Linker Bond Research Articles

6-Endo-dig vs 5-exo-dig: Exploring Radical Cyclization Preference with First-, Second-, and Third-row Linkers using High-level Quantum Chemical Methods.

As an expansion upon Baldwin rules, the cyclization reactions of hex-5-yn-1-yl radical systems with different first-, second-, and third-row linkers are explored at the CCSD(T) level via means of the SMD(benzene)-G4(MP2) thermochemical protocol. Unlike C, O, and N linkers, systems with B, Si, P, S, Ge, As, and Se linkers are shown to favor 6-endo-dig cyclization. This offers fundamental insights into the rational synthetic design of cyclic compounds. A thorough analysis of stereoelectronic effects, cyclization barriers, and intrinsic barriers illustrates that structural changes alter the cyclization preference by mainly impacting 5-exo-dig reaction barriers. Based on the high-level computational modeling, we proceed to develop a new tool for cyclization preference prediction from the correlation between cyclization barriers and radical structural parameters (e.g., linker bond length and bond angle). A strong correlation is found between the radical attack trajectory angle and the reaction barrier heights, i.e., cyclization preference. Finally, the influence of stereoelectronic effects on the two radical cyclization pathways is further investigated in stereoisomers of hypervalent silicon system, which provides novel insight into cyclization control.

Sequential-delivery nanocomplex for combined anti-angiogenesis and gene therapy against colorectal cancer

Neovascularization can provide tumors with essential nutrients and oxygen, as well as maintain a microenvironment for tumor cell growth. In this study, we combined anti-angiogenic therapy and gene therapy for synergistic anti-tumor therapy. We co-delivered the vascular endothelial growth factor receptor inhibitor fruquintinib (Fru) and small interfering RNA CCAT1 (siCCAT1) inhibiting epithelial-mesenchymal transition using 1,2-distearoyl-snglycero-3-phosphoethanolamine-N- [methoxy (polyethylene glycol)] with a pH-responsive benzoic imine linker bond (DSPE-Hyd-mPEG) and polyethyleneimine-poly (d, l-lactide) (PEI-PDLLA) nanocomplex (Fru and siCCAT1 co-delivery NP, FCNP). Due to the characteristics of pH-response, DSPE-Hyd-mPEG removed from FCNP after enrichment at the tumor site, which had a protective effect in the body. Meanwhile, Fru acting on the peritumor blood vessels was rapidly released, and then the nanoparticles loaded with siCCAT1 (CNP) was engulfed by cancer cells and facilitate the successful lysosomal escape of siCCAT1 in, playing the role of silencing CCAT1. Efficient silencing of CCAT1 by FCNP was observed, and simultaneously, the expression of VEGFR-1 was also down-regulated. Furthermore, FCNP elicited significant synergistic antitumor efficacy via anti-angiogenesis and gene therapy in the SW480 subcutaneous xenograft model with favorable biosafety and biocompatibility during the treatment. Overall, FCNP was considered a promising strategy for the combined anti-angiogenesis-gene treatment against colorectal cancer.

Size-Dependent Thermal Shifts to MOF Nanocrystal Optical Gaps Induced by Dynamic Bonding

Conventional semiconductor nanocrystals exhibit wide-ranging optical behavior, whereas the size-dependent photophysical properties of metal-organic framework (MOF) nanocrystals remain an open research frontier. Here, we present size- and temperature-dependent optical absorption spectra of common MOFs with particle sizes ranging from tens of nanometers to several micrometers. All materials exhibit optical gaps that decrease at elevated temperatures, which we attribute to the dynamic nature of MOF metal-linker bonds. Accordingly, whereas the labile titanium-carboxylate bonds of MIL-125 give rise to bandgaps that red-shift by ∼600 meV over 300 K, the more rigid zinc-imidazolate bonds of ZIF-8 produce a red-shift of only ∼10 meV. Furthermore, smaller particles induce far larger decreases to optical gaps. Taken together, these results suggest MOF bonding becomes more flexible with smaller nanocrystal sizes, offering a powerful tool for manipulating optical behavior through composition, temperature, and dimensionality.

Molecular Framework Analysis of the Generated Database GDB-13s.

The generated databases (GDBs) list billions of possible molecules from systematic enumeration following simple rules of chemical stability and synthetic feasibility. To assess the originality of GDB molecules, we compared their Bemis and Murcko molecular frameworks (MFs) with those in public databases. MFs result from molecules by converting all atoms to carbons, all bonds to single bonds, and removing terminal atoms iteratively until none remain. We compared GDB-13s (99,394,177 molecules up to 13 atoms containing simplified functional groups, 22,130 MFs) with ZINC (885,905,524 screening compounds, 1,016,597 MFs), PubChem50 (100,852,694 molecules up to 50 atoms, 1,530,189 MFs), and COCONUT (401,624 natural products, 42,734 MFs). While MFs in public databases mostly contained linker bonds and six-membered rings, GDB-13s MFs had diverse ring sizes and ring systems without linker bonds. Most GDB-13s MFs were exclusive to this database, and many were relatively simple, representing attractive targets for synthetic chemistry aiming at innovative molecules.

Switchable Metal Sites in Metal-Organic Framework MFM-300(Sc): Lewis Acid Catalysis Driven by Metal-Hemilabile Linker Bond Dynamics.

Uncommon reversible guest-induced metal-hemilabile linker bond dynamics in MOF MFM-300(Sc) was unraveled to switch on/switch off catalytic open metal sites. The catalytic activity of this MOF with non-permanent open metal sites was demonstrated using a model Strecker hydrocyanation reaction as a proof-of-concept. Conclusively, the catalytic activity was evidenced to be fully reversible, preserving the conversion performance and structure integrity of MFM-300(Sc) over multiple cycles. These experimental findings were corroborated by quantum-calculations that revealed a reaction mechanism driven by the Sc-open metal sites. This discovery paves the way towards the design of new effective and easily regenerable heterogeneous MOF catalysts integrating switchable metal sites.

Switchable Metal Sites in Metal–Organic Framework MFM‐300(Sc): Lewis Acid Catalysis Driven by Metal–Hemilabile Linker Bond Dynamics

AbstractUncommon reversible guest‐induced metal‐hemilabile linker bond dynamics in MOF MFM‐300(Sc) was unraveled to switch on/switch off catalytic open metal sites. The catalytic activity of this MOF with non‐permanent open metal sites was demonstrated using a model Strecker hydrocyanation reaction as a proof‐of‐concept. Conclusively, the catalytic activity was evidenced to be fully reversible, preserving the conversion performance and structure integrity of MFM‐300(Sc) over multiple cycles. These experimental findings were corroborated by quantum‐calculations that revealed a reaction mechanism driven by the Sc‐open metal sites. This discovery paves the way towards the design of new effective and easily regenerable heterogeneous MOF catalysts integrating switchable metal sites.

Challenges for the application of EGFR-targeting peptide GE11 in tumor diagnosis and treatment

Abnormal regulation of cell signaling pathways on cell survival, proliferation and migration contributes to the development of malignant tumors. Among them, epidermal growth factor receptor (EGFR) is one of the most important biomarkers in many types of malignant solid tumors. Its over-expression and mutation status can be served as a biomarker to identify patients who can be benifit from EGFR tyrosine kinase inhibitors and anti-EGFR monocloncal antibody (mAb) therapy. For decades, researches on EGFR targeted ligands were actively carried out to identify potent candidates for cancer therapy. An ideal EGFR ligand can competitively inhibit the binding of endogenous growth factor, such as epidermal growth factor (EGF) and transforming growth factor-α(TGF-α) to EGFR, thus block EGFR signaling pathway and downregulate EGFR expression. Alternatively, conjugation of EGFR ligands on drug delivery systems (DDS) can facilitate targeting delivery of therapeutics or diagnostic agents to EGFR over-expression tumors via EGFR-mediated endocytosis. GE11 peptide is one of the potent EGFR ligand screened from a phage display peptide library. It is a dodecapeptide that can specifically binds to EGFR with high affinity and selectivity. GE11 has been widely used in the diagnosis and targeted delivery of drugs for radiotherapy, genetherapy and chemotherpy against EGFR positive tumors. In this review, the critical factors affecting the in vivo and in vitro targeting performance of GE11 peptide, including ligand-receptor intermolecular force, linker bond properties and physiochemical properties of carrier materials, are detailedly interpreted. This review provides a valuable vision for the rational design and optimization of GE11-based active targeting strategies for cancer treatment, and it will promote the translation studies of GE11 from lab research to clinical application.

Functionalization of an extended-gate field-effect transistor (EGFET) for bacteria detection

Traditional sensing technologies have drawbacks as they are time-consuming, cost-intensive, and do not attain the required accuracy and reproducibility. Therefore, new methods of measurements are necessary to improve the detection of bacteria. Well-established electrical measurement methods can connect high sensitive sensing systems with biological requirements. One approach is to functionalize an extended-gate field-effect transistor’s (EGFET) sensing area with modified porphyrins containing two different linkers. One linker connects the electrode surface with the porphyrin. The other linker bonds bacteria on the functional layer through a specific peptide chain. The negative charge on the surface of the cells regulates the surface potential which has an impact on the electrical behavior of the EGFET. The attendance of attached bacteria on the functionalized sensing area could successfully be detected.

Donor-Acceptor Conjugated Macrocycles with Polyradical Character and Global Aromaticity.

SummaryPolyradical character and global aromaticity are fundamental concepts that govern the rational design of cyclic conjugated macromolecules for optoelectronic applications. Here, we report donor-acceptor (D−A) conjugated macromolecules with and without π-spacer derivatives to tune the antiferromagnetic couplings between the unpaired electrons. The macromolecules without π-spacer have a closed-shell electronic configuration and show global nonaromatic character in the singlet and lowest triplet states. However, the derivatives with π-spacer develop a nearly pure open-shell diradical and a very high polyradical character, not reported for D−A type macromolecules. Furthermore, the π-spacer derivatives display global nonaromaticity in the singlet ground state, but global aromaticity in the lowest triplet state, according to Baird's rule. The absorption spectra of the open-shell macromolecules calculated with time-dependent density functional theory indicate intensive light absorption in the near-infrared region and broadening to 2,500 nm, making these materials suitable for numerous optoelectronic applications.

Isolating the Role of the Node-Linker Bond in the Compression of UiO-66 Metal–Organic Frameworks

Understanding the mechanical properties of metal–organic frameworks (MOFs) is essential to the fundamental advancement and practical implementations of porous materials. Recent computational and experimental efforts have revealed correlations between mechanical properties and pore size, topology, and defect density. These results demonstrate the important role of the organic linker in the response of these materials to physical stresses. However, the impact of the coordination bond between the inorganic node and organic linker on the mechanical stability of MOFs has not been thoroughly studied. Here, we isolate the role of this node–linker coordination bond to systematically study the effect it plays in the compression of a series of isostructural MOFs, M-UiO-66 (M = Zr, Hf, or Ce). The bulk modulus (i.e., the resistance to compression under hydrostatic pressure) of each MOF is determined by in situ diamond anvil cell (DAC) powder X-ray diffraction measurements and density functional theory (DFT) simulations. These experiments reveal the distinctive behavior of Ce-UiO-66 in response to pressures under 1 GPa. In situ DAC Raman spectroscopy and DFT calculations support the observed differences in compressibility between Zr-UiO-66 and the Ce analogue. Monitoring changes in bond lengths as a function of pressure through DFT simulations provides a clear picture of those which shorten more drastically under pressure and those which resist compression. We hypothesize that the presence of ∼10% Ce3+ in the nodes of Ce-UiO-66 may contribute to the weakening of the node–linker coordination, manifesting in the distinct behavior under pressure. This study demonstrates that changes to the node–linker bond can have significant ramifications on the mechanical properties of MOFs.

Engineering Structural Dynamics of Zirconium Metal-Organic Frameworks Based on Natural C4 Linkers.

Engineering the structural flexibility of metal-organic framework (MOF) materials for separation-related applications remains a great challenge. We present here a strategy of mixing rigid and soft linkers in a MOF structure to achieve tunable structural flexibility, as exemplified in a series of stable isostructural Zr-MOFs built with natural C4 linkers (fumaric acid, succinic acid, and malic acid). As shown by the differences in linker bond stretching and bending freedom, these MOFs display distinct responsive dynamics to external stimuli, namely, changes in temperature or guest molecule type. Comprehensive in situ characterizations reveal a clear correlation between linker character and MOF dynamic behavior, which leads to the discovery of a multivariate flexible MOF. It shows an optimal combination of both good working capacity and significantly enhanced selectivity for CO2/N2 separation. In principle, it provides a new avenue for potentially improving the ability of microporous MOFs to separate other gaseous and liquid mixtures.

Ammonia Adsorption and Co-adsorption with Water in HKUST-1: Spectroscopic Evidence for Cooperative Interactions

Ammonia interactions and competition with water at the interface of nanoporous metal organic framework thin films of HKUST-1 (Cu3Btc2, Btc = 1,3,5-benzenedicarboxylate) are investigated with ambient pressure X-ray photoelectron spectroscopy (APXPS). In the absence of water, ammonia adsorption at the Cu2+ metal center weakens the metal–linker bond of the framework. In the presence of water, due to the higher binding energy (adsorption strength) of ammonia compared to water, ammonia replaces water at the unsaturated Cu2+ metal centers. The water molecules remaining in the pores are stabilized by hydrogen bonding to ammonia. Hydrogen bonding between the water and ammonia strengthens the metal–ammonia interaction due to cooperative interactions. Cooperative interactions result in a reduction in the metal center oxidation state facilitating linker replacement by other species explaining the previously reported structure degradation.

Crystal Structure of 4,4′-Bi(3-(1-methylethoxy)-3-cyclobutene-1,2-dione)

Bisquaric acid, a hydrolysed form of 4,4¢-bi(3-(1methylethoxy)-3-cyclobutene-1,2-dione) (title compound, Fig. 1), reported by Liebeskind et al.1 possesses unique characteristics in the single-crystal phase, such as a dielectric response2 and an increase in the p-resonance,3 due to proton migration via quasi-one-dimensional hydrogen bonding. These characteristics originate from the concerted dynamics of the p-electrons and proton involved in strong hydrogen bonding, which has been confirmed by crystal structure, 13C-NMR, and DFT analyses. Most of the discussion emphasises the effect of hydrogen bonding. Further, the property originating from a bisquaric framework is not well considered. Accordingly, we analysed the single-crystal structure of the title compound in which the hydrogen bonding is quenched so as to investigate the p-electron system in the molecular framework. The title compound and its single crystal were prepared by Liebeskind’s method.1 The single crystal was mounted on a glass capillary, transferred to a Bruker AXS SMART APEX diffractometer equipped with a CCD area detector and Mo Ka (l = 0.71073 A) radiation, and centred in the beam at room temperature (293 K). The structure was solved and refined with SHELXS-97 and SHELXL-2014/7 (ref. 4), respectively, by the direct method before being expanded by Fourier techniques. A least-squares refinement was first carried out with all nonhydrogen atoms refined isotropically, with a subsequent assignment of the anisotropic thermal parameters to these atoms to achieve convergence. Hydrogen atoms were located by difference Fourier mapping, and all parameters were refined. All isotropic displacements of the hydrogen atoms were greater than the equivalent isotropic displacements of their connecting atoms. Crystal data are given in Table 1, as well as an ORTEP view is illustrated by ORTEP-3 (ref. 5). The atom numbering scheme is shown in Fig. 2. PLATON software6 suggested the presence of very weak intramolecular (C5–H5·O2) and intermolecular (C5– H5·O1i) hydrogen bonds. However, these are non-classical hydrogen bonds, and hence are insignificant for conjugated p-electron systems due to the low probability of proton migration. Table 2 summarises the lengths of the weak hydrogen bonds and C–C bonds of four membered ring and linker bond. The length of the C1–C4 bond is similar to that of the ethylene carbon–carbon double bond (1.33 A),7 while the cyclic linker C1–C1a and the adjacent C1–C2 bond lengths are similar to the sp2–sp2 bond length (1.47 A).7 On the other hand, the C2–C3 and C3–C4 bonds are shorter than the carbon–carbon Crystal Structure of 4,4¢-Bi(3-(1-methylethoxy)-3-cyclobutene-1,2-dione)

ChemInform Abstract: Beyond Post‐Synthesis Modification: Evolution of Metal—Organic Frameworks via Building Block Replacement

AbstractReview: 132 refs.

Surface-Induced Interphases During Curing Processes Between Bi- and Pentafunctional Components: Reactive Coarse-Grained Molecular Dynamics Simulations

The present reactive molecular dynamics (RMD) simulations discuss the formation of interphase regions in cured polymer adhesives. The latter are obtained from the curing of reactive liquid mixtures composed of pentafunctional linkers and bifunctional monomers in contact with idealized surfaces. The present reactive scheme mimics the one of epoxies with amine linkers, i.e., processes investigated experimentally by Possart and co-workers. Generic RMD simulations are performed in a coarse-grained (CG) resolution to evaluate basic principles in curing characterized by preferential interactions. The creation of linker-rich domains is promoted by preferential surface-linker as well as linker-linker interactions in the reactive mixtures. The dimension of the interphase both in the starting mixture and the cured network depends on these preferential interactions which lead to a retardation of the curing velocity. This retardation behavior is mapped by conversion curves as a function of the number of reactive steps and by the spatially resolved profiles of the connected linkers. Although derived by generic potentials, the simulated reduction of the curing velocity is in agreement with experimental results in epoxies. The chosen interactions also imply a smaller number of linker bonds in the interphase than in the bulk region. The present RMD approach offers insight into key parameters of curing processes under the influence of preferential surface interactions coupled to selective attractions in the liquid starting mixture.

The Acyclic 2,4-Diaminopyrimidine Nucleoside Phosphonate Acts as a Purine Mimetic in HIV-1 Reverse Transcriptase DNA Polymerization

The acyclic pyrimidine nucleoside phosphonate (ANP) phosphonylmethoxyethoxydiaminopyrimidine (PMEO-DAPym) differs from other ANPs in that the aliphatic alkyloxy linker is bound to the C-6 of the 2,4-diaminopyrimidine base through an ether bond, instead of the traditional alkyl linkage to the N-1 or N-9 of the pyrimidine or purine base. In this study, we have analyzed the molecular interactions between PMEO-DAPym-diphosphate (PMEO-DAPym-pp) and the active sites of wild-type (WT) and drug-resistant HIV-1 reverse transcriptase (RT). Pre-steady-state kinetic analyses revealed that PMEO-DAPym-pp is a good substrate for WT HIV-1 RT: its catalytic efficiency of incorporation (k(pol)/K(d)) is only 2- to 3-fold less than that of the corresponding prototype purine nucleotide analogs PMEA-pp or (R)PMPA-pp. HIV-1 RT recognizes PMEO-DAPym-pp as a purine base instead of a pyrimidine base and incorporates it opposite to thymine (in DNA) or uracil (in RNA). Molecular modeling demonstrates that PMEO-DAPym-pp fits into the active site of HIV-1 RT without significant perturbation of key amino acid residues and mimics an open incomplete purine ring that allows the canonical Watson-Crick base pairing to be maintained. PMEO-DAPym-pp is incorporated more efficiently than (R)PMPA-pp by mutant K65R HIV-1 RT and is not as efficiently excised as (R)PMPA by HIV-1 RT containing thymidine analog mutations. Overall, the data revealed that PMEO- DAPym represents the prototype compound of a novel class of pyrimidine acyclic nucleoside phosphonates that are recognized as a purine nucleotide and should form the rational basis for the design and development of novel purine nucleo(s)(t)ide mimetics as potential antiviral or antimetabolic agents.

Cooperativity and frustration in protein-mediated parallel actin bundles.

We examine the mechanism of bundling of cytoskeletal actin filaments by two representative bundling proteins, fascin and espin. Small-angle x-ray studies show that increased binding from linkers drives a systematic overtwist of actin filaments from their native state, which occurs in a linker-dependent fashion. Fascin bundles actin into a continuous spectrum of intermediate twist states, while espin only allows for untwisted actin filaments and fully overtwisted bundles. Based on a coarse-grained, statistical model of protein binding, we show that the interplay between binding geometry and the intrinsic flexibility of linkers mediates cooperative binding in the bundle. We attribute the respective continuous (discontinuous) bundling mechanisms of fascin (espin) to difference in the stiffness of linker bonds themselves.

Didanosine ester prodrugs: Synthesis, albumin binding properties and pharmacokinetic studies in rats

Three half-ester derivatives 10– 12 of 5′- O-2′,3′-dideoxydidanosine (DDI, 1) have been synthesized. The compounds exhibited excellent correlation between partition coefficients Log P and relative in vitro bovine serum albumin binding. Using high-performance liquid chromatography–mass spectrometry (LC–MS), DDI ( 1) was quantitatively determined in rat plasma after intravenous injection of the azelaic acid monoester derivative ( 11) of DDI. The pharmacokinetic data obtained for DDI were consistent with literature. The pharmacokinetic profile of 11 showed no significant difference in AUC 0–360 or curve shape compared to the parent drug DDI ( 1). The data indicate that the prodrug was converted to DDI within minutes after administration. High relative protein binding in vitro holds a promise for validity of the concept using more stable linker bonds.

Single-molecule surface-enhanced Raman spectroscopy from a molecularly-bridged silver nanoparticle dimer

Silver nanoparticle dimers were produced and immobilized on a functionalized TEM finder grid, by sequential assembly using bifunctional molecular linker 4,4′-diaminoazobenzene. SERS spectra recorded were ascribed to the specific dimer by TEM-imaging. Temporal fluctuations (blinking) of SERS signal demonstrate observation of single-molecule Raman. By linker-mediated assembly at small linker to nanoparticle ratios, electromagnetic hot spots are created with one or very few molecular linkers localized in them. Observed recurrence times are consistent with known surface diffusion constants, suggesting that single molecule dynamics causing the blinking might arise from breaking of linker bond to one of the nanoparticles, linker diffusion over the other nanoparticle and return to the hot spot.

Screening-based Discovery and Structural Dissection of a Novel Family 18 Chitinase Inhibitor

Family 18 chitinases play key roles in the life cycles of a variety of organisms ranging from bacteria to man. Very recently it has been shown that one of the mammalian chitinases is highly overexpressed in the asthmatic lung and contributes to the pathogenic process through recruitment of inflammatory cells. Although several potent natural product chitinase inhibitors have been identified, their chemotherapeutic potential or their use as cell biological tools is limited due to their size, complex chemistry, and limited availability. We describe a virtual screening-based approach to identification of a novel, purine-based, chitinase inhibitor. This inhibitor acts in the low micromolar (Ki=2.8+/-0.2 microM) range in a competitive mode. Dissection of the binding mode by x-ray crystallography reveals that the compound, which consists of two linked caffeine moieties, binds in the active site through extensive and not previously observed stacking interactions with conserved, solvent exposed tryptophans. Such exposed aromatics are also present in the structures of many other carbohydrate processing enzymes. The compound exhibits favorable chemical properties and is likely to be useful as a general scaffold for development of pan-family 18 chitinase inhibitors.