linker histone H5 and the globular domain of Xenopus H1(0) associate asymmetrically with DNA at one edge of the TRbetaA nucleosome. Nevertheless, the asymmetric association of H5 leads to a significant rearrangement of core histone-DNA contacts at the dyad axis of the nucleosome. In the presence of linker histone, cross-linkings of H4 within 15 bp to one side of the dyad axis, of histone H2A at the dyad axis, and of H2A and H2B 40-80 bp to one side of the dyad axis are all reduced. This reduction in cross-linking occurs preferentially on the side of the nucleosome to which H5 is bound. Our results indicate that core histone contacts within mononucleosomes are conformationally dynamic and that linker histone incorporation at the edge of the nucleosome can influence core histone-DNA interactions in an asymmetric way including contacts at the dyad axis.

Asymmetric linker molecules for recombinant DNA constructions

Asymmetric EcoRI DNA linkers consisting of an AATTC(A) 7 dodecamer and a complementary G(T) 7 octamer were synthesized. Ligation of such linkers to DNA fragments obviates the need for EcoRI digestion prior to cloning in EcoRI-cleaved vectors.