Hydrophobic Chains Research Articles

Porphyrin-Camptothecin (CPT) Grafted Polyoxazoline Amphiphiles for Tumor Photodynamic-Chemotherapy Combination Treatment.

Porphyrin-based photosensitizers are extensively utilized in the realm of photodynamic therapy, capitalizing on their advantageous optical, chemical, and electronic properties. Nonetheless, their application is often constrained by their pronounced hydrophobicity. Structures with a high load capacity and excellent biocompatibility are preferred options to circumvent this obstacle. Herein, we constructed a novel porphyrin-camptothecin (CPT) polymer, which is composed of amphiphilic oxazoline segments, and the drug monomers containing disulfide bonds are modified on the hydrophobic chain of polyoxazoline. The polyoxazoline-porphyrin-CPT (OPC) polymer can self-assemble into nanoparticles in the aqueous phase, possesses excellent stability, and generates abundant singlet oxygen (1O2) under laser irradiation. Additionally, the OPC nanoparticles exhibit satisfactory biocompatibility and high light toxicity against 4T1 cells. In the microenvironment of the tumor, drugs were released from the OPC nanoparticles owing to the high concentration of GSH, causing direct damage to the tumor cell, achieving the combination of photo-chemotherapy. The findings of this research indicate that polyoxazoline porphyrin demonstrates adaptability as a nanoplatform for cancer treatment.

Mannose/stearyl chloride doubly functionalized polyethylenimine as a nucleic acid vaccine carrier to promote macrophage uptake

Transmembrane transport remains a significant challenge for nucleic acid vaccine vectors. Promoting the ability of immune cells, such as macrophages, to capture foreign stimuli is also an effective approach to improving cross-presentation. In addition, polyethyleneimine (PEI) has gained attention in the field of nucleic acid vaccine carriers due to its excellent gene transfection efficiency and unique proton buffering effect. However, although high molecular weight PEI exhibits high efficiency, its high-density positive charges make it highly toxic, which limits its application. In this study, mannose/stearyl chloride functionalized polyethylenimine (SA-Man-PEI) was prepared by functionalizing PEI (molecular weight of 25 kDa) with mannose with immunomodulatory and phagocyte targeting effects, and an alkyl hydrophobic chain segment, which could easily promote cell uptake. Moreover, the functionalized-PEI retains a strong proton buffering effect, which helps the carrier escape from the lysosome. The particle sizes of the composite particles formed by SA-Man-PEI and ovalbumin (OVA) were below 200 nm, with good storage stability at both 4 °C and 37 °C. At a drug concentration of 2 μg/mL, the cell survival rate of functionalized-PEI was 19.2% higher than that of unfunctionalized PEI. In vitro macrophage endocytosis experiments showed that SA-Man-PEI could significantly enhance the macrophage uptake of composite particles, compared to unfunctionalized PEI or single-functionalized PEI. This study offers a new approach for developing PEI as a nucleic acid vaccine carrier, which could simultaneously enhance cell targeting and promote cell uptake.

Organic Materials with Ultrabright Phosphorescence at Room Temperature under Physiological Conditions for Bioimaging

AbstractIn contrast to the high efficiency of room temperature phosphorescence in crystal states, the generally utilized nanoparticles of organic materials in bioimaging demonstrated sharply decreased performance by orders of magnitude under physiological conditions, badly limiting the realization of their unique advantages. This case, especially for organic red/near‐infrared (NIR) phosphorescence materials, is not only the challenge present in reality but more importantly, for the theoretical problem of deeply understanding and avoiding the quenching effect by oxygen and water toward excited triplet states. Herein, thanks to the intelligent molecular design by the introduction of abundant hydrophobic chains and highly‐branched structures, bright and persistent red/NIR phosphorescence under physiological conditions has been realized, which demonstrated the shielding effect towards oxygen, and the strengthened intermolecular interactions to suppress the non‐radiative transitions. Accordingly, the record phosphorescence intensity of nanoparticles in bioimage, up to 8.21±0.36×108 p s−1 cm−2 sr−1, was achieved, to realize the clear phosphorescence imaging of liver and tumors in living mice, even lymph nodes in rabbit models with high SBRs. This work afforded an efficient way to achieve the bright red/NIR phosphorescence nanoparticles, guiding their further applications in biology and medicine.

Pillar[5]arene-based Polymer Network for Efficiently Removing Perfluorooctanoic Acid through Synergistic Binding Interactions.

Perfluorooctanoic acid (PFOA) is currently one of the most important chemicals posing environmental risks, and there is an urgent need to find methods to efficiently remove PFOA from environmental media. Here, two decaamino-pillar[5]arene-based fluorine-rich polymer networks, called FA2P-P and FA6P-P, were constructed using a convenient method. FA6P-P had an excellent ability to take up PFOA, and had a capacity of 1423 (mg PFOA) (g FA6P-P)-1, which is the second highest adsorption capacity reported for any PFOA sorbent. FA6P-P removed >99 % of the PFOA from a solution and decreased the PFOA concentration from 1000 μg L-1 in 5 min at an exceedingly low adsorbent loading of 0.7 mg L-1, giving a final PFOA concentration <4 ng L-1, which is lower than the most recent enforceable maximum concentration set by the United States Environmental Protection Agency. A high rate constant (kobs) of 55.8 g mg-1 h-1 was observed. Pillar[5]arene gives the material hydrophobic properties and also amino sites and hydrophobic chains, which are synergistic PFOA binding sites. The polymer was very stable and readily regenerated. The results indicated that pillar[5]arene-based porous organic polymer sorbents are excellent candidates for capturing PFOA.

The Effect on Poly-β-hydroxybutyrate Production the Presence of Different Carbohydrate Sources in Bacillus ceresus and Cupriavidus necator

Polyhydroxybutyrates (PHB) are granular polyesters synthesized by many bacteria as a carbon and energy source in environments where substances such as nitrogen, oxygen, carbon, and phosphorus are limited. Polyhydroxybutyrates is biodegradable, consisting of hydrophobic long chains, and is non-toxic. It is classified as one of the basic polymers of polyhydroxyalkanoates. In this study, the Polyhydroxybutyrates production of Bacillus cereus (ATCC 10876) and Cupriavidus necator (formerly Ralstonia eutropha ATCC17699) in the presence of different minimal carbon sources was investigated under static and shaking (150 rpm) states. According to the results of the research, the highest PHB production was observed in Bacillus cereus PBS + 1% xylose medium (7.395 µg/ml) in static conditions; Cupriavidus necator exhibited the highest production of polyhydroxybutyrates under shaking conditions in PBS + 1% fructose medium (9.626 µg/ml). The lowest polyhydroxybutyrates production was observed in Cupriavidus necator in PBS + 1% maltose medium (0.027 µg/ml) under static conditions; however, under shaking conditions, it was carried out in PBS + 1% dextrose medium (0.122 µg/ml). Considering these results, it is evident that there is an increase in the production of polyhydroxybutyrates by microorganisms as the shaking speed.

Insight into the Antibacterial Activities of Pyridinium-Based Cationic Pillar[5]arene with Controllable Hydrophobic Chain Lengths against Staphylococcus aureus.

The increasing number of infections caused by pathogenic bacteria has severely affected human society. More and more deaths were originated from Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) infection each year. The potential and excellent bacteriostatic activity and resistance to biofilm formation of pillar[5]arene with different functional groups attract important attention to further study the relationship between antimicrobial activity and cytotoxicity by varying the length of the hydrophobic chain, the number of positive charges, and the hydrophobic/hydrophilic balance of the molecule. In this work, four pyridinium-based cationic pillar[5]arene (PPs) with linear aliphatic chains of different lengths were synthesized. After systematic characterization, their inhibition activities against S. aureus were investigated. It revealed that PP6 (six methylenes in each linker) exhibited excellent inhibition activity against S. aureus (ATCC 6538) with a minimum inhibitory concentration (MIC) of 3.91 μg/mL and a minimum bactericidal concentration (MBC) of 62.50 μg/mL. As expected, PP6 exhibited the strongest antibiofilm ability and negligible antimicrobial resistance even after the 20th passage. A study of the action mechanism of selected PPs on the bacterial membrane depolarization and permeability by transmission electron microscopy (TEM) disclosed that the cationic pyridine groups of PPs inserted into the negatively charged bacterial membranes, thereby leading to membranolysis, cytoplasmic content leakage, and cell death. Importantly, PPs all showed very low toxicity to mammalian cells (L929 and HBZY-1), which provided a significant reference for the construction of hypotoxic antibacterial biomaterials for multiple drug-resistant bacteria based on pyridinium-grafted cationic macrocycles with controllable hydrophobic chain lengths.

Searching for the role of membrane lipids in the mechanism of antibacterial effect of hinokitiol

The aim of this work was to investigate the effect of monoterpenoid hinokitiol (β-thujaplicin) on the monolayers and bilayers composed of lipids typical for bacteria membranes and gain insight into the potential role of the lipids in antibacterial activity and selectivity of this compound. To explore this issue, the in vitro studies were performed on different bacterial strains to verify antibacterial potency of hinokitiol. Then, the experiments on E. coli and S. aureus bacteria membrane models (i.e. model multicomponent monolayers and bilayers) were done. Finally, the effect of hinokitiol on one component lipid monolayers was investigated. The lipids used in the experiments included Phosphatidylethanolamines (PEs), Phosphatidylglycerols (PGs) and Cardiolipins differing in the structure of the polar head and/or the hydrophobic chains. This choice allowed the analysis of correlations between the lipid structure and the effect of hinokitiol.In vitro tests confirmed the antimicrobial activity of hinokitiol against most of the strains tested. In addition, the in vitro tests showed that E. coli bacteria were more sensitive to hinokitiol than S. aureus bacteria. Interestingly, the studies on model systems evidenced that hinokitiol molecules are of stronger effect on E.coli film and they are able to insert into these systems even at membrane-related surface pressures. Moreover, the structure of the lipid and its content in the model system correlated with the effect exerted by hinokitiol on the monolayer properties. It was found that hinokitiol differs in the affinity to particular lipids and additionally hinokitiol/lipid interactions may occur according to different mechanisms. Namely, depending on the lipid structure, hinokitiol may incorporate into the lipid film (Cardiolipins and PEs) or interact preferentially with the lipid polar head (PGs) and form hydrogen bonds. The effect of hinokitiol on the lipids was determined by the charge and size of the polar head as well as by the spatial size of the lipid molecule. Moreover, comparing the lipids of the same polar heads, hinokitiol caused stronger expansion of the film formed from the lipid having unsaturated chains. The results obtained may explain the difference in the effect of hinokitiol on particular bacterial strains. In conclusions, it can be suggested that the lipids should be considered as the bacteria membrane structural elements of a possible role in the mechanism of action of hinokitiol.

β-Cyclodextrin Derivatives Bind Aromatic Side Chains of the Cyclic Peptide Lanreotide

Cyclodextrin complexation has a potential to modulate the physicochemical properties of peptide drugs. The ability of peptides to form an inclusion complex can be influenced by factors such as size, amino acid sequence of peptide and the size and charge of the cyclodextrin cavity. In this study, the inclusion complexes of cyclic peptide drug lanreotide acetate with two common β-cyclodextrin derivatives, Sulfobutyl ether β-CD (SBEβ-CD) and hydroxypropyl β-CD (HPβ-CD) were investigated. NMR spectroscopy was used to examine the interaction between β-cyclodextrin derivatives and specific residues of lanreotide. It was observed that the hydrophobic side chain of aromatic residues in the lanreotide sequence can be fit into the cavity of both β-cyclodextrin derivatives. Additionally, NMR revealed a lower diffusion coefficient and higher hydrodynamic radius of complex, indicative of binding to the cavities. Each aromatic residue was individually studied by substituting alanine in lanreotide to measure its association binding with both β-cyclodextrin derivatives. The alanine-substitute study indicated a stronger binding of SBEβ-CD to Lanreotide compared to HPβ-CD. Docking studies suggested that the 1:1 inclusion complex is more favorable than higher order complexes due to the steric hindrance and size considerations. The docking analysis indicated the stable conformation of all three aromatic side chains with both β-cyclodextrin derivatives, SBEβ-CDand HPβ-CD.

A simple two-step reaction for synthesizing demulsifiers for a high salt crude oil emulsion

In this paper, two demulsifiers (PDA-L and GDA-L) were synthesized by grafting lauric acid on polyethylene glycol diglycidyl ether or glycerol triglycidyl ether. The structure of PDA-L and GDA-L were analyzed by FTIR and 1HNMR, and the demulsification performance in water-in-oil emulsion was detailly evaluated by the bottle test. The results showed that PDA-L exhibited higher demulsification efficiency (DE) compared to GDA-L, attributed to its more appropriate amphiphilic characteristics. Judging by the results, when the dosage of PDA-L was 500 mg/L, the DE could achieve 100 % within 4 h at a temperature of 50 °C, and it also had excellent demulsification performance in a wide pH range (4–10) and high salinity. The competitive adsorption behavior of asphaltenes and PDA-L at the oil–water interface was studied by interfacial tension and three-phase contact angle. Moreover, the effect of PDA-L on the interfacial film strength was studied by coalescence time of droplets and viscoelastic modulus. Based on previous tests, a possible demulsification mechanism was proposed. PDA-L features a hydrophilic core and two extended hydrophobic alkyl chains, allowing it to readily move to the oil–water interface. This process facilitates the replacement of asphaltene and the formation of an unstable composite film, thereby promoting demulsification.

Tunable macroscopic self-healing of supramolecular gel through host–guest inclusion

Supramolecular gels (SGs) consisted of noncovalent cross-linking network structures are fascinating due to their efficient energy dissipation and reversible self-healing properties. However, it is unknown how the noncovalent interactions alter the macroscopic self-healing and mechanical properties of SGs. Herein, the peculiar nature of SGs manufactured by combining covalent and noncovalent (host–guest inclusion of β-cyclodextrin and C16 hydrophobic chain) cross-linking structures was studied and compared with covalent cross-linking preformed particle gels. The macroscopic self-healing behaviors, rheology, mechanical tensile properties, as well as the tunable mechanisms of self-healing were explored by visual inspection, rheological, and atomic force microscopy probing methods. The results show that the SGs exhibit excellent self-healing efficiency and mechanical strength after interfacial cutting. Moreover, the SGs exhibited excellent mechanical tensile properties, including loading–unloading, successive loading–unloading, and recovery loading–unloading tensile performances. Notably, the macroscopic self-healing of SGs has good tunability by changing the covalent and noncovalent crosslinker contents and salt contents. This peculiar phenomenon is attributed to certain host–guest inclusion forces (4.7 and 0.3 nN) between different SGs under the distilled and high-salinity water conditions, respectively. This study is beneficial for the development of stimuli–response supramolecular gels in different applications, such as oil recovery in fractured reservoirs.

Van der Waals interactions between nonpolar alkyl chains and polar oxide surfaces prevent catalyst deactivation in aldehyde gas sensing

Catalysis-based electrical sensing of volatile organic compounds on metal oxide surfaces is a powerful method for molecular discrimination. However, catalyst deactivation caused by the poisoning of catalytic sites by analytes and/or catalyzed products remains a challenge. This study highlights the underestimated role of van der Waals interactions between hydrophobic aliphatic alkyl chains and hydrophilic ZnO surfaces in mitigating catalyst deactivation during aliphatic aldehyde sensing. By immobilizing octadecylphosphonic acid (ODPA) on ZnO nanowire sensors, recovery times for nonanal detection are significantly reduced without compromising sensitivity. Temperature-programmed measurements demonstrate a reduction in desorption temperature of carboxylates on ODPA-modified ZnO to below 150 °C, whereas carboxylates on bare ZnO remain above 300 °C, indicating a significant decrease in catalyst deactivation. Density functional theory calculations reveal that accumulated van der Waals interactions between alkyl chains and ZnO surfaces significantly contributed to adsorption molecular kinetics. IR spectroscopy using deuterated self-assembled monolayers (SAMs) reveals conformational changes of alkyl chains within the SAMs caused by aldehyde adsorption, supporting the suggested adsorption kinetics. A model is proposed based on the dynamic surface-covering by alkyl chains destabilizes catalytically oxidized carboxylic acids.

Exploring C2 and N6 Substituent Effects on Truncated 4'-Thioadenosine Derivatives as Dual A2A and A3 Adenosine Receptor Ligands.

Based on high binding affinity of truncated 2-hexynyl-4'-thioadenosine (3a) at both A2A adenosine receptor (AR) and A3 AR, we explored structure-activity relationship (SAR) of the C2-substitution by altering chain length of the 2-hexynyl moiety, thereby evaluating the hydrophobic pocket size. A series of truncated N6-substituted 4'-thioadenosine derivatives with C2-alkynyl substitution were successfully synthesized from D-mannose, using a palladium-catalyzed Sonogashira coupling reaction as the key step, whose structures were confirmed by the X-ray crystal structure of 4h. As the size of the alkynyl group at the C2-position increased, the binding affinity improved; however, when the substituted group was larger than hexynyl, the binding affinity decreased. The introduction of a bulky hydrophobic group such as 3-halobenzyl group at the free N6-amino group decreased the binding affinity at hA2AAR. These results confirm our previous findings that a free amino group at N6-position and longer hydrophobic chain at C2-position are essential for hA2A AR binding affinity. The introduction of a bulky hydrophobic group at free N6-amino group maintained the binding affinity at hA3 AR. The binding mode of truncated 2-substituted-4'-thioadenosine derivatives to hA2A and hA3 AR were predicted by a molecular docking study.

Hydrophobically Modified Polyacrylamide Incorporating Both Hydrophilic and Hydrophobic Units: Enhanced Printability and Stability in Aqueous Ink.

For this research, three hydrophobically modified polyacrylamides, HPAAB, HPAAF, and HPAAS, with multiple hydrophobic monomers were designed, synthesized, and used as thickeners in aqueous ink for digital ink-jet printing. The structures were characterized by Fourier transform infrared (FTIR) analysis and nuclear magnetic resonance (NMR) spectroscopy. The viscosity-average molecular weight was determined by intrinsic viscosity determination and was adjusted according to hydrophobic content. The critical association concentration (CAC) of polymers was measured simultaneously using the apparent viscosity method and the fluorescence spectrum. The formation of a network structure and the mechanism of hydrophobic association are visualized dynamically with a scanning electron microscope (SEM) at different concentrations. Under the same conditions, HPAAB exhibited excellent thickening ability across different pH levels, temperatures, and shear rates, which is caused by the longer hydrophobic side chain and the stronger hydrophobic effect of the behenyl polyoxyethylene ether methacrylate (BEM) group. Furthermore, an aqueous ink using HPAAB as a thickener displays significant printability and stability, functioning much better than a corresponding aqueous ink that uses a commercial thickener. This is the first example of a hydrophobic associating polyacrylamide, incorporating both hydrophilic and hydrophobic units within a single hydrophobic chain, thereby serving as an efficient thickener for aqueous ink.

Molecular and energetic analysis of the interaction and specificity of Maximin 3 with lipid membranes: In vitro and in silico assessments.

In this study, the interaction of antimicrobial peptide Maximin 3 (Max3) with three different lipid bilayer models was investigated to gain insight into its mechanism of action and membrane specificity. Bilayer perturbation assays using liposome calcein leakage dose-response curves revealed that Max3 is a selective membrane-active peptide. Dynamic light scattering recordings suggest that the peptide incorporates into the liposomal structure without producing a detergent effect. Langmuir monolayer compression assays confirmed the membrane inserting capacity of the peptide. Attenuated total reflection-Fourier transform infrared spectroscopy showed that the fingerprint signals of lipid phospholipid hydrophilic head groups and hydrophobic acyl chains are altered due to Max3-membrane interaction. On the other hand, all-atom molecular dynamics simulations (MDS) of the initial interaction with the membrane surface corroborated peptide-membrane selectivity. Peptide transmembrane MDS shed light on how the peptide differentially modifies lipid bilayer properties. Molecular mechanics Poisson-Boltzmann surface area calculations revealed a specific electrostatic interaction fingerprint of the peptide for each membrane model with which they were tested. The data generated from the in silico approach could account for some of the differences observed experimentally in the activity and selectivity of Max3.

Stimuli-Responsive Vesicles and Hydrogels Formed by a Single-Tailed Dynamic Covalent Surfactant in Aqueous Solutions.

Controlling the hierarchical self-assembly of surfactants in aqueous solutions has drawn much attention due to their broad range of applications, from targeted drug release, preparation of smart material, to biocatalysis. However, the synthetic procedures for surfactants with stimuli-responsive hydrophobic chains are complicated, which restricts the development of surfactants. Herein, a novel single-tailed responsive surfactant, 1-methyl-3-(2-(4-((tetradecylimino) methyl) phenoxy) ethyl)-3-imidazolium bromides (C14PMimBr), was facilely fabricated in situ by simply mixing an aldehyde-functionalized imidazolium cation (3-(2-(4-formylphenoxy) ethyl)-1-methyl imidazolium bromide, BAMimBr) and aliphatic amine (tetradecylamine, TDA) through dynamic imine bonding. With increasing concentration, micelles, vesicles, and hydrogels were spontaneously formed by the hierarchical self-assembly of C14PMimBr in aqueous solutions without any additives. The morphologies of vesicles and hydrogels were characterized by cryogenic transmission electron microscopy and scanning electron microscopy. The mechanical properties and microstructure information of hydrogels were demonstrated by rheological measurement, X-ray diffraction, and density functional theory calculation. In addition, the vesicles could be disassembled and reassembled with the breakage and reformation of imine bonds by adding acid/bubbling CO2 and adding alkali. This work provides a simple method for constructing stimuli-responsive surfactant systems and shows great potential application in targeted drug release, drug delivery, and intelligent materials.

Distinct Solubilization Mechanisms of Medroxyprogesterone in Gemini Surfactant Micelles: A Comparative Study with Progesterone

The solubilization behavior of medroxyprogesterone (MP) within gemini surfactant micelles (14-6-14,2Br−) was investigated and compared with that of progesterone to uncover distinct solubilization mechanisms. We employed 1H-NMR and 2D ROESY spectroscopy to elucidate the spatial positioning of MP within the micelle, revealing that MP integrates more deeply into the micellar core. This behavior is linked to the unique structural features of MP, particularly its 17β-acetyl group, which promotes enhanced interactions with the hydrophobic regions of the micelle, while the 6α-methyl group interacts with the hydrophilic regions of the micelle. The 2D ROESY correlations specifically highlighted interactions between the hydrophobic chains of the surfactant and two protons of MP, H22 and H19. Complementary machine learning and electron density analyses supported these spectroscopic findings, underscoring the pivotal role of the molecular characteristics of MP in its solubilization behavior. These insights into the solubilization dynamics of MP not only advance our understanding of hydrophobic compound incorporation in gemini surfactant micelles but also indicate the potential of 14-6-14,2Br− micelles for diverse drug delivery applications.

Decisive Effect of Hydrophobic Rigid-Flexible Coupled Side Chains of Polycarbazoles on the Performance of Anion Exchange Membranes for Fuel Cells

Decisive Effect of Hydrophobic Rigid-Flexible Coupled Side Chains of Polycarbazoles on the Performance of Anion Exchange Membranes for Fuel Cells

Enhancement of Moisture‐Resistant Performance of Epoxy Resins via Introduction of Hydrophobic and Flexible Chains

AbstractThe introduction of long and flexible polyether chains in epoxy resins is an effective method to improve their toughness. However, using the hydrophilicity/hydrophobicity of polyether chains to tune their moisture resistance has been overlooked currently. In this work, two types of polyether‐based diglycidyl ethers with hydrophilic poly(oxyethylene) (DGEPOE) and relatively hydrophobic poly(oxybutylene) segments (DGEPOB) are synthesized and then binary‐cured with commercial diglycidyl ether of bisphenol A (DGEBA), respectively, yielding the corresponding DGEPOE:DGEBA‐m:ns and DGEPOB:DGEBA‐m:ns based on various ratios. For comparison, pure DGEPOEr, DGEPOBr, and DGEBAr resins are also prepared. Results show that the equilibrium water uptake of DGEPOB:DGEBA‐m:ns is at least less than one‐fifth of that of DGEPOE:DGEBA‐m:ns; meanwhile, the diffusion coefficients of water molecules in DGEPOB:DGEBA‐m:ns are also 1–2 orders of magnitude lower than those in DGEPOE:DGEBA‐m:ns, demonstrating that the incorporation of hydrophobic POB chains can significantly reduce the hygroscopicity of resins. Moreover, DGEPOB:DGEBA‐m:ns not only exhibit superior flexibility and ductility relative to pure DGEBAr, but display exceptional strength and toughness in comparison with pure DGEPOBr. These findings suggest that tuning the hydrophilicity/hydrophobicity of building units of epoxy monomers offers a promising strategy for developing high‐performance epoxy materials, especially suitable for humid environments.

Behavior of Trapped Molecules in Lantern-Like Carcerand Superphanes.

Superphanes are a group of organic molecules from the cyclophane family. They are characterized by the presence of two parallel benzene rings joined together by six bridges. If these bridges are sufficiently long, the superphane cavity can be large enough to trap small molecules or ions. Using ab initio (time scale of 80 ps) and classical (up to 200 ns) molecular dynamics (MD) methods, we study the behavior of five fundamental molecules (M = H2O, NH3, HF, HCN, MeOH) encapsulated inside the experimentally reported lantern-like superphane and its two derivatives featuring slightly modified side bridges. The main focus is studying the dynamics of hydrogen bonds between the trapped M molecule and the imino nitrogen atoms of the side chains of the host superphane. The length of the N···H hydrogen bond increases in the following order: HF < HCN < H2O < MeOH < NH3. The mobility of the trapped molecule and its preferred position inside the superphane cage depend not only on the type of this molecule but also largely on the in/out conformational arrangement of the imino nitrogens in the side chains of the superphane. Their inward-pointing positions allow the formation of strong N···H hydrogen bonds. For this reason, these nitrogens are the preferred sites of interaction. The mobility of the molecules and their residence times on each side of the superphane have been explained by referring to the symmetry and conformation of the given superphane cage. All force field MD simulations have shown that the encapsulated molecule remained inside the superphane cage for 200 ns without any escape event to the outside. Moreover, our simulations based on some endohedral complexes in the water box also showed no exchange event. Thus, the superphanes we study are true carcerand molecules. We attribute this property to the hydrophobic side chains and their pinwheel arrangement, which makes the side walls of the studied superphanes fairly impenetrable to small molecules.

The pivotal role of histidine 976 in human histone deacetylase 4 for enzyme function and ligand recognition

Human histone deacetylase 4 (HDAC4) belongs to class IIa of the zinc-dependent histone deacetylases. HDAC4 is an established target for various indication areas, in particular Huntington’s disease, heart failure and cancer. To reduce unwanted side effects, it is advantageous to develop isozyme-selective inhibitors, which poses a major challenge due to the highly conserved active centers of the HDAC family.According to current knowledge it is assumed that H976 in HDAC4wt occurs exclusively in the out-conformation and thus the selective foot pocket is constitutively open. In contrast, the side chain of the corresponding tyrosine in HDAC4H976Y adopts the in-conformation, and is thus able to stabilize the intermediate state of the deacetylation reaction and block access to the foot pocket.In this study, we provide evidence that a dynamic equilibrium exists between the in- and out-conformation in HDAC4wt. The binding of selective HDAC4 inhibitors that address the foot pocket can be enhanced in HDAC4 variants with mainly small, but also medium hydrophobic or polar side chains. We attribute this to the fact that these side chains are preferentially present in the out-conformation.Therefore, we propose HDAC4H976A and other HDAC4 variants as promising tools to find and enrich HDAC4-selective foot pocket binders in screening campaigns that might have been overlooked in conventional screens with HDAC4wt.