- Stabilization of polymerized vesicular systems: An application of the dynamic molecular shape concept
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A series of glycolipid surfactants derived from Tris(hydroxymethyl)acrylamidomethane (THAM) and bearing hydrocarbon or perfluorocarbon tails and an acryloyl group attached to their polar head was prepared to explore the aqueous behavior of the supramolecular systems they form. The dispersion of surfactants was achieved in water under ultrasonication conditions. Hydrocarbon compounds give heterogeneous vesicular assemblies. In the case of perfluorocarbon derivatives homogeneous vesicles were obtained. However after 1-day storage, all these systems fuse. To stabilize these vesicles, polymerization by ultra violet (UV) irradiation was carried out. During this reaction, a precipitation in water was observed for the hydrocarbon surfactants, whereas fluorocarbon structures provide stable vesicles without any alteration of their size. According to these results, the polymerization process was achieved, in the case of hydrocarbon glycolipid, in the presence of different cosurfactants bearing a single hydrocarbon tail or a polyhydroxylated head and a cholesterol terminus. In such conditions, homogeneous stable vesicles were prepared. Moreover, the THAM derived telomers bearing a cholesterol terminus were able to stabilize and reduce the size of vesicles formed with synthetic glycolipid surfactants. The drug encapsulation ability of these systems was investigated by measurement of the release kinetics of a fluorescent dye, carboxyfluorescein (CF), before and after polymerization.
- Wathier, Michel,Polidori, Ange,Ruiz, Karine,Fabiano, Anne-Sylvie,Pucci, Bernard
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- A novel on-resin synthesis of C-terminally amidated peptides
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An efficient method for solid-phase synthesis of peptide alkyl- and aryl amides is developed based on cleavage of peptide-thioester linker, HS- (CH)2-CO-Nle, by a silver ion-amine complex. The metal ion-assisted acyl transfer reaction is usually completed in less than 1 h with high yields. This method is particularly suitable for preparing peptide aryl amides which are difficult to synthesize by other methods and also can be adopted for the combinatorial synthesis of nonpeptide amide libraries.
- Kaljuste, Kalle,Tam, James P.
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Read Online
- Development of cell-penetrating peptide-modified MPEG-PCL diblock copolymeric nanoparticles for systemic gene delivery
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To develop a safe and efficient systemic non-viral gene vector, methoxy poly(ethylene glycol) (MPEG)/poly(e{open}-caprolactone) (PCL) diblock copolymers conjugated with a Tat analog through the ester or disulfide linkage were synthesized and their suitability as a systemic non-viral gene carrier evaluated. The physicochemical properties of the MPEG-PCL diblock copolymers were determined by GPC, 1H NMR and FT-IR spectroscopy. The particle sizes and in vitro (COS7 and S-180 cells) transfection efficiencies and cytotoxicity were evaluated. Furthermore, the luciferase activity was then determined in various tissues after intravenous injection of MPEG-PCL-SS-Tat/pCMV-Luc complex into mice bearing S-180 cells. The particle sizes of the MPEG-PCL-Tat copolymers with or without pDNA were about 40 and 60nm, respectively. The luciferase activity in COS7 cells transfected with pCMV-Luc with MPEG-PCL-ester-Tat or MPEG-PCL-SS-Tat was higher than that with pDNA only. MPEG-PCL-SS-Tat greatly increased the transfection efficiency compared to MPEG-PCL-ester-Tat in COS7 and S-180 cells. In an in vitro cytotoxicity test MPEG-PCL-SS-Tat did not induce any remarkable cytotoxicity. In an in vivo experiment, the synthesized MPEG-PCL-SS-Tat copolymers promoted the delivery and expression of pDNA into tumor tissue in tumor-bearing mice. In conclusion, this vector might be applicable as a tumor-targeting non-viral systemic gene carrier in the clinical setting.
- Tanaka, Ko,Kanazawa, Takanori,Shibata, Yasunori,Suda, Yumiko,Fukuda, Tsunehiko,Takashima, Yuuki,Okada, Hiroaki
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- “Precipitation on Nanoparticles”: Attractive Intermolecular Interactions Stabilize Specific Ligand Ratios on the Surfaces of Nanoparticles
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Confining organic molecules to the surfaces of inorganic nanoparticles can induce intermolecular interactions between them, which can affect the composition of the mixed self-assembled monolayers obtained by co-adsorption from solution of two different molecules. Two thiolated ligands (a dialkylviologen and a zwitterionic sulfobetaine) that can interact with each other electrostatically were coadsorbed onto gold nanoparticles. The nanoparticles favor a narrow range of ratios of these two molecules that is largely independent of the molar ratio in solution. Changing the solution molar ratio of the two ligands by a factor of 5 000 affects the on-nanoparticle ratio of these ligands by only threefold. This behavior is reminiscent of the formation of insoluble inorganic salts (such as AgCl), which similarly compensate positive and negative charges upon crystallizing. Our results pave the way towards developing well-defined hybrid organic–inorganic nanostructures.
- Chu, Zonglin,Han, Yanxiao,Král, Petr,Klajn, Rafal
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- Conformational control in a photoswitchable coiled coil
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The coiled coil is a common protein tertiary structure intimately involved in mediating protein recognition and function. Due to their structural simplicity, coiled coils have served as attractive scaffolds for the development of functional biomaterials. Herein we describe the design of conformationally-defined coiled coil photoswitches as potential environmentally-sensitive biomaterials.
- Torner, Justin M.,Arora, Paramjit S.
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- Human somatostatin receptor specificity of backbone-cyclic analogues containing novel sulfur building units
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Somatostatin 14 (somatostatin) and its clinically available analogues octreotide, lanreotide, and vapreotide are potent inhibitors of growth hormone, insulin, and glucagon release. Recently, a novel backbone cyclic somatostatin analogue c(GABA-Phe-Trp-(D)Trp-Lys-Thr-Phe-GlyC3-NH2) (analogue 1, PTR 3173) that possesses in vivo endocrine selectivity was described. This long-acting octapeptide exhibits high affinity to human recombinant somatostatin receptors (hsst) hsst2, hsst4, and hsst5. Its novel binding profile resulted in potent in vivo inhibition of growth hormone but not of insulin release. We report the synthesis, bioactivity, and structure-activity relationship studies of compounds related to 1. In these analogues, the lactam bridge of 1 was replaced by a backbone disulfide bridge. We present a novel approach for conformational constraint of peptides by utilizing sulfur-containing building units for on-resin backbone cyclization. These disulfide backbone cyclic analogues of 1 showed significant metabolic stability as tested in various enzyme mixtures. Receptor binding assays revealed different receptor selectivity profiles for these analogues in comparison to their prototype. It was found that analogues of 1, bearing a disulfide bridge, had increased selectivity to hsst2 and hsst5; however, they exhibited weaker affinity to hsst4 as compared to 1. These studies imply that ring chemistry, ring size, and ring position of the peptide template may affect the receptor binding selectivity.
- Gazal, Sharon,Gelerman, Garry,Ziv, Ofer,Karpov, Olga,Litman, Pninit,Bracha, Moshe,Afargan, Michel,Gilon, Chaim
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- A hetero-bifunctional spacer for the smart engineering of carbon-based nanostructures
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Efforts have been made in recent years to develop novel functionalisation protocols aimed at imparting multimodality and improved properties to complex carbon-based nanostructures. The incorporation of cleavable bonds to the nanomaterial surface for the controlled release (or exchange) of specific molecules under appropriate chemical and biological settings is relatively unexplored. The design and synthesis of a hetero-bifunctional linker joining a "cleavable" disulfide moiety for the covalent anchoring of a wide range of thiol end-capped (bio)molecules and a "clickable" terminal acetylene group is described. The strategy is based on the well-established copper-mediated acetylene-azide coupling reaction between the acetylene linker and single-walled carbon nanotubes decorated with phenylazido pendant arms. As a result, easily "post-derivatisable" and traceable nanostructured platforms containing a linking group potentially available for a wide range of biological probes are prepared and completely characterised.
- Tuci, Giulia,Luconi, Lapo,Rossin, Andrea,Baldini, Francesco,Cicchi, Stefano,Tombelli, Sara,Trono, Cosimo,Giannetti, Ambra,Manet, Ilse,Fedeli, Stefano,Brandi, Alberto,Giambastiani, Giuliano
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Read Online
- Grid coatings for capture of proteins and other compounds
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Grids comprising a coating modified with one or more capture agents and a deactivating agent are disclosed. Methods of using such grids in connection with suitable microscopy techniques, such as for determining the structure of target compounds including proteins, are also disclosed.
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Page/Page column 19-20
(2021/04/28)
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- Thiol- And Disulfide-Containing Vancomycin Derivatives against Bacterial Resistance and Biofilm Formation
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Antibiotic-resistant and biofilm-associated infections constitute a rapidly growing issue. Use of the last-resort antibiotic vancomycin is under threat due to the increasing appearance of vancomycin-resistant bacteria as well as the formation of biofilms. Herein, we report a series of novel vancomycin derivatives carrying thiol- and disulfide-containing moieties. The new compounds exhibited enhanced antibacterial activity against a broad range of bacterial strains, including vancomycin-resistant microbes and Gram-negative bacteria. Moreover, all obtained derivatives demonstrated improved antibiofilm formation activity against VanB-resistant Enterococcus compared to vancomycin. This work establishes a promising strategy for combating drug-resistant bacterial infections or disrupting biofilm formation and advances the knowledge on the structural optimization of antibiotics with sulfur-containing modifications.
- Gademann, Karl,Shchelik, Inga S.
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supporting information
p. 1898 - 1904
(2021/11/16)
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- Multivalent dextran hybrids for efficient cytosolic delivery of biomolecular cargoes
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The development of novel biotherapeutics based on peptides and proteins is often limited to extracellular targets, because these molecules are not able to reach the cytosol. In recent years, several approaches were proposed to overcome this limitation. A plethora of cell-penetrating peptides (CPPs) was developed for cytoplasmic delivery of cell-impermeable cargo molecules. For many CPPs, multimerization or multicopy arrangement on a scaffold resulted in improved delivery but also higher cytotoxicity. Recently, we introduced dextran as multivalent, hydrophilic polysaccharide scaffold for multimerization of cell-targeting cargoes. Here, we investigated covalent conjugation of a CPP to dextran in multiple copies and assessed the ability of resulted molecular hybrid to enter the cytoplasm of mammalian cells without largely compromising cell viability. As a CPP, we used a novel, low-toxic cationic amphiphilic peptide L17E derived from M-lycotoxin. Here, we show that cell-penetrating properties of L17E are retained upon multivalent covalent linkage to dextran. Dextran-L17E efficiently mediated cytoplasmic translocation of an attached functional peptide and a peptide nucleic acid (PNA). Moreover, a synthetic route was established to mask the lysine side chains of L17E with a photolabile protecting group thus opening avenues for light-triggered activation of cellular uptake.
- Becker, Bastian,Englert, Simon,Schneider, Hendrik,Yanakieva, Desislava,Hofmann, Sarah,Dombrowsky, Carolin,Macarrón Palacios, Arturo,Bitsch, Sebastian,Elter, Adrian,Meckel, Tobias,Kugler, Benedikt,Schirmacher, Anastasyia,Avrutina, Olga,Diederichsen, Ulf,Kolmar, Harald
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- Multi-hydrogen sulfide fluorescent probe as well as preparation method and application thereof (by machine translation)
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The invention belongs to the technical field of fluorescent probes, and particularly relates to a multi-hydrogen sulfide fluorescent probe as well as a preparation method and application thereof. The preparation method comprises the following steps: 1) condensing 2 - mercaptoacetic acid or 2 - mercaptopropionic acid with triphenylphosphine to obtain an intermediate; 2) reacting the intermediate obtained in step 1) with a fluorescein to obtain the multi-hydrogen sulfide fluorescent probe. The multi-hydrogen sulfide fluorescent probe is used for detecting multiple hydrogen sulfide, has high selectivity, high sensitivity and detection H. 2 Sn The concentration is convenient and fast. (by machine translation)
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Paragraph 0041-0043
(2020/11/05)
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- Compound comprising Hsp90 inhibitor targeting mitochondria and pharmaceutical composition for photodynamic therapy comprising the compound
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The present invention relates to mitochondrial target Hsp90 inhibitor-based compounds and pharmaceutical compositions for photodynamic therapy comprising the same. According to the present invention, provided are compounds obtained by conjugating an indocyanine derivative and a purine derivative, a diastereomer thereof, or a pharmaceutically acceptable salt thereof. The present invention relates to compositions for photodynamic diagnosis, treatment or cancer treatment comprising the above compounds, diastereomer, and salt as active ingredients.
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Paragraph 0070-0075
(2020/09/26)
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- Design, Synthesis, and Evaluation of Lipopeptide Conjugates of Mercaptoundecahydrododecaborate for Boron Neutron Capture Therapy
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We developed new 10B carriers for boron neutron capture therapy (BNCT) that can effectively transport and accumulate boron clusters into cells. These carriers consist of a lipopeptide, mercaptoundecahydrododecaborate (BSH), and a disulfide linker. The carriers were conceived according to the structure of pepducin, a membrane-penetrating lipopeptide targeting protease-activated receptor 1 (PAR1). To improve the membrane permeability of BSH, the structure was optimized using various lipopeptides possessing different peptides and lipid moieties. These synthesized lipopeptides were conjugated with BSH and evaluated for intracellular uptake using T98G glioblastoma cells. Among them, the most effectively incorporated and accumulated in the cells was compound 5 a, which contains a peptide of 13 residues derived from the intracellular third loop of PAR1 and a palmitoyl group. For further improvement of 10B accumulation in cells, the introduction of an amine linker was investigated; intracellular uptake similar to that of 5 a was observed for compound 14, which has a piperazine linker. Both compounds 5 a and 14 showed a stronger radiosensitizing effect than BSH along on T98G cells under mixed-neutron beam irradiation. The results demonstrate that lipopeptide conjugation is effective for enhancing intracellular delivery and accumulation of BSH and improving the cytotoxic effect of BNCT.
- Isono, Aoi,Tsuji, Mieko,Sanada, Yu,Matsushita, Akari,Masunaga, Shinichiro,Hirayama, Tasuku,Nagasawa, Hideko
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supporting information
(2019/03/07)
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- Mitochondrial heat shock protein-guided photodynamic therapy
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Mitochondria targeting sensitizers are continuing to gain importance in photodynamic therapy (PDT). Members of the 90 kDa heat shock protein (Hsp90) family, including TRAP1 (Hsp75), are overexpressed in cancer cells and help to control the antiapoptotic protein activity. The present work introduces an Hsp90 inhibitor-mitochondria targeting indocyanine dye conjugate (IR-PU) for high PDT efficacy.
- Thomas, Ajesh P.,Lee, An-Jung,Palanikumar,Jana, Batakrishna,Kim, Kibeom,Kim, Sangpil,Ok, Haewon,Seol, Jihoon,Kim, Dongseok,Kang, Byoung Heon,Ryu, Ja-Hyoung
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supporting information
p. 12631 - 12634
(2019/10/28)
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- Mixing End Groups in Thiol-Ene/Yne Reactions as a Simple Approach toward Multienzyme-Responsive Polymeric Amphiphiles
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Taking advantage of the high fidelity of thiol-ene and thiol-yne chemistries, we used mixtures of thiols to prepare degradable PEG-dendron amphiphiles functionalized with two different types of enzymatically cleavable end groups. By tuning the feed ratios of the two thiols, we achieved mixtures of hybrids with statistically different ratios of end groups. Studies of the disassembly of statistically mixed hybrids showed that these amphiphiles have higher degrees of response when incubated with each of the activating enzymes, whereas a greater degree of selectivity was observed for a control mixture of two distinct amphiphiles, which required the presence of both types of enzyme to undergo complete disassembly. The potential to introduce different end groups by using a mixture of thiols in an efficient single thiol-ene or thiol-yne step opens the way for simple modification of various ene- or yne-containing polymers and tailoring of their structural and functional properties.
- Harnoy, Assaf J.,Papo, Nitsan,Slor, Gadi,Amir, Roey J.
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supporting information
p. 2582 - 2587
(2018/11/30)
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- Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs
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Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOTmeta) gave highest affinity (50 nM Ki), selectivity (34-fold), and agonist potency (34 nM EC50, 87-fold selectivity) towards OTR. Surprisingly, ortho-cyclized analogs demonstrated OTR and vasopressin V1a receptor subtype affinity (220 nM and 69 nM, respectively) and pharmacological activity (294 nM and 35 nM, respectively). V1a binding and selectivity for ortho-cyclized peptides could be improved 6-fold by substituting a neutral residue at position 8 with a basic amino acid, providing potent antagonists (14 nM IC50) that displayed no activation of the OTR. Furthermore, xylene-bridged analogs demonstrated increased stability compared to OT at elevated temperature, demonstrating promising therapeutic potential for these analogs which warrants further study.
- Beard, Rhiannon,Stucki, Andy,Schmitt, Muriel,Py, Gabrielle,Grundschober, Christophe,Gee, Antony D.,Tate, Edward W.
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p. 3039 - 3045
(2018/03/29)
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- Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged Peptidomimetics
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A general strategy is introduced for the efficient synthetic access of disulfide linked artificial macrocycles via a Ugi four-component reaction (U4CR) followed by oxidative cyclization. The double-mercapto input is proposed for use in the Ugi reaction, thereby yielding all six topologically possible combinations. The protocol is convergent and short and enables the production of novel disulfide peptidomimetics in a highly general fashion.
- Vishwanatha, Thimmalapura M.,Bergamaschi, Enrico,D?mling, Alexander
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supporting information
p. 3195 - 3198
(2017/06/23)
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- Synthetic method of 3-(triphenylmethylthio)propionic acid
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The invention relates to a synthetic method of 3-(triphenylmethylthio)propionic acid. The technical problems of high cost, participation of a toxic raw material in a reaction, and adverseness to massive production of present synthetic methods are mainly solved. The synthetic method of 3-(triphenylmethylthio)propionic acid comprises the following steps: 1, dissolving 3-thiopropionic acid in acetate acid gracial at room temperature; 2, dissolving triphenylmethanol in tetrahydrofuran at room temperature; 3, adding the obtained tetrahydrofuran solution of triphenylmethanol to the acetate acid gracial solution of 3-thiopropionic acid in step 1; 4, dropwise adding concentrated sulfuric acid; 5, carrying out a heat insulation reaction for 3-5 h; and 6, filtering a solid obtained after the reaction, dissolving the filtered solid in dimethyl formamide, adding water, and crystallizing to obtain fine 3-(triphenylmethylthio)propionic acid. The synthetic method provided by the invention is a method for large-scale production of 3-(triphenylmethylthio)propionic acid.
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Paragraph 0017; 0018; 0019; 0020
(2017/03/08)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF (1S, 4S, 7Z, 10S, 16E, 21R)- 7-ETHYLIDENE-4,21-BIS(1-METHYLETHYL)-2-OXA-12,13-DITHIA-5, 8, 20, 23- TETRAAZABICYCLO[8.7.6]TRICOS-16-ENE-3, 6, 9, 19, 22-PENTONE
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The present invention is relates to an improved process for the preparation (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabi-cyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone of formula I.
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Page/Page column 25; 26
(2017/05/19)
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- Interrogating the Role of Receptor-Mediated Mechanisms: Biological Fate of Peptide-Functionalized Radiolabeled Gold Nanoparticles in Tumor Mice
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(Graph Presented) To get a better insight on the transport mechanism of peptide-conjugated nanoparticles to tumors, we performed in vivo biological studies of bombesin (BBN) peptide functionalized gold nanoparticles (AuNPs) in human prostate tumor bearing mice. Initially, we sought to compare AuNPs with thiol derivatives of acyclic and macrocyclic chelators of DTPA and DOTA types. The DTPA derivatives were unable to provide a stable coordination of 67Ga, and therefore, the functionalization with the BBN analogues was pursued for the DOTA-containing AuNPs. The DOTA-coated AuNPs were functionalized with BBN[7-14] using a unidentate cysteine group or a bidentate thioctic group to attach the peptide. AuNPs functionalized with thioctic-BBN displayed the highest in vitro cellular internalization (≈ 25%, 15 min) in gastrin releasing peptide (GRP) receptor expressing cancer cells. However, these results fail to translate to in vivo tumor uptake. Biodistribution studies following intravenous (IV) and intraperitoneal (IP) administration of nanoconjugates in tumor bearing mice indicated that the presence of BBN influences to some degree the biological profile of the nanoconstructs. For IV administration, the receptor-mediated pathway appears to be outweighed by the EPR effect. By contrast, in IP administration, it is reasoned that the GRPr-mediated mechanism plays a role in pancreas uptake.
- Silva, Francisco,Zambre, Ajit,Campello, Maria Paula Cabral,Gano, Lurdes,Santos, Isabel,Ferraria, Ana Maria,Ferreira, Maria Jo?o,Singh, Amolak,Upendran, Anandhi,Paulo, António,Kannan, Raghuraman
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p. 1153 - 1164
(2016/05/19)
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- Bulky toroidal and vesicular self-assembled nanostructures from fullerene end-capped rod-like polymers
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In this work, we present novel fullerene (C60) end-capped rod-like polypeptide-polymers, obtained by one-pot thiol-ene chemistry. These systems are able to self-assemble in water creating precise bulky microstructures of toroidal or vesicular shapes. Independent molecular dynamics simulations supported the observed experimental results. the Partner Organisations 2014.
- Mazzier,Mba,Zerbetto,Moretto
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supporting information
p. 4571 - 4574
(2014/05/06)
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- COMPOUNDS AND METHODS FOR PRODUCING A CONJUGATE
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The present disclosure provides conjugate structures and compound structures used to produce these conjugates. Also provided are methods of producing drug-polypeptide or detectable label-polypeptide conjugates linked through a modified amino acid. Structures of the modified amino acids used in producing the conjugates are disclosed.
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Paragraph 00406-00408
(2014/05/24)
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- Multivalent alteration of quorum sensing in Staphylococcus aureus
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Virulence in Staphylococcus aureus is strongly and positively correlated with local cell density. Here we present an effective approach to modulate this group behaviour using multivalent peptide-polymer conjugates. Our results show that by attaching multiple AIP-4′ units to macromolecular scaffolds, the agr QS response in S. aureus was affected strongly, while displaying a clear multivalency effect.
- Melamed Yerushalmi, Sarit,Buck, Maren E.,Lynn, David M.,Lemcoff, N. Gabriel,Meijler, Michael M.
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p. 5177 - 5179
(2013/06/27)
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- PESTICIDAL COMPOSITIONS
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Molecules according to Formula One: and their uses are disclosed herein.
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Paragraph 0180; 0181
(2013/03/26)
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- Thalidomide derivatives for the treatment of neuroinflammation
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The precise mechanism-of-action of thalidomide remains uncertain and might differ between diseases and under different clinical condition. With implications in the treatment of a variety of inflammatory and autoimmune diseases, as well as for use as an anticancer agent, alone or in combination with established therapeutics, it is clear that thalidomide and its derivatives deserve further scrutiny. In particular, thalidomide was shown to be effective in a mouse model of multiple sclerosis (MS), an autoimmune inflammatory disorder, called experimental autoimmune encephalomyelitis (EAE). Herein, we describe the synthesis and preliminary biological evaluation of new macromolecular prodrugs of thalidomide bearing an aminoalkyl group on the phthalimide ring. The effectiveness of these compounds to limit EAE was investigated, and it was shown that, at 100 mgkg-1 thalidomide-equivalent dose, they abrogated the clinical and pathological features of EAE.
- Contino-Pepin, Christiane,Parat, Audrey,Patinote, Cindy,Roscoe, Wendi A.,Karlik, Stephen J.,Pucci, Bernard
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scheme or table
p. 2057 - 2064
(2011/12/15)
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- Sunlight mediated disruption of peptide-based soft structures decorated with gold nanoparticles
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This communication reports morphological studies of a novel C 3-symmetric thiolated, tren-based ditryptophan conjugate. The exposed thiol groups on the soft structures interacted with gold nanoparticles and mediated the release of encapsulated fluorescent dye, when exposed to natural sunlight.
- Barman, Apurba Kr.,Verma, Sandeep
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supporting information; experimental part
p. 6992 - 6994
(2010/10/19)
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- Synthesis, redox properties, and conformational analysis of vicinal disulfide ring mimics
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A vicinal disulfide ring (VDR) results from disulfide-bond formation between two adjacent cysteine residues. This eight-membered ring is a rare motif in protein structures and is functionally important to those few proteins that posses it. This article focuses on the construction of strained and unstrained VDR mimics, discernment of the preferred conformation of these mimics, and the determination of their respective disulfide redox potentials.
- Ruggles, Erik L.,Deker, P. Bruce,Hondal, Robert J.
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scheme or table
p. 1257 - 1267
(2009/05/07)
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- A novel linker methodology for the synthesis of tailored conjugate vaccines composed of complex carbohydrate antigens and specific TH-cell peptide epitopes
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Pathogenic organisms or oncogenically transformed cells often express complex carbohydrate structures at their cell surface, which are viable targets for active immunotherapy. We describe here a novel, immunologically neutral, linker methodology for the efficient preparation of highly defined vaccine conjugates that combine complex saccharide antigens with specific T H-cell peptide epitopes. This novel heterobifunctional approach was employed for the conjugation of a (1→-2)-β-mannan trisaccharide from the pathogenic fungus Candida albicans as well as the carbohydrate portion of tumor-associated ganglioside GM2 to a TH-cell peptide epitope derived from the murine 60 kDa self heat-shock protein (hsp60). Moreover, the linkage chemistry has proven well suited for the synthesis of more complex target structures such as a biotinylated glycopeptide, a three component vaccine containing an immunostimulatory peptide epitope from interleukin-1β (IL-1β), and for the conjugation of complex carbohydrates to carrier proteins such as bovine serum albumin.
- Dziadek, Sebastian,Jacques, Sandra,Bundle, David R.
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experimental part
p. 5908 - 5917
(2009/05/31)
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- Glucose-based surfactants with hydrogenated, fluorinated, or hemifluorinated tails: Synthesis and comparative physical-chemical characterization
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(Chemical Equation Presented) (Hemi)fluorinated hydrophobic chains have been found to minimize the denaturating propensity of surfactants toward membrane proteins. The work reported herein deals with the synthesis of a new series of non-ionic glucose-based surfactants endowed with a hybrid hemifluorocarbon chain. The convergent synthesis is based on a one-pot reduction/alkylation of hemifluorinated thioacetate and glucosylated trishydroxymethyl acrylamidomethane using NaBH4 in methanol. This "mild" alkylation was studied in order to improve yields and to pass up the use of an excess of commercially unavailable hemifluorinated thiols. The physical-chemical properties in aqueous solution of this novel series were studied by surface tension measurement and dynamic light scattering (DLS), as well as their behavior upon reverse-phase chromatography, and were compared with those of their hydrogenated and perfluorinated analogues. The atypical effect of the additional ethyl tip to the fluorinated chain was demonstrated by higher critical micellar concentration values and abnormal hydrophobicities measured by reverse-phase chromatography. Moreover, according to Israelachvili's concept, DLS studies showed that surfactants bearing bulkier polar head self-assemble into small and well-defined aggregates, suggesting the formation of spherical micelles rather than the cylindrical ones usually observed with classical fluorinated surfactants.
- Abla, Maher,Durand, Gregory,Pucci, Bernard
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scheme or table
p. 8142 - 8153
(2009/04/04)
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- REACTIVE HETEROCYCLIC DERIVATIVES AND METHODS FOR THEIR SYNTHESIS AND USE
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The present invention describes molecules having a core structure that is an indole or an indolene that is modified to provide a functional moiety, and methods for their synthesis and use. Such functionalized heterocyclic derivatives may be used in a variety of assay formats.
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Page/Page column 42-43
(2010/11/27)
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- Conjugate addition reactions for the controlled delivery of pharmaceutically active compounds
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The invention features polymeric biomaterials formed by nucleophilic addition reactions to conjugated unsaturated groups. These biomaterials may be used for medical treatments.
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- Exotic aqueous behavior of synthetic lipids: Formation of vesicular nanotubes
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The work reported herein deals with the synthesis and the aggregation behavior studies of synthetic lipids bearing a non-ionic polar head made up of a tris(hydroxymethyl) aminomethane (tris) moiety linked with an aminoglycerol interface. The hydrophobic chains with variable lengths were grafted onto the hydroxyl functions of the aminoglycerol residue through ester or carbamate bonds. Tiny chemical modifications within this family of non-ionic surfactants brought about major variations in their aggregation behavior. They formed vesicles, tubules, and also small stable end-capped tubules - called vesicular nanotubes -, when the polar head bore two heptadecyl chains linked through a carbamate bond. Various techniques (nanosizer measurements, freeze fracture electron microscopy (FFEM), transmission electron microscopy (TEM), carboxyfluorescein (CF)) encapsulation were used to specify the structure of these assemblies. Notably, the vesicular nanotubes exhibited a small size, a fair polydispersity, great stability in an aqueous solution (up to 1 year) and a good efficiency to entrap and slowly release a probe such as carboxyfluoresceine: all these properties are perfectly suitable for their use as potential drug carriers.
- Polidori, Ange,Michel, Nicolas,Fabiano, Anne Sylvie,Pucci, Bernard
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- Novel methods for the delivery of polynucleotides to cells
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Process are described for the delivery of a polynucleotide to a cell. The process comprises forming a salt stable complex between the polynucleotide and a cationic surfactant. Ternary complexes are also made by associating an amphipathic compound with the binary complex. The resultant complexes are suitable for delivery of the polynucleotide to cells in vitro and in vivo.
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- A study of the relationship between biological activity and prolyl amide isomer geometry in oxytocin using 5-tert-butylproline to augment the Cys6- Pro7 amide cis-isomer population
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Three [5-t-BuPro7]oxytocin analogues were synthesized by substituting (2S,5R)-5-tert-butyl-proline for proline in oxytocin, [Mpa1]oxytocin, and [dPen1]oxytocin. Relative to oxytocin, [5-t-BuPro7]oxytocin and [Mpa1,5-t- BuPro7]oxytocin exhibited strongly reduced binding affinity to the receptor; however, both peptides maintained the pharmacophore characteristics responsible for signal transfer evoking the same maximal response as oxytocin in the single-dose procedure and exhibiting partial agonistic activity in the cumulative dose-response procedure. Although [dPen1]oxytocin exhibited inhibitory as well as partial agonistic activity, [dPen1,5-t- BuPro7]oxytocin exhibited only inhibitory potency with a similar in vitro pA2 value of 7.50 in the absence of magnesium. In the presence of magnesium, [dPen1,5-t-BuPro7]oxytocin exhibited stronger inhibitory potency than [dPen1]oxytocin and no partial agonism. Assignment of the proton signals for the 5-tert-butylprolyl amide cis- and trans-isomers by two-dimensional NMR experiments in water indicated that the Cys6-Pro7 peptide bond cis-isomer population was augmented relative to the prolyl peptides and measured respectively at 35%, 33%, and 20% in the 5-tert-butylproline7 analogues of oxytocin, [Mpa1]oxytocin and [Dpen1]oxytocin. Although caution must be taken when relating the increase in cis-isomer population with an influence on biological activity in [5-t-BuPro7]oxytocin analogues, the synthesis and evaluation of analogues 1-3 have provided additional evidence that can be used to support the hypothesis that the prolyl amide cis-isomer may favor antagonism and the trans-isomer is necessary for agonist activity.
- Bélec, Laurent,Slaninova, Jirina,Lubell, William D.
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p. 1448 - 1455
(2007/10/03)
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- 1,2-dithia-5-azacyclooctan-6-one and related compounds: Synthesis and conformation
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The first synthesis of 1,2-dithia-5-azacyclooctan-6-one 11, the parent member of a heterocyclic ring synthesis is reported. Compound 11 was found by hoe experiments to exist in a conformation with a trans-amide bond. The substituted derivatives 12 and 13 were also prepared and compound 12 was found to possess a trans-amide bond whilst for compound 13 three conformations were identified with the major conformer possessing a cis- amide bond.
- Cepas, Susana Caveda,North, Michael
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p. 16859 - 16866
(2007/10/03)
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- 168. Lipid masking and reactivation of angiotensin analogues
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Studies on post-angioplastic restenosis have shown the implication of angiotensin II (Ang) as a myoproliferative mediator. The antiproliferative efficacy of non-peptide Ang antagonists on the rat carotid model is of 50%, whereas a continuously infused peptide antagonist at low doses totally blocks neointimal growth. To explore the feasibility of depot forms of Ang that may be introduced during angioplasty and thus prevent restenosis, lipid-masked Ang analogues of the following general structure were prepared: [Xxx0,Yyy1]Ang with Xxx = decanoyl or palmitoyl and Yyy = Ser, Cys, Asp, β-lactoyl, 3-mercaptopropanoyl or succinyl. All fatty acylated peptides [Xxx0,Yyy1]Ang were practically inactive, and O- or S-esterified Ser and Cys peptides underwent intramolecular transacylation giving inactive Nα-acylated peptides. O-Acylated [β-mercaptopropanoyl1]Ang were easily hydrolyzed into their biologically active [Yyy1]Ang forms, either by mild saponification or by lipase activity.
- Maletinska, Lenka,Neugebauer, Witold,Pare, Marie-Christine,Perodin, Jacqueline,Pham, Dung,Escher, Emanuel
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p. 2023 - 2034
(2007/10/03)
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- DNA-Binding Compounds. III Synthesis of a Peptide-Linked Binuclear Platinum(II)-Terpyridine Complex
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A procedure has been developed for linking two terpyridineplatinum(II), Pt(tpy), chromophores by an oligopeptide chain.It relies on the use of a new reagent, succinimido 3-(triphenylmethylthio)propanoate (2), to acylate the amino end groups of an α,ω-diaminoalkane peptide.Subsequent deprotection of the sulfhydryl groups and coupling with IICl>Cl yields the binuclear complexes in good yields.This procedure allowed the synthesis of Cl2 (5b).
- Bray, Andrew M.,Kelly, David P.,Mack, Philip O.-L.,Martin, Roger F.,Wakelin, Laurence P. G.
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p. 629 - 634
(2007/10/02)
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