Hydrocarbon Bridge Research Articles

Pyrolytic stage evolution mechanism of Zhundong coal based on reaction consistency analysis of mono/multi molecular models

Zhundong coalfield is the largest coalfield in China and the unclear stage evolution mechanism of Zhundong coal pyrolysis is the key factor restricting its coal fire control. Here, the monomolecular model (299 atoms) and large-scale multimolecular model (5083 atoms) were constructed for Liu huanggou (LHG) coal from Zhundong coalfield. The pyrolysis processes of the two models were calculated by ReaxFF MD method. Based on the reaction consistency analysis, the reaction paths tracing on pyrolysis stage evolution and toxic gases formation mechanisms were obtained. The LHG coal pyrolysis process is mainly because of the breakages of the ether oxygen bridge bonds, thioether bridge bonds and aliphatic hydrocarbon bridge bonds. It begins with the shedding of small molecules and then undergoes the thermal decomposition of the main structure and pyrolytic fragments. During the pyrolysis process, the LHG coal has constantly broken out tars, gases and other key products, accompanied by a large number of free radicals and intermediates produced. The main sources of CO are the active reaction sites where the carbonyl group and the carboxyl group located; H2S is directly produced from the sulfhydryl group. The research results will guide the staged control and directional transformation of coal fire.

Computational design and experimental confirmation of conformationally constrained peptides to compete with coactivators for pediatric PPAR[Formula: see text] by minimizing indirect readout effect.

The peroxisome proliferator-activated receptor-[Formula: see text] (PPAR[Formula: see text]) is a member of PPAR nuclear receptor family, and its antagonists have been widely used to treat pediatric metabolic disorders. Traditional type-1 and type-2 PPAR[Formula: see text] antagonists are all small-molecule compounds that have been developed to target the ligand-binding site (LBS) of PPAR[Formula: see text], which is not overlapped with the coactivator-interacting site (CIS) of PPAR[Formula: see text]. In this study, we described the rational design of type-3 peptidic antagonists that can directly disrupt PPAR[Formula: see text]-coactivator interaction by physically competing with coactivator proteins for the CIS site. In the procedure, seven reported PPAR[Formula: see text] coactivator proteins were collected and eight 11-mer helical peptide segments that contain the core PPAR[Formula: see text]-binding LXXLL motif were identified in these coactivators, which, however, possessed a large flexibility and intrinsic disorder when splitting from coactivator protein context, and thus would incur a considerable entropy penalty (i.e. indirect readout) upon binding to PPAR[Formula: see text] CIS site. By carefully examining the natively folded conformation of these helical peptides in their parent protein context and in their interaction mode with the CIS site, we rationally designed a hydrocarbon bridge across the solvent-exposed, ([Formula: see text], [Formula: see text]+ 4) residues to constrain their helical conformation, thus largely minimizing the unfavorable indirect readout effect but having only a moderate influence on favorable enthalpy contribution (i.e. direct readout) upon PPAR[Formula: see text]-peptide binding. The computational findings were further substantiated by fluorescence competition assays.

Backbone Hydrocarbon-Constrained Nucleic Acids Modulate Hybridization Kinetics for RNA.

The binding affinity of therapeutic oligonucleotides (ONs) for their cognate RNA is determined by the rates of association (ka) and dissociation (kd). Single-stranded ONs are highly flexible and can adopt multiple conformations in solution, some of which may not be conducive for hybridization. We investigated if restricting rotation around the sugar-phosphate backbone, by tethering two adjacent backbone phosphonate esters using hydrocarbon bridges, can modulate hybridization kinetics of the modified ONs for complementary RNA. Given the large number of possible analogues with different tether lengths and configurations at the phosphorus atoms, we employed molecular dynamic simulations to optimize the size of the hydrocarbon bridge to guide the synthetic efforts. The backbone-constrained nucleotide trimers with stereodefined configurations at the contiguous backbone phosphorus atoms were assembled using a ring-closing metathesis reaction, then incorporated into oligonucleotides by an in situ synthesis of the phosphoramidites followed by coupling to solid supports. Evaluation of the modified oligonucleotides revealed that 15-membered macrocyclic-constrained analogues displayed similar or slightly improved on-rates but significantly increased off-rates compared to unmodified DNA ONs, resulting in reduced duplex stability. In contrast, LNA ONs with conformationally preorganized furanose rings showed similar on-rates to DNA ONs but very slow off-rates, resulting in net improvement in duplex stability. Furthermore, the experimental data generally supported the molecular dynamics simulation results, suggesting that this strategy can be used as a predictive tool for designing the next generation of constrained backbone ON analogues with improved hybridization properties.

Computational design and experimental substantiation of conformationally constrained peptides from the complex interfaces of transcriptional enhanced associate domains with their cofactors in gastric cancer

Transcriptional enhanced associate domains (Teads) are the downstream effectors of the hippo signaling pathway and have been recognized as attractive druggable targets of gastric cancer. The biological function of Teads is regulated by diverse cofactors. In this study, the intermolecular interactions of Teads with their cognate cofactors were systematically characterized at structural, thermodynamic and dynamic levels. The Teads possess a double-stranded helical hairpin that is surrounded by three independent structural elements β-sheet, α-helix and Ω-loop of cofactor proteins and plays a central role in recognition and association with cofactors. A number of functional peptides were split from the hairpin region at Tead–cofactor complex interfaces, which, however, cannot maintain in native conformation without the support of protein context and would therefore incur a considerable entropy penalty upon competitively rebinding to the interfaces. Here, we further used disulfide and hydrocarbon bridges to cyclize and staple the hairpin and helical peptides, respectively. The chemical modification strategies were demonstrated to effectively constrain peptide conformation into active state and to largely reduce peptide flexibility in free state, thus considerably improving their affinity. Since the cyclization and stapling only minimize the indirect entropy cost but do not influence the direct enthalpy effect upon peptide binding, the designed conformationally constrained peptides can retain in their native selectivity over different cofactors. This is particularly interesting because it means that the cyclized/stapled, affinity-improved peptides can specifically compete with their parent Teads for the cofactor arrays as they share consistent target specificity.

Development of Biphenylthiazoles Exhibiting Improved Pharmacokinetics and Potent Activity Against Intracellular Staphylococcus aureus.

Exploring the structure-activity relationship (SAR) at the cationic part of arylthiazole antibiotics revealed hydrazine as an active moiety. The main objective of the study is to overcome the inherited toxicity associated with the free hydrazine. A series of hydrocarbon bridges was inserted in between the groups, to separate the two amino groups. Hence, the aminomethylpiperidine-containing analog 16 was identified as a new promising antibacterial agent with efficient antibacterial and pharmacokinetic profiles. Briefly, compound 16 outperformed vancomycin in terms of the antibacterial spectrum against vancomycin-resistant staphylococcal and enterococcal strains with minimum inhibitory concentrations (MICs) ranging from 2 to 4 μg/mL, which is a faster bactericidal mode of action, completely eradicating the high staphylococcal burden within 6-8 h, and it has a unique ability to completely clear intracellular staphylococci. In addition, the initial pharmacokinetic assessment confirmed the high metabolic stability of compound 16 (biological half-life >4 h); it had a good extravascular distribution and maintained a plasma concentration higher than the average MIC value for over 12 h. Moreover, compound 16 significantly reduced MRSA burden in an in vivo MRSA skin infection mouse experiment. These attributes collectively suggest that compound 16 is a good therapeutic candidate for invasive staphylococcal and enterococcal infections. From a mechanistic point of view, compound 16 inhibited undecaprenyl diphosphate phosphatase (UppP) with an IC50 value of 29 μM.

Macrocyclic Control in Helix Mimetics.

The α-helix is the most commonly found natural secondary structure in proteins and is intrinsic to many protein-protein interactions involved in important biological functions. Novel peptides designed to mimic helices found in nature employ a variety of methods to control their structure. These approaches are significant due to potential applications in developing new therapeutic agents and materials. Over the years, many strategies have emerged to influence, initiate, and propagate helical content in short, synthetic peptides. Early innovations used the natural macrocycle tether of disulfide bond formation, metal-mediated or lactam group addition as a means to prompt helical formation. These examples have been applied to a host of peptides as inhibitors toward relevant diseases including cancer, viral and bacterial infection. In the most recent decades, hydrocarbon bridges to "staple" peptides across side chains or hydrogen bond surrogates in the backbone of peptides have been effective in producing biologically functional, helical peptidomimetics with non-natural elements, increased protease resistance and potency in vitro and in vivo. Modern methods expand and elaborate these, with applications of functional peptides from both synthetic and recombinant origins. Overall, efforts persist using these strategies to create peptides with great biological potential and a better understanding of the control of helical structure in protein folding.

Genome-wide analysis of LXXLL-mediated DAX1/SHP-nuclear receptor interaction network and rational design of stapled LXXLL-based peptides to target the specific network profile.

The atypical orphan receptors DAX1 and SHP constitute the NR0B subgroup of human nuclear receptor (hNR) family; they play key roles in metabolism, reproduction, nutrition and steroidogenesis, and are involved in the pathogenesis of a variety of diseases such as cancer and adrenal hypoplasia. The two receptors lack the classical DNA-binding domain and act as the corepressors of other hNRs. The DAX1 and SHP contains three and two conserved LXXLL motifs, respectively, which can be recognized and bound by the activation function-2 (AF-2) domain of hNR proteins in agonist conformation. Here, we attempt to explore the systematic interaction profile between the five DAX1/SHP LXXLL motifs and all the 48 hNR AF-2 domains found in the human genome, to analyze the binding affinity and specificity of these motifs towards the complete domain array, and to design LXXLL-based, hydrocarbon-stapled peptides that can target the specific interaction profile for each motif. A weighted source-target network from motifs to domains is created based on the modeled domain-motif complex structures and calculated binding potencies, from which the specific interaction profile of each motif against the whole hNR array is depicted and clustered to measure the binding similarity and relationship among these motifs. Dynamics simulations reveal that the LXXLL-based peptides are highly flexible in free unbound state, thus unfavorable to be recognized and bound by AF-2 domains. Hydrocarbon-stapling technique is employed to help the constraint of these unstructured peptides to active helical conformation, thus largely improving their binding affinity to the hNR array. The hydrocarbon bridge is designed to point out of the domain's active pocket, which would not disrupt the direct interaction between the domain and peptide. Energetic decomposition imparts that the stapling has only a very modest influence on the interaction enthalpy and desolvation effect of domain-peptide binding, but can substantially reduce entropy penalty upon the binding. For a peptide ligand, the entropic reduction can be roughly regarded as a constant, which only improves (absolute) peptide binding affinity towards the whole domain array, but does not alter (relative) peptide binding specificity over different domains in the array. Overall, the stapled peptides can be considered as potent competitors to selectively target the specific interaction networks mediated by their parent LXXLL motifs in DAX1 and SHP proteins.

Grafting, Stripping and Stapling of Helical Peptides from the Dimerization Interface of ONFH-Related Bone Morphogenetic Protein-2.

Transforming growth factor-β/bone morphogenetic protein (TGF-β/BMP) signaling plays a fundamental role in embryonic skeletal development and postnatal bone homeostasis. The signaling pivot protein BMP-2 belongs to the TGF-β superfamily and has been implicated in the pathogenesis of osteonecrosis of femoral head (ONFH). The biologically functional BMP-2 is a homodimer that has two tightly packed cores at its dimerization interface; each core is defined by the intermolecular interaction between a helical arm from one monomer and a hydrophobic pocket from another monomer. Inhibition and disruption of BMP-2 dimerization have been recognized as an attractive therapeutic strategy against ONFH. Here, we investigate the self-binding behavior of helical arm-derived peptides to the BMP-2 dimerization interface. The native BMP-2 helical arm and its several grafted versions from BMP-4, BMP-6 and BMP-7 are stripped from the intact dimerization interface to generate a number of isolated helical peptides. Computational simulations demonstrate that the stripping does not substantially influence the direct intermolecular interaction between BMP-2 monomer and these helical peptides or desolvation effect upon the interaction. However, the C-terminus of stripped peptides is found to have an intrinsic disorder and large flexibility in the isolated state, which would impair the rebinding of stripped peptides to BMP-2. Next, we rationally design a hydrocarbon bridge across the C-terminal residues 65 and 69 of helical peptides, which can effectively constrain peptide conformational flexibility in the isolated state, thus considerably promoting the binding potency of stripped helical peptides. Circular dichroism (CD) spectroscopy reveals that the peptide helicity increases from 51.8 to 67.9% upon hydrocarbon stapling. Fluorescence polarization assays substantiate that, as designed, the stapling can convert these helical peptides from weak binders to moderate or good binders of BMP-2 protein; their Kd values are improved by up to ~ fourfold.

Improving the rectifying performance of the pyrene-benzene system by optimizing its hydrocarbon bridge: A first-principles investigation

We report a computational study on enhancing the rectification ratio (RR) of the pyrene-benzene junction by modifying the structure of its acyclic aliphatic hydrocarbon bridge. The RR values for a series of pyrene-benzene systems with different types of bridges are determined. Notably, the maximum RR of the pyrene-(CH)3-(CH2)3-(CH)3-benzene system is 93.8, and the same hydrocarbon bridge increases the RR of the organic photovoltaic materials pyrene-DMA (N,N-dimethylaniline) and pyrene-DCNB (p-dicyanobenzene) by 10 times and limits reverse current during photo-induced electron transfer. These findings are particularly important for the design of molecular devices where both a high RR and conductivity are desirable. Moreover, they provide new insight into phenomena that indirectly affects the photoelectric conversion efficiency viz. enhancing the RR of the materials.

Some Pequliarities of Complex Formation of Tantalum Pentafluoride with Ph2P(O)(CH2)2C(O)NМе2: Stereochemistry of Hydrolysis Products

The compositions and structures of the products of the reaction of TaF5 with Ph2P(O)(CH2)2C(O)NМе2 (L) in СН3СN and СН2Сl2 are studied by the 19F and 31Р NMR methods. As the hydrocarbon bridge between the Р=О and С=О donor groups in carbamoylphosphine oxides elongates from –СН2– to (–СН2–)2, the chelation ability of the ligand is retained and the composition of the complexes formed in a solution is determined by the ratio of components. The compositions and structures of the hydrolysis products are studied. Distinctions in the coordination behavior of the considered ligand during complex formation with tantalum pentafluoride and titanium tetrafluoride are studied.

Targeting oncogenic transcriptional corepressor Nac1 POZ domain with conformationally constrained peptides by cyclization and stapling

The oncogenic transcriptional corepressor Nac1 contains a conserved POZ protein–protein interaction module that mediates homodimerization or heterodimerization with itself or other POZ proteins. The dimerization has been recognized as an attractive target for cancer therapy. Here, we attempted to (i) discover those potential binding partners of Nac1 in the human genome, (ii) derive key peptide segments from the complex interface of Nac1 with its putative partners, and (iii) improve the peptide binding affinity to Nac1 POZ domain. In the procedure, Nac1 POZ dimerization with 136 human POZ domains was modeled, simulated and analyzed at atomic level to elucidate structural basis, energetic property and dynamics behavior. Two hotspot regions, namely α1-helix and α2/α3-hairpin, at the dimerization interface were identified that are responsible for stabilizing the formed POZ–POZ dimer complexes. The α1-helix and α2/α3-hairpin were stripped from the interface to derive their respective isolated SIP peptides, which, however, exhibited a large flexibility and intrinsic disorder in free state, and thus would incur a considerable penalty upon rebinding to Nac1 POZ domain. By carefully examining the natively folded structures of α1-helix and α2/α3-hairpin in protein context and their interaction modes with the domain, we rationally designed a hydrocarbon bridge and a disulfide bond separately for the two peptides in order to constrain their conformational flexibility in free state, thus largely minimizing the flexibility penalty. Consequently, three α1-helix peptides derived from Nac1, Miz1 and Slx4 were stapled by all-hydrocarbon bridge, while four α2/α3-hairpin peptides derived from Nac1, Bacd1, Klh28 and Mynn were cyclized by disulfide bond. Binding affinity analysis revealed that, as designed, these peptides were converted from non- or weak binders to moderate or good binders of Nac1 POZ domain upon the stapling and cyclization.

Hydrocarbon Stapled Antimicrobial Peptides

Antimicrobial peptides are promising candidates for anti-infective pharmaceuticals. Unfortunately, because of their low proteolytic and chemical stability, their usage is generally narrowed down to topical formulations. Until now, numerous approaches to increase peptide stability have been proposed. One of them, peptide hydrocarbon stapling, a modification based on stabilizing peptide secondary structure with a side-chain covalent hydrocarbon bridge, have been successfully applied to many peptides. Moreover, constraining secondary structure of peptides have also been proven to increase their biological activity. This review article describes studies on hydrocarbon stapled antimicrobial peptides with respect to improved drug-like properties.

Efficient synthesis of hydrocarbon-bridged diaminodiacids through nickel-catalyzed reductive cross-coupling

Solid-phase incorporation of pre-prepared diaminodiacids has been established as an efficient strategy for the chemical synthesis of peptide disulfide bond mimics. Hydrocarbon-bridged diaminodiacids represent one important category of diaminodiacids but they remain difficult to synthesize. In the present work, we reported the use of newly-developed nickel catalyzed reductive cross-coupling reaction to efficiently synthesize diaminodiacids with hydrocarbon bridges. Through optimization of the reaction conditions, the yield of the hydrocarbon bridge formation reached about 50%, even when the reaction was scaled up to the gram level. Subsequently, using our recently developed Dmab/ivDde protecting group system, we obtained a new hydrocarbon-bridged diaminodiacid that are suitable for metal-free deprotection conditions. We demonstrated the utility of this Dmab/ivDde protected hydrocarbon-bridged diaminodiacid in the synthesis of a disulfide surrogate of oxytocin.

Synthesis and activity of new triphenylphosphonium derivatives of betulin and betulinic acid against Schistosoma mansoni in vitro and in vivo

We studied the antischistosomal activity of betulin, betulinic acid and its 9 triphenylphosphonium derivatives characterized by a covalently linkage of the hydrophobic fragment of triterpenoid at C(2)- or C(30)-position with the triphenylphosphonium moiety via a hydrocarbon bridge. The triphenylphosphonium salts showed in vitro antischistosomal activity against newly transformed schistosomula (NTS) and adult worms of Schistosoma mansoni at low micromolar concentrations. In contrast betulin and betulinic acid were inactive against NTS and adult S. mansoni. Of the 9 triphenylphosphonium derivatives tested, the allyl salts 10 (IC50 of 0.76μg/mL) and 11 (IC50 of 0.64μg/mL) demonstrated the highest antischistosomal activity against adult S. mansoni. Low worm burden reductions of 22% were observed in vivo for these two compounds. In conclusion, triphenylphosphonium derivatives were obtained from available natural betulin by simple transformations, rendering it practical and useful for large scale application. However, further structural modifications are necessary to translate the promising antischistosomal in vitro activities into in vivo.

Characterization of novel store-operated calcium entry effectors

2-Aminoethyl diphenylborinate (2-APB) is a well-known effector of the store-operated Ca2+ entry of several cell types such as immune cells, platelets and smooth muscle cells. 2-APB has a dual effect: potentiation at 1–5μM and inhibition at >30μM. Unfortunately, it is also able to modify the activity of other Ca2+ transporters and, thus, cannot be used as a therapeutic tool to control the leukocyte activity in diseases like inflammation. Previously, we have shown that SOCE potentiation by 2-APB depends on the presence of the central boron-oxygen core (BOC) and that the phenyl groups determine the sensitivity of the molecule to inhibit and/or potentiate the SOCE.We hypothesized that by modifying the two phenyl groups of 2-APB, we could identify more efficient and specific analogues. In fact, the addition of methoxyl groups to one phenyl group greatly decreased the potentiation ability without any significant effect on the inhibition. Surprisingly, when the free rotation of the two phenyl groups was blocked by a new hydrocarbon bridge, the BOC was no longer able to potentiate. Furthermore, larger aryl groups than phenyl also impaired the activity of the BOC. Thus, the potentiation site in the Ca2+ channel is not accessible by the BOC when the lateral groups are too large or unable to freely rotate. However, these molecules are potent inhibitors of store-operated calcium entry with affinities below 1μM, and they can block the activation of the Jurkat T cells.Thus, it is possible to characterize 2-APB analogues with different properties that could be the first step in the discovery of new immunomodulators. This article is part of a special issue entitled “Calcium Signaling in Health and Disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.

ChemInform Abstract: A Role for Ring‐Closing Metathesis in Medicinal Chemistry: Mimicking Secondary Architectures in Bioactive Peptides

AbstractReview: 141 refs.

Electronic Communication through Unsaturated Hydrocarbon Bridges in Homobimetallic Organometallic Complexes

Electronic Communication through Unsaturated Hydrocarbon Bridges in Homobimetallic Organometallic Complexes

Bridged β3-Peptide Inhibitors of p53-hDM2 Complexation: Correlation between Affinity and Cell Permeability

Beta-peptides possess several features that are desirable in peptidomimetics; they are easily synthesized, fold into stable secondary structures in physiologic buffers, and resist proteolysis. They can also bind to a diverse array of proteins to inhibit their interactions with alpha-helical ligands. beta-peptides are usually not cell-permeable, however, and this feature limits their utility as research tools and potential therapeutics. Appending an Arg(8) sequence to a beta-peptide improves uptake but adds considerable mass. We previously reported that embedding a small cationic patch within a PPII, alpha-, or beta-peptide helix improves uptake without the addition of significant mass. In another mass-neutral strategy, Verdine, Walensky, and others have reported that insertion of a hydrocarbon bridge between the i and i + 4 positions of an alpha-helix also increases cell uptake. Here we describe a series of beta-peptides containing diether and hydrocarbon bridges and compare them on the basis of cell uptake and localization, affinities for hDM2, and 14-helix structure. Our results highlight the relative merits of the cationic-patch and hydrophobic-bridge strategies for improving beta-peptide uptake and identify a surprising correlation between uptake efficiency and hDM2 affinity.

A role for ring-closing metathesis in medicinal chemistry: Mimicking secondary architectures in bioactive peptides

Synthetically versatile and easy to carry out, Ring-Closing Metathesis (RCM) constitutes an attractive chemical tool, easily amenable for multiple substrates in mild conditions. In medicinal chemistry, the use of RCM has been especially prolific during the last few years. An important application that has benefited from this reaction is the stabilization of spatial conformations in bioactive peptides, since their 3D arrangements play relevant roles in biomolecular recognition processes. RCM reaction is being widely used to introduce conformational constraints into small peptides, through the generation of cyclic structures from appropriate linear precursors. As an alternative to strategies like disulfide or lactam-bridged cyclizations, RCM shows the additional advantage of generating hydrocarbon bridges, less prone to metabolic degradation, and metabolically more stable, which could benefit their pharmacokinetic properties. Particularly remarkable is the application of RCM to the preparation of small peptide modulators able to mimic epitopes identified as hotspots within the surface contact areas in protein-protein interactions (PPIs). This review deals with the replacement of S-S and thioether linkages of cyclic peptides by C-C-bridges and with the stabilization of peptide secondary architectures (α-helix, β-hairpins, β-turns) through RCM, as a useful strategy for the modulation of therapeutically relevant signaling pathways.

Clicking onto Nanofibers

CHEMISTRY Vertically aligned carbon nanofibers—stacked “cups” of grapheme—are of interest for electrochemistry because they expose a high fraction of edge sites with much faster electron transfer rates than the basal plane sites that predominate on carbon nanotubes. For applications such as sensing, it would be useful to attach redox-active groups to the surface of these materials. Landis and Hamers report that copper click chemistry can be used to attach groups such as ferrocene. The carbon nanofiber surfaces were functionalized with azide groups, and ethynyl-substituted ferrocenes were then covalently attached through the Cu(I)-catalyzed cyclization reaction. The attachment was quite stable—the redox couple could be cycled at least 1500 times. The rates through this pi-bonded bridge were similar to those for ferrocene groups attached through saturated alkyl linkages, suggesting that electron transfer occurs through the aqueous solvent rather than the hydrocarbon bridges. — PDS Chem. Mater. 21 , 724 (2009).