Side-chain Substitution Research Articles

Co‐Carbonization of Medium‐ and Low‐Temperature Coal Tar Pitch and Coal‐Based Hydrogenated Diesel Oil Prepare Mesophase Pitch for Needle Coke Precursor

Herein, a better mesophase pitch as precursor for the manufacturing of green needle coke is obtained by a new process, whereas the refined medium‐ and low‐temperature coal tar pitch (RCTP) is obtained by a solvent sedimentation method, and then, it is co‐carbonized with coal‐based hydrogenated diesel oil at 420 °C for 6 h. The mesophase pitch structure is characterized by a polarized light optical microscope, Fourier transform IR (FT‐IR) spectroscopy, and 1 H nuclear magnetic resonance (NMR). The results indicate that the aromatic hydrogen content of mesophase pitch gradually increases, as the carbonization temperature increases. Also, the mesophase pitch with aliphatic side chain substitution (CH3 and CH2) is obtained at 420 °C for 2 h, which is conducive for polyaromatic hydrocarbon to the orderly accumulation. It is also a basis for preparing better green needle coke. The polarized light analysis results propose that the mesophase with a wide‐area streamlined structure is obtained at a constant temperature of 420 °C for 6 h, whose temperature and soaking time are lower than that of the high‐temperature coal tar pitch and petroleum pitch for preparing the mesophase pitch. Also, the better direction and order fiber of green needle coke with 53 % fiber are acquired.

Carbon Materials Derived from an Array of Zeolitic-Imidazolate Frameworks and Their Applications in Capacitive Deionization

Capacitive deionization (CDI) represents one of the most thermodynamically efficient technologies for brackish water desalination, and its performance is highly dependent on the intrinsic properties of carbon materials. Ideally, CDI carbons should have high ion-accessible surface area, high porosity for ion mobility, great hydrophilic properties, excellent corrosion tolerance and good processability. Pyrolysis of precursory zeolitic-imidazolate frameworks (ZIFs) serves as a promising way to produce carbonaceous materials with great compositional and structural tunability.In this work, we systematically prepared an array of ZIFs (Zn(ligand)2) with different side-chain substitutions, which upon pyrolysis gave rise to carbon materials with variable elemental compositions, surface properties, wettability and graphitization levels; all are impacting the CDI performance. Zn(4abIm)2-C afforded the best salt adsorption capacity, while Zn(mIm)2-C showed the best overall salt adsorption capacity and rate; both exceeded the performance of the commercial carbon blacks.After careful correlation between the structures and the electrochemical results, it has been demonstrated that the CDI salt adsorption capacity increases with the carbon’s double layer capacitance. Additionally, graphitization level is significantly correlated with the CDI charge efficiency and energy consumption with more electronic conductive higher charge efficiency and lower energy consumption, which provides new insights to the field.

Design, Synthesis, and Antitumor Activity of Olmutinib Derivatives Containing Acrylamide Moiety.

Two series of olmutinib derivatives containing an acrylamide moiety were designed and synthesized, and their IC50 values against cancer cell lines (A549, H1975, NCI-H460, LO2, and MCF-7) were evaluated. Most of the compounds exhibited moderate cytotoxic activity against the five cancer cell lines. The most promising compound, H10, showed not only excellent activity against EGFR kinase but also positive biological activity against PI3K kinase. The structure–activity relationship (SAR) suggested that the introduction of dimethylamine scaffolds with smaller spatial structures was more favorable for antitumor activity. Additionally, the substitution of different acrylamide side chains had different effects on the activity of compounds. Generally, compounds H7 and H10 were confirmed as promising antitumor agents.

Improving the field-effect transistor performance of (E)-1,2-di(thiophen-2-yl)ethenyl-co-naphthalenyl-based polymers by introducing alkoxy sidechains

Three donor-donor type conjugated polymers (namely PTVTN1, PTVTN2 and PTVTN3) are designed and synthesized containing naphthalene unit with different sidechain substitutions. The introducing of alkoxy sidechains on the naphthalene unit could mitigate the polymer backbone twisting through S···O non-covalent interactions and therefore improve the charge carrier mobility. Besides, different sidechain positions also have a significant impact on the molecular orientation and charge carrier mobility. The best field-effect transistor (FET) mobility of 0.014 cm2/Vs is achieved based on PTVTN3 as-cast device, which is due to the favorable edge-on orientation, interdigitation and fine fiber network morphology. This work shows that how sidechains influence the polymer morphology and charge carrier mobility.

Preparation and characterization of the side-chain quaternized poly(phthalazinone ether ketone)s with phenyl groups for vanadium redox flow battery

A series of new side-chain substitution poly (phthalazinone ether ketone)s with benzyl chloride moieties (CMPPEK-P) were synthesized through the chloromethylation of poly (aryl ether ketone)s containing pendant phenyl groups (PPEK-P). The content of side-chain phenyl groups in the PPEK-P was controlled by the feed ratios of 4-(4-hydroxyphenyl)-2,3-phthalazin-1-ketone to 4-(3-phenyl-4-hydroxyphenyl)-2,3-phthalazin-1-ketone during polymerization process. The chemical structures of PPEK-P and CMPPEK-P were assessed by 1H NMR and FTIR spectroscopy. Based on the characterization results, a new anion exchanged membrane (QAPPEK-P) was prepared by amination reaction used for vanadium redox flow batteries. The ion-exchange capacity of QAPPEK-P membranes (0.21–0.88 mmol g−1) was related to the content of side-chain phenyl groups. The cell performance of QAPPEK-P membrane was increased with the increasing values of IEC. Compared with Nafion 115, QAPPEK-P-50 displayed higher voltage efficiency (82.8% vs. 76.9%) and energy efficiency (80.2% vs. 76.5%) at the current density of 140 mA/cm2. Furthermore, the efficiencies of QAPPEK-P-50 remained stable for 150 cycles and there was no obvious change in its structure.

New Anticancer Vinca Alkaloids in the Last Decade - A Mini-Review

The chemistry and pharmacology of the important Vinca alkaloids such as vinblastine and vincristine used in anticancer therapy are still investigated widely. Several new derivatives, e.g., vinflunine, vinorelbine, and vindesine, have been synthesized and become successful medicines in anti-cancer therapy. In 2012, we published a paper that reviewed the Vinca derivatives. Nevertheless, the interest in the preparation of new modified structures is not decreasing either in recent years. In this review, the vinblastine-type molecules with several substituents, e.g., amide, nitrile, hydrazide, substituted side chains, etc. in different positions of catharanthine and/or vindoline cores are presented. An important part of the review is the derivatization of the monomer alkaloid vindoline, which possesses no antitumor effect. Additionally, new hybrid molecules of these alkaloids are also discussed in this mini-review.

Synthesis and Characterization of Urethane Side Chain Substituted Diketopyrrolopyrrole

The synthesis of Diketopyrrolopyrrole (DPP) having secondary interaction in the side chain explores its possibility to use in electronic and sensing applications. Herein we report easy method to engineer side chains of DPP. The hydrogen bonding is introduced on the side chain by substitution of urethane side chains on Diketopyrrolopyrrole (DPPurethane).The urethane side chain comprises a branched alkyl chain with good yields and purities. The DPPurethane characterized by NMR and IR, optical properties along with energy minimized structure were studied.

Degradation of imidazolium ionic liquids in a thermally activated persulfate system

Thermally activated persulfate (PS) oxidation, a clean source of sulfate radicals (SO4•–), has been used as a promising advanced oxidation method for the treatment of organic contaminants. In this study, the degradation of ionic liquids (ILs) by thermally activated PS was investigated with 1-alkyl-3-methylimidazolium bromides (C4mimBr) as a model compound. The effects of various factors including temperature, initial IL and PS concentrations, solution pH, alkyl chain length of imidazolium cation, and common water constituents such as humic acid (HA), HCO3-and Cl- were evaluated. Results showed that C4mimBr can be completely degraded in 2 h at 60 °C, indicating effective removal of C4mimBr by thermally activated PS oxidation. The oxidation followed a pseudo-first-order kinetics model, and the rate constant increased with increasing temperature, PS concentration and initial solution pH. Alkyl chain length had no effect on the degradation. HA and Cl- had negative effects on C4mimBr removal, while 5 mM HCO3- increased C4mimBr degradation. Multiple intermediate products were identified by HPLC-MS/MS and the degradation pathway and mechanism were proposed. The free radicals generated in the activated PS system (e.g., SO4•– and •OH) showed different effects on the degradation. SO4•– radicals select to attack the substituted side chain of ILs cation, producing more chance for •OH to attack the imidazolium core. Moreover, toxicity tests using bioluminescent bacteria Vibrio Qinghaiensis sp.-Q67 and nematode C. elegans demonstrated efficient detoxification of CnmimBr treatment. These findings may offer an environmentally friendly approach for ILs treatment in aqueous solution.

Feruloyl esterase (FAE-1) sourced from a termite hindgut and GH10 xylanases synergy improves degradation of arabinoxylan

Cereal feedstocks have high arabinoxylan content as their main hemicellulose, which is linked to lignin by hydroxycinnamic acids such as ferulic acid. The ferulic acid is linked to arabinoxylan by ester bonds, and generally, the high substitution of ferulic acid leads to a loss of activity of xylanases targeting the arabinoxylan. In the current study, a feruloyl esterase (FAE-1) from a termite hindgut bacteria was functionally characterised and used in synergy with xylanases during xylan hydrolysis. The FAE-1 displayed temperature and pH optima of 60 ℃ and 7.0, respectively. FAE-1 did not release reducing sugars from beechwood xylan (BWX), wheat arabinoxylan (WAX) and oat spelt xylan (OX), however, displayed high activity of 164.74 U/mg protein on p-nitrophenyl-acetate (pNPA). In contrast, the GH10 xylanases; Xyn10 and XT6, and a GH11 xylanase, Xyn2A, showed more than two-fold increased activity on xylan substrates with low sidechain substitutions; BWX and OX, compared to the highly branched substrate, WAX. Interestingly, the FAE-1 and GH10 xylanases (Xyn10D and XT6) displayed a degree of synergy (DS) that was higher than 1 in all enzyme loading combinations during WAX hydrolysis. The 75%XT6:25%FAE-1 synergistic enzyme combination increased the release of reducing sugars by 1.34-fold from WAX compared to the control, while 25%Xyn10D:75%FAE-1 synergistic combination released about 2.1-fold of reducing sugars from WAX compared to controls. These findings suggest that FAE-1 can be used in concert with xylanases, particularly those from GH10, to efficiently degrade arabinoxylans contained in cereal feedstocks for various industrial settings such as in animal feeds and baking.

Enhancement of air-stability, π-stacking ability, and charge transport properties of fluoroalkyl side chain engineered n-type naphthalene tetracarboxylic diimide compounds

In this study, the impact of fluoroalkyl side chain substitution on the air-stability, π-stacking ability, and charge transport properties of the versatile acceptor moiety naphthalene tetracarboxylic diimide (NDI) has been explored. A density functional theory (DFT) study has been carried out for a series of 24 compounds having different side chains (alkyl, fluoroalkyl) through the imide nitrogen position of NDI moiety. The fluoroalkyl side chain engineered NDI compounds have much deeper highest occupied molecular orbitals (HOMO) and lowest unoccupied molecular orbitals (LUMO) than those of their alkyl substituted compounds due to the electron withdrawing nature of fluoroalkyl groups. The higher electron affinity (EA > 2.8 eV) and low-lying LUMO levels (<−4.00 eV) for fluoroalkyl substituted NDIs reveal that they may exhibit better air-stability with superior n-type character. The computed optical absorption spectra (∼386 nm) for all the investigated NDIs using time-dependent DFT (TD-DFT) lie in the ultra-violet (UV) region of the solar spectrum. In addition, the low value of the LOLIPOP (Localized Orbital Locator Integrated Pi Over Plane) index for fluoroalkyl side chain comprising NDI compounds indicates better π–π stacking ability. This is also in good agreement for the predicted π–π stacking interaction obtained from a molecular electrostatic potential energy surface (ESP) study. The π–π stacking is thought to be of cofacial interaction for the fluoroalkyl substituted compounds and herringbone interaction for the alkyl substituted compounds. The calculated results shed light on why side chain engineering with fluoroalkyl groups can effectively lead to better air-stability, π-stacking ability and improved charge transport properties.

Structure–activity relationship of ipglycermide binding to phosphoglycerate mutases

Catalysis of human phosphoglycerate mutase is dependent on a 2,3-bisphosphoglycerate cofactor (dPGM), whereas the nonhomologous isozyme in many parasitic species is cofactor independent (iPGM). This mechanistic and phylogenetic diversity offers an opportunity for selective pharmacologic targeting of glycolysis in disease-causing organisms. We previously discovered ipglycermide, a potent inhibitor of iPGM, from a large combinatorial cyclic peptide library. To fully delineate the ipglycermide pharmacophore, herein we construct a detailed structure–activity relationship using 280 substituted ipglycermide analogs. Binding affinities of these analogs to immobilized Caenorhabditis elegans iPGM, measured as fold enrichment relative to the index residue by deep sequencing of an mRNA display library, illuminated the significance of each amino acid to the pharmacophore. Using cocrystal structures and binding kinetics, we show that the high affinity of ipglycermide for iPGM orthologs, from Brugia malayi, Onchocerca volvulus, Dirofilaria immitis, and Escherichia coli, is achieved by a codependence between (1) the off-rate mediated by the macrocycle Cys14 thiolate coordination to an active-site Zn2+ in the iPGM phosphatase domain and (2) shape complementarity surrounding the macrocyclic core at the phosphotransferase–phosphatase domain interface. Our results show that the high-affinity binding of ipglycermide to iPGMs freezes these structurally dynamic enzymes into an inactive, stable complex.

Imidazolium-based ionic liquids for asphaltene dispersion; experimental and computational studies

Heavy and bituminous crude oils containing asphaltene are expected to compensate for the decline of conventional oil production in the upcoming days. Asphaltene precipitation is detrimental to petroleum processing owing to blockage of the wellbores and formation of tough emulsions that diminishes the recovered oil amount. As a result, the petroleum industry resorts to asphaltene dispersants to overcome these challenges. In this regard, ionic liquids (ILs) can be utilized as a green chemistry alternative to the surfactants to prevent asphaltene aggregation in the petroleum feed stream. Ionic liquids are environmental, recyclable, and non-corrosive candidates, which destabilize or breakdown water in oil (W/O) or oil in water (O/W) emulsions through dispersing or replacing asphaltene molecules at the interface. Also, ionic liquids containing long alkyl chains can be effective asphaltene dispersants owing to the formation of hydrogen bonding and π-π∗ interactions with asphaltene aggregates. In this work, different ILs salts and their modified Lewis-acid structure were synthesized by mixing iron (III) chloride with different halogenated alkyl imidazolium salts with yield% of 73.56, 72.9, and 71.12% respectively. The thermogravimetric analysis indicates the thermal stability of the synthesized ILs to 463 °C. The critical micelle concentration (CMC) and interfacial tension (IFT) were investigated at simulated reservoir conditions of high-pressure high temperature (HPHT). ILs exhibited CMC values at 1000, 800, and 600 ppm, while IFT values lie in the range of 3–8 mN/m at 298 K. ILs efficiency as asphaltene dispersants were assessed experimentally through viscometric and spectroscopic methods using 1000 ppm of asphaltene extract. The viscometric method displays asphaltene onset precipitation at 65% n-heptane after the addition of [(-C4H9-IL) FeCl4−] dispersant, while spectroscopic method asphaltene onset precipitation at 55, 60 and 75% after the addition of [(-CH3-IL) FeCl4−], [(-C2H5-IL) FeCl4−] and [(-C4H9-IL) FeCl4−], respectively. Molecular dynamics (MD) simulation was carried out to investigate the compatibility of ionic liquids as a function of asphaltene and crude oil molecules. The asphaltene molecules modeled as a continental model involves a dominant polyaromatic nucleus linked to peripheral substituted side chains. The computational results are in great compliance with the experimental ones.

A new steric tetra-imidazole for facile synthesis of high loading atomically dispersed FeN4 electrocatalysts

Abstract Atomically dispersed FeN4 rich carbon-based electrocatalysts obtained by pyrolysis of Zn-based metal-organic frameworks (mainly Fe modified ZIF-8) exhibits remarkable catalytic performance for oxygen reduction reaction (ORR). However, the independence of each ZIF-8 particle with rhomb dodecahedral results in a physical stack and undesirable charge transfer path and subsequently induce the iron buried in the carbon matrix after the pyrolysis process, which further impedes the high loading of atomic iron (usually less than 1 wt%). Herein, we newly designed a novel steric tetra-imidazole structure to anchor iron in a cross way. This strategy achieves the synthesis of atomically dispersed FeN4 rich carbon-based electrocatalyst in one-step approach without any pretreatment and/or further acid leaching. Unlike the traditional imidazole in ZIF-8, the novel steric tetra-imidazole structure exhibits a benzene ring located in the center of each four imidazole groups acting as sharing side-chain substitution, which can control the distance of each metal rivet center and impede the aggregation of iron effectively. The obtained catalyst, named as TimB-Fe5-C, exhibits high atomic iron loading content up to 2.58 wt% and exhibits efficient ORR electrocatalytic performance in both alkaline and acid medium. Significantly, this new steric tetra-imidazole endows one-step facile synthesis of atomically dispersed electrocatalysts with high loading and to avoid unpredictable changes of structure brought by tedious pre-treatment as well as post-treatment.

The N-terminal length and side-chain composition of CXCL13 affect crystallization, structure and functional activity.

CXCL13 is the cognate chemokine agonist of CXCR5, a class A G-protein-coupled receptor (GPCR) that is essential for proper humoral immune responses. Using a `methionine scanning' mutagenesis method on the N-terminus of CXCL13, which is the chemokine signaling region, it was shown that minor length alterations and side-chain substitutions still result in CXCR5 activation. This observation indicates that the orthosteric pocket of CXCR5 can tolerate these changes without severely affecting the activity. The introduction of bulk on the ligand was well tolerated by the receptor, whereas a loss of contacts was less tolerated. Furthermore, two crystal structures of CXCL13 mutants were solved, both of which represent the first uncomplexed structures of the human protein. These structures were stabilized by unique interactions formed by the N-termini of the ligands, indicating that CXCL13 exhibits substantial N-terminal flexibility while the chemokine core domain remains largely unchanged. Additionally, it was observed that CXCL13 harbors a large degree of flexibility in the C-terminal extension of the ligand. Comparisons with other published structures of human and murine CXCL13 validate the relative rigidity of the core domain as well as the N- and C-terminal mobilities. Collectively, these mutants and their structures provide the field with additional insights into how CXCL13 interacts with CXCR5.

Alkyl chain engineering of non-fullerene small molecule acceptors for solution-processable organic solar cells

The impact of alkyl side chain substitutions of small molecule non-fullerene acceptors (NFAs) on their photovoltaic performance of bulk heterojunction (BHJ) organic solar cells (OSCs) has been studied. To further investigate the effects of side chains, in this work a series of NFAs based on a Y6 core derivatized with various alkyl groups of 6-phenylhexyl, 6-phenoxylhexyl and n-octyl (named Y6-phC6, Y6-phOC6, and Y6-nC8) are synthesized, and their detailed structure-properties correlations are investigated. The results in terms of UV– vis absorption, cyclic voltammetry and density functional theory calculation show the variations of alkyl chains have little influence on the absorption spectra and energy levels. However, these seemingly negligible changes have a pronounced impact on the molecular aggregation or crystallinity in the neat films, which in turn influences the photovoltaic properties of these devices resulting from the various microstructures of the BHJ blends and carrier dynamics in the corresponding devices. Among these three systems, OSCs based on a blend of Y6-phC6 and polymer donor PM6 show the highest power conversion efficiency of 11.77%. A series of small molecule acceptors based on a Y6 core derivatized with various alkyl groups are synthesized, and their detailed structure-properties correlations are investigated. • Three new non-fullerene acceptors, namely Y6-phC6, Y6-phOC6, and Y6-nC8, are reported. • PM6: Y6-phC6 system shows the highest PCE of 11.77% in these devices. • Introducing phenyl to the linear alkyl chain can optimize the blend morphology.

Capacitive deionization using carbon derived from an array of zeolitic-imidazolate frameworks

Abstract Capacitive deionization (CDI) represents one of the most thermodynamically efficient technologies for brackish water desalination. Its performance is highly reliant on the surface properties of carbon-based electrodes. Zeolitic-imidazolate framework (ZIF)-derived carbon materials have emerged among the most promising candidates owing to their high structural and compositional tuneability. However, the impacts of the precursory ZIF structure on the properties of the final carbon, and therefore, CDI capacity and efficiency remain to be further explored. In this work, four Zn-based ZIFs with different side-chain substitutions on the imidazolates were synthesized on a gram scale with high yields to produce N-doped carbons by pyrolysis. The resulting carbons along with four commercial carbon blacks were characterized physically and electrochemically to explore the structure-performance relationship. We demonstrated that the imidazole side-chain substitution alters the ZIF's decomposition during pyrolysis, influencing the elemental compositions, surface properties, wettability and graphitization levels. The diverse carbon properties result in variable double layer capacitance and charge-transfer resistance, ultimately impacting the CDI performance. Among these carbons, Zn (4abIm)2-C afforded the greatest salt adsorption capacity of 14.19 mgNaCl·gC−1, while Zn (mIm)2-C showed the highest overall salt adsorption capacity and rate; both exceeded the performance of the commercial carbon blacks.

Identification and structural characterization of lipid A from Escherichia coli, Pseudomonas putida and Pseudomonas taiwanensis using liquid chromatography coupled to high-resolution tandem mass spectrometry.

Lipid A is a part of the lipopolysaccharide layer, which is a main component of the outer membrane from Gram-negative bacteria. It can be sensed by mammalians to identify the presence of Gram-negative bacteria in their tissues and plays a key role in the pathogenesis of bacterial infections. Lipid A is also used as an adjuvant in human vaccines, emphasizing the importance of its structural analysis. In order to distinguish and characterize various lipid A species, a liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS) method was developed. Isolation of lipid A from different bacteria was carried out using a modified Bligh and Dyer extraction following a mild acid hydrolysis. Chromatography was performed using a bifunctional reversed-phase-based stationary phase. High-resolution MS using negative electrospray ionization was applied and MS/MS experiments utilizing high-energy collisional dissociation generated diagnostic product ions, which allowed the assignment of the side chains to distinct positions of the lipid A backbone. The method was applied to lipid A isolations of Escherichia coli (E. coli), Pseudomonas putida (P. putida) and Pseudomonas taiwanensis (P. taiwanensis). Various lipid A species were identified by their accurate masses and their structures were characterized using MS/MS experiments. Previously described lipid A structures from E. coli were identified and their structures confirmed by MS/MS. For the biotechnologically relevant strains P. putida and P. taiwanensis, we confirmed species by MS/MS, which have previously only been analyzed using MS. In addition, several lipid A species were discovered that have not been previously described in the literature. The combination of LC and MS/MS enabled the selective and sensitive identification and structural characterization of various lipid A species from Gram-negative bacteria. These species varied in their substituted side chains, speaking of fatty acids and phosphate groups. Characteristic product ions facilitated the assignment of side chains to distinct positions of the lipid A backbone.

Investigation of Hierarchical Structure Formation in Merocyanine Photovoltaics

Author(s): Murrey, TL; Hertel, D; Nowak, J; Bruker, R; Limbock, T; Neudorfl, J; Ruth, S; Schelter, J; Olthof, S; Radulescu, A; Moule, AJ; Meerholz, K | Abstract: Merocyanines (MCs) are a versatile class of small-molecule dyes. Their optoelectronic properties are easily tunable by chemically controlling their donor-acceptor strength, and their structural properties can be tuned by simple side-chain substitution. This manuscript demonstrates a novel series of MCs featuring an indoline donor with varying hydrocarbon side-chain length (from 6 to 12 carbons) and a tert-butyl-thiazole acceptor, labeled InTBT. Bulk heterojunction organic photovoltaics are fabricated with a [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) acceptor and characterized. Films composed of I8TBT:PCBM and I9TBT:PCBM produced the highest power conversion efficiency of 4.5%, which suggests that the morphology is optimized by controlling the side-chain length. Hierarchical structure formation in InTBT:PCBM films is studied using grazing incidence X-ray diffraction (GIXRD), small-angle neutron scattering (SANS), and atomic force microscopy (AFM). When mixed with PCBM, InTBTs with ≤8 side-chain carbons form pure crystalline domains, while InTBTs with ≥9 side-chain carbons mix well with PCBM. SANS demonstrates that increasing side-chain length increases the InTBT-rich domain size. In addition, a branched hexyl-dodecyl side-chain IHDTBT:PCBM film was studied and found to exhibit the worst-performance organic photovoltaic (OPV) device. The large-branched side chain inhibited mixing between IHDTBT and PCBM resulting in large segregated phases.

Design of a Fe4 S4 cluster into the core of a denovo four-helix bundle.

We explore the capacity of the de novo protein, S824, to incorporate a multinuclear iron-sulfur cluster within the core of a single-chain four-helix bundle. This topology has a high intrinsic designability because sequences are constrained largely by the pattern of hydrophobic and hydrophilic amino acids, thereby allowing for the extensive substitution of individual side chains. Libraries of novel proteins based on these constraints have surprising functional potential and have been shown to complement the deletion of essential genes in E. coli. Our structure-based design of four first-shell cysteine ligands, one per helix, in S824 resulted in successful incorporation of a cubane Fe4 S4 cluster into the protein core. A number of challenges were encountered during the design and characterization process, including nonspecific metal-induced aggregation and the presence of competing metal-cluster stoichiometries. The introduction of buried iron-sulfur clusters into the helical bundle is an initial step toward converting libraries of designed structures into functional de novo proteins with catalytic or electron-transfer functionalities.

Ku80-Targeted pH-Sensitive Peptide-PNA Conjugates Are Tumor Selective and Sensitize Cancer Cells to Ionizing Radiation.

The development of therapeutic agents that specifically target cancer cells while sparing healthy tissue could be used to enhance the efficacy of cancer therapy without increasing its toxicity. Specific targeting of cancer cells can be achieved through the use of pH-low insertion peptides (pHLIP), which take advantage of the acidity of the tumor microenvironment to deliver cargoes selectively to tumor cells. We developed a pHLIP-peptide nucleic acid (PNA) conjugate as an antisense reagent to reduce expression of the otherwise undruggable DNA double-strand break repair factor, KU80, and thereby radiosensitize tumor cells. Increased antisense activity of the pHLIP-PNA conjugate was achieved by partial mini-PEG sidechain substitution of the PNA at the gamma position, designated pHLIP-αKu80(γ). We evaluated selective effects of pHLIP-αKu80(γ) in cancer cells in acidic culture conditions as well as in two subcutaneous mouse tumor models. Fluorescently labeled pHLIP-αKu80(γ) delivers specifically to acidic cancer cells and accumulates preferentially in tumors when injected i.v. in mice. Furthermore, pHLIP-αKu80(γ) selectively reduced KU80 expression in cells under acidic conditions and in tumors in vivo. When pHLIP-αKu80(γ) was administered to mice prior to local tumor irradiation, tumor growth was substantially reduced compared with radiation treatment alone. Furthermore, there was no evidence of acute toxicity associated with pHLIP-αKu80(γ) administration to the mice. These results establish pHLIP-αKu80(γ) as a tumor-selective radiosensitizing agent. IMPLICATIONS: This study describes a novel agent, pHLIP-αKu80(γ), which combines PNA antisense and pHLIP technologies to selectively reduce the expression of the DNA repair factor KU80 in tumors and confer tumor-selective radiosensitization.