- Peptide Derivatives of Some Physiologically Active Substances
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Abstract: The synthesis of Boc-Gly-Pro-Dox, Boc-Gly-Pro-DOPA, and Boc-Gly-Pro-Srt and their deuterated analogues was carried out. The condensation is accompanied by side reactions, which could be minimized by optimizing the reaction conditions. The most versatile approach to the synthesis of Boc-Gly-Pro-Dox, Boc-Gly-Pro-DOPA, and Boc-Gly-Pro-Srt and their deuterated analogues is condensation of Boc-Gly-Pro or Boc-Gly-[2H]Pro with the amino groups of dopamine, serotonin, and doxorubicin. For the introduction of hydrogen isotopes into ΔPro, hydrogenation of its aqueous solution followed by condensation of the reduced proline with Boc-GlyOSu is recommended. Mass spectrometry was used to determine the content of isotopomers in the deuterated products.
- Shevchenko,Andreeva,Nagaev, I. Yu.,Myasoedov
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Read Online
- Versatile phosphoramidation reactions for nucleic acid conjugations with peptides, proteins, chromophores, and biotin derivatives
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Chemical conjugations of nucleic acids with macromolecules or small molecules are common approaches to study nucleic acids in chemistry and biology and to exploit nucleic acids for medical applications. The conjugation of nucleic acids such as oligonucleotides with peptides is especially useful to circumvent cell delivery and specificity problems of oligonucleotides as therapeutic agents. However, current approaches are limited and inefficient in their ability to afford peptide - oligonucleotide conjugates (POCs). Here, we report an effective and reproducible approach to prepare POCs and other nucleic acid conjugates based on a newly developed nucleic acid phosphoramidation method. The development of a new nucleic acid phosphoramidation reaction was achieved by our successful synthesis of a novel amine-containing biotin derivative used to systematically optimize the reactions. The improved phosphoramidation reactions dramatically increased yields of nucleic acid - biotin conjugates up to 80% after 3 h reaction. Any nucleic acids with a terminal phosphate group are suitable reactants in phosphoramidation reactions to conjugate with amine-containing molecules such as biotin and fluorescein derivatives, proteins, and, most importantly, peptides to enable the synthesis of POCs for therapeutic applications. Polymerase chain reactions (PCRs) to study incorporation of biotin or fluorescein-tagged DNA primers into the reaction products demonstrated that appropriate controls of nucleic acid phosphoramidation reactions incur minimum adverse effects on inherited base-pairing characteristics of nucleotides in nucleic acids. The phosphoramidation approach preserves the integrity of hybridization specificity in nucleic acids when preparing POCs. By retaining integrity of the nucleic acids, their effectiveness as therapeutic reagents for gene silencing, gene therapy, and RNA interference is ensured. The potential for POC use was demonstrated by two-step phosphoramidation reactions to successfully synthesize nucleic acid - tetraglycine conjugates. In addition, phosphoramidation reactions provided a facile approach to prepare nucleic acid - BSA conjugates with good yields. In summary, the new approach to phosphoramidation reactions offers a universal method to prepare POCs and other nucleic acid conjugates with high yields in aqueous solutions. The methods can be easily adapted to typical chemistry or biology laboratory setups which will expedite the applications of POCs for basic research and medicine.
- Wang, Tzu-Pin,Chiou, Yi-Jang,Chen, Yi,Wang, Eng-Chi,Hwang, Long-Chih,Chen, Bing-Hung,Chen, Yen-Hsu,Ko, Chun-Han
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Read Online
- Argininamide-type neuropeptide y Y1 receptor antagonists: The nature of: N Ω-carbamoyl substituents determines Y1R binding mode and affinity
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The recently resolved crystal structure of the neuropeptide Y Y1 receptor (Y1R), co-crystallized with the high-affinity (pKi: 10.11), argininamide-type Y1R antagonist UR-MK299 (2), revealed that the NΩ-carbamoyl substituent (van der Waals volume: 139 ?3) is deeply buried in the receptor, occupying a hydrophobic pocket. We synthesized and characterized a series of argininamides, structurally related to 2. Y1R affinity decreased with increasing size of the carbamoyl residue (minimal pKi: 5.67). Exceeding a critical size of the substituent (van der Waals volume: 212 ?3), the ligands bound in an inverted mode with the carbamoyl side chain located at the surface of the receptor, as suggested by induced-fit docking and MD simulations.
- Buschmann, Jonas,Keller, Max,Seiler, Theresa,Wifling, David,Bernhardt, Günther
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supporting information
p. 274 - 282
(2020/04/17)
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- Synthesis of pyrimidine nucleoside and amino acid conjugates
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The synthesis of novel pyrimidine nucleoside bioconjugates with amino acids is presented. The N4-amino acid-acylated 2′-deoxycytidine analogues, modified with various amino acids, were synthesized using a three-step synthesis and obtained in moderate overall yields. Novel amino acid-alkylated 2′-deoxycytidine derivatives were obtained during the rearrangement of amino acid-acylated derivatives that occurred during Boc deprotection.
- Koplūnait?, Martyna,Butkut?, Kamil?,Me?kys, Rolandas,Taurait?, Daiva
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supporting information
(2020/11/13)
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- Design, synthesis and anxiolytic activity evaluation of N-Acyltryptophanyl- containing dipeptides, potential TSPO ligands
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Background: The 18 kDa translocator protein (TSPO), previously known as the peripheral- type benzodiazepine receptor, plays a key role for the synthesis of neurosteroids by promoting transport of cholesterol from the outer to the inner mitochondrial membrane, which is the ratelimiting step in neurosteroid biosynthesis. Neurosteroids interact with nonbenzodiazepine site of GABAa receptor causing an anxiolytic effect without the side effects. Methods: Using the original peptide drug-based design strategy, the first putative dipeptide ligand of the TSPO N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide (GD-23) was obtained. Molecular docking of GD-23 in the active pocket of the TSPO receptor using Glide software was carried out. The lead compounds GD-23 and its analogues were synthesized using activated succinimide esters coupling method. The anxiolytic activity of GD-23 and its analogues was investigated in vivo, using two validated behavioral tests, illuminated open field and elevated plus-maze. Results: The in vivo studies revealed that the following parameters are necessary for the manifestation of anxiolytic activity of new compounds: the L-configuration of tryptophan, the presence of an amide group at the C-terminus, the specific size of the N-acyl substituent at the Nterminus. Compound GD-23 (N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide) demonstrated a high anxiolytic-like effect in the doses of 0.05-1.0 mg/kg i.p. comparable with that of diazepam. Compound GD-23 was also active in the open field test when was administered orally in the doses of 0.1-5.0 mg/kg. The involvement of TSPO receptor in the mechanism of anxiolytic-like activity of new compounds was proved by the antagonism of compound GD-23 with TSPO selective inhibitor PK11195 as well as with inhibitors of enzymes which are involved in the biosynthesis of neurosteroids, trilostane and finasteride. Conclusion: A series of N-acyl-tryptophanyl-containing dipeptides were designed and synthesized as 18 kDa translocator protein (TSPO) ligands. Using a drug-based peptide design method a series of the first dipeptide TSPO ligands have been designed and synthesized and their anxiolytic activity has been evaluated. In general, some of the compounds displayed a high level of anxiolytic efficacy comparable with that of diazepam. The involvement of TSPO receptor in the mechanism of anxiolytic activity of new compounds was proved using two methods. On this basis, the N-acyl-Ltryptophanyl- isoleucine amides could potentially be a novel class of TSPO ligands with anxiolytic activity.
- Deeva, Olga A.,Dyabina, Alina S.,Gudasheva, Tatiana A.,Mokrov, Grigory V.,Seredenin, Sergey B.,Yarkova, Milada A.
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p. 383 - 399
(2019/07/12)
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- Amino acid substrate and preparation method and purpose thereof
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The invention discloses an amino acid substrate. A structural formula of the substrate is shown in Figure 1. By means of development and innovation of a synthetic process of dipeptide in the amino acid substrate and a coupling process of the dipeptide and chromogen and innovation and application verification of an extraction and purification process, the reaction yield of each step of a product isgreatly improved, the color is close to white, the influence of the substrate color in the identification process is reduced, and the sensitivity and the accuracy of the aerobic flora vaginitis detection process are improved to a greater extent. The substrate is in the form of hydrochloride, and the solubility of the substrate can be greatly improved when the detection is carried out in the formof the hydrochloride. In a detection application, the corresponding preparation work is conducted according to the preparation requirement of the aerobic flora vaginitis detection, and the color rendering performance of the synthetic substrate is compared with the color rendering performance of the existing aerobic flora vaginitis detection in the market according to a detection standard. The color rendering performance is better than that of an aerobic flora vaginitis detection reagent in the market.
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Paragraph 0019; 0020
(2019/02/10)
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- Organoarsenic compound and use thereof
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The invention discloses an organoarsenic compound. The organoarsenic compound has the following structural formula as shown in the specification, wherein n is 1 or 2; R, R1, R2, R3, R4 and R5 are respectively and independently amino, R6-CO-NH, R7-CO-O, alkyl, aryl, a heterocyclic substituent, alkoxyl, alkylamino, a halogen atom, nitro, hydroxyl or a hydrogen atom; R6 is alkyl, aminoalkyl or aryl;R7 is alkyl, aminoaryl or aryl. The organoarsenic compound has good inhibitory activity for thioredoxin reductase, has strong cytotoxicity for tumor cell HL-60, and can be used for preparing a thioredoxin reductase inhibitor or an antitumor drug with thioredoxin reductase as a target spot.
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Paragraph 0098-0102
(2019/03/06)
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- MICRO/NANO MATERIALS, PRODUCTS OBTAINED BY COVALENTLY MODIFYING SURFACE OF MICRO/NANO MATERIALS WITH HYDROPHILIC MATERIALS, AND METHOD FOR MAKING SAME
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Micro-nano materials, products obtained by covalently modifying the surfaces of micro/nano materials with hydrophilic materials, and methods for making the same. The micro/nano materials on the surfaces have carboxyl groups or/and pro-carboxyl groups which are converted into their active esters. The products are covalently modified by forming amide bonds between the active esters on the surfaces and the modification agents; where the modification agents are hydrophilic compounds and/or hydrophilic polymers bearing primary and/or secondary aliphatic amines. Monomers bearing carboxyl groups and/or pro-carboxyl groups are used to produce an adequate number of carboxyl groups and/or pro-carboxyl groups on the surface of a polymer material to be modified. The carboxyl groups and/or pro-carboxyl groups are converted into active esters. A reasonably-sized modification agent bearing primary and/or secondary amines, zwitterions and hydrophilic linear spacer arms is used to form amide bonds and obtain a covalently modified surface layer.
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Paragraph 0190
(2019/03/30)
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- Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome
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Antibiotic chloramphenicol (CHL) binds with a moderate affinity at the peptidyl transferase center of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving properties of this inhibitor, we explored ribosome binding and inhibitory activity of a number of amino acid analogs of CHL. The L-histidyl analog binds to the ribosome with the affinity exceeding that of CHL by 10 fold. Several of the newly synthesized analogs were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CHL. However, the inhibitory properties of the semi-synthetic CHL analogs did not correlate with their affinity and in general, the amino acid analogs of CHL were less active inhibitors of translation in comparison with the original antibiotic. The X-ray crystal structures of the Thermus thermophilus 70S ribosome in complex with three semi-synthetic analogs showed that CHL derivatives bind at the peptidyl transferase center, where the aminoacyl moiety of the tested compounds established idiosyncratic interactions with rRNA. Although still fairly inefficient inhibitors of translation, the synthesized compounds represent promising chemical scaffolds that target the peptidyl transferase center of the ribosome and potentially are suitable for further exploration.
- Tereshchenkov, Andrey G.,Dobosz-Bartoszek, Malgorzata,Osterman, Ilya A.,Marks, James,Sergeeva, Vasilina A.,Kasatsky, Pavel,Komarova, Ekaterina S.,Stavrianidi, Andrey N.,Rodin, Igor A.,Konevega, Andrey L.,Sergiev, Petr V.,Sumbatyan, Natalia V.,Mankin, Alexander S.,Bogdanov, Alexey A.,Polikanov, Yury S.
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p. 842 - 852
(2018/02/26)
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- Propargyl-Assisted Selective Amidation Applied in C-terminal Glycine Peptide Conjugation
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Alkyl esters, such as propargyl esters, typically lack the electron-withdrawing inductive effects needed to participate in nucleophilic acyl substitution reactions. Herein, we report an unusual observation in which glycine propargyl ester derivatives displayed selective, base-independent reactivity towards linear alkylamines under mild, metal-free conditions. Through global reaction route mapping (GRRM) modeling calculations, it is predicted that these observations may be governed by factors related to hydrogen-bonding and intermolecular interactions, rather than electron-withdrawing inductive effects. Based on this concept of propargyl-assisted selective amidation, a direct application was made to develop a novel site-specific C-terminal glycine peptide bioconjugation technique as a proof-of-concept, which relies upon the selective reactivity of glycine propargyl esters over that of aspartate and glutamate side-chain-linked propargyl esters.
- Vong, Kenward King Ho,Maeda, Satoshi,Tanaka, Katsunori
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supporting information
p. 18865 - 18872
(2016/12/26)
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- Sulfonate derived phosphoramidates as active intermediates in the enzymatic primer-extension of DNA
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Novel unnatural 5′-phosphoramidate nucleosides, capable of being processed as substrates by DNA polymerases for multiple nucleotide incorporations, have been designed. The mimics feature metabolites such as taurine and a broad range of aliphatic sulfonates coupled through a P-N bond to the 5′-phosphate position of deoxynucleotides, to allow binding interactions in the enzyme active site. The utility of all of the analogues as pyrophosphate mimics was demonstrated for the chain elongation of DNA, using both thermophilic and mesophilic microbial polymerases. This journal is
- De,Groaz,Margamuljana,Abramov,Marlière,Herdewijn
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p. 3950 - 3962
(2015/03/30)
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- Kilogram-Scale Synthesis of Osteogenic Growth Peptide (10-14) Using a Fragment Coupling Approach
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Kilogram-scale synthesis of a bioactive pentapeptide in solution by "3 + 2" fragment coupling strategy has been successively accomplished in the development of OGP (10-14), a minimal OGP-derived sequence that retains the full proliferative activity of the osteogenic growth peptide. The synthetic scheme, coupling conditions, and scaling-up of the process are systematically studied; the epimerization of the tripeptide fragment and pentapeptide are also evaluated.
- Zhang, Teng,Chen, Zhenxing,Tian, Yan,Han, Bin,Zhang, Ning,Song, Wei,Liu, Zhulan,Zhao, Jinli,Liu, Jianli
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supporting information
p. 1257 - 1262
(2015/09/28)
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- NOVEL FAP INHIBITORS
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The present invention relates to novel inhibitors having high selectivity and specificity for FAP (fibroblast activation protein). Said inhibitors are useful as a human and/or veterinary medicine, in particular for the treatment and/or prevention of FAP-related disorders such as but not limited to proliferative disorders.
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Paragraph 0265; 0268; 0269
(2014/12/09)
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- Design, synthesis, and pharmacological evaluation of fluorescent and biotinylated antagonists of ρ1 GABAC receptors
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The ρ1 GABAC receptor is a ligand-gated chloride ion channel that shows promise as a therapeutic target for myopia, sleep disorders, memory and learning facilitation, and anxiety-related disorders. As such, there is a need for molecular probes to understand the role GABA C receptors play in physiological and pathological processes. To date, no labeled (either radioactive or fluorescent) GABAC selective ligand has been developed that can act as a marker for GABAC receptor visualization and localization studies. Herein, we report a series of fluorescent ligands containing different-sized linkers and fluorophores based around (S)-4-ACPBPA [(4-aminocyclopenten-1-yl)-butylphosphinic acid], a selective GABAC antagonist. One of these conjugates, (S)-4-ACPBPA-C5-BODIPY (13), displayed moderate potency (IC50 = 58.61 μM) and selectivity (>100 times) for ρ1 over α1β2γ2L GABAA receptors. These conjugates are novel lead agents for the development of more potent and selective fluorescent probes for studying the localization and function of GABAC receptors in living cells.
- Gavande, Navnath,Kim, Hye-Lim,Doddareddy, Munikumar R.,Johnston, Graham A. R.,Chebib, Mary,Hanrahan, Jane R.
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supporting information
p. 402 - 407
(2013/06/05)
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- NOVEL FAP INHIBITORS
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The present invention relates to novel inhibitors having high selectivity and specificity for FAP (fibroblast activation protein). Said inhibitors are useful as a human and/or veterinary medicine, in particular for the treatment and/or prevention of FAP-related disorders such as but not limited to proliferative disorders.
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Page/Page column 42; 43
(2013/07/31)
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- Depsipeptide containing lactic acid residue
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Disclosed are a compound represented by the general formula (I) below and a polymer compound obtained by polymerizing such a compound. [in-line-formulae]R1-Gly-Lac-Pro-R2 ??(I):[/in-line-formulae] where -Gly-Lac-Pro- represents a structure represented by the following formula (II), R1 represents a hydrogen atom, or an amino acid, a polypeptide or a hydroxycarboxylic acid which are linked through an amide bond, R2 represents a hydroxyl group, or an amino acid or a polypeptide which are linked through an amide bond, or a hydroxycarboxylic acid which is linked through an ester bond.
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- NOVEL SEMI-SYNTHETIC GLYCOPEPTIDES AS ANTIBACTERIAL AGENTS
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Semi-synthetic glycopeptides having antibacterial activity are described, in particular, the semi-synthetic glycopeptides described herein are made by chemical modification of the a glycopeptide (Compound A, Compound B, Compound H or Compound C) or the monosaccharide made by hydrolyzing the disaccharide moiety of the amino acid-4 of the parent glycopeptide in acidic medium to give the amino acid-4 monosaccharide; conversion of the monosaccharide to the amino-sugar derivative; acylation of the amino substituent on the amino acid-4 amino-substituted sugar moiety on these scaffolds with certain acyl groups; conversion of the amide group in amino acid-3 on these scaffolds to various acylamide, acylsulfonamide, acylsulfonylurea derivatives; aminomethylation with substituent containing sulfonamide or acylsulfonamide group on amino acid-7 through Mannich reaction; and conversion of the acid moiety on the macrocyclic ring of these scaffolds to certain substituted amides. Also provided are methods for the synthesis of the compounds, pharmaceutical compositions containing the compounds, and methods of use of the compounds for the treatment and/or prophylaxis of diseases, especially bacterial infections.
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- Synthesis and biological evaluation of boron peptide analogues of Belactosin C as proteasome inhibitors
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A series of boron peptides 11, 13, 15 and 17 were designed and synthesized as proteasome inhibitors based on the structure of Belactosin C. Matteson homologation was a key step in the synthesis of the boron peptides. Compounds 11a and 13 showed significant inhibition of 20S proteasome chymotrypsin-like (β5) activity (IC50 = 0.28 and 0.51 μM, respectively). Furthermore, like PS-341, compound 11a increased the G2/M cell distribution. A biparametric cytofluorimetric analysis with FITC-labeled annexin V and propidium iodide showed induction of apoptosis by compound 11a at >1 μM concentrations of compound.
- Nakamura, Hiroyuki,Watanabe, Mizuyoshi,Ban, Hyun Seung,Nabeyama, Wataru,Asai, Akira
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scheme or table
p. 3220 - 3224
(2010/04/05)
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- AMINO ACID DERIVED PRODRUGS OF PROPOFOL, COMPOSITIONS AND USES THEREOF
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The present invention provides propofol prodrugs, methods of making propofol prodrugs, pharmaceutical compositions of propofol prodrugs and methods of using propofol prodrugs and pharmaceutical compositions thereof to treat or prevent diseases or disorders such as migraine headache pain and post?chemotherapy or post?operative surgery nausea and vomiting.
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(2008/06/13)
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- Relaxivity and transmetallation stability of new benzyl-substituted derivatives of gadolinium-DTPA complexes
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In our efforts of finding new specific contrast agents of higher relaxivity and selectivity, we have prepared the two new benzyl-functionalized DTPA ('diethylenetriamine pentaacetate') gadolinium complexes (S)-3 and (R,S)-4, and compared their properties with those of the known regioisomers (S)-2 and (S)-1. The theoretical fitting of the reduced transverse relaxation rates of the 17O-nucleus of H2O gave values for the water-residence time (τM) of 86-143 ns at 310 K, values that are not limiting the proton relaxivity at body temperature. 1H-NMRD (nuclear magnetic-relaxation dispersion) Profiles showed that the relaxivity of 1-4 (r1=4.3-5.1 s-1 mM-1 at 20 MHz and 310 K) is higher than for the Gd-DTPA parent compound 5. Transmetallation assessment demonstrated that all substituted compounds, except for (S)-2, are more stable than 5. The highest stability towards Zn2+-induced transmetallation was achieved with complexes 3, 1, and 4 (in decreasing order). Apparently, the steric hindrance of the benzyl substituents in positions 5, 4, and 2, respectively, favorably reduces the accessibility of Zn ions. From a synthetic point of view, 4-substituted DTPA complexes of type 1 are more readily accessible than 5-substituted compounds of type 3. Therefore, the former seem to be superior for linking substituted DTPA complexes to macromolecules or specific vectors.
- Laurent, Sophie,Botteman, Francois,Vander Elst, Luce,Muller, Robert N.
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p. 1077 - 1089
(2007/10/03)
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- Cell-permeable small molecule probes for site-specific labeling of proteins.
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We have successfully synthesized a number of small molecule probes designed for site-specific labeling of N-terminal cysteine-containing proteins expressed in live cells. Their utility for site-specific, covalent modifications of proteins was successfully demonstrated with purified proteins in vitro, and with live bacterial cells in vivo.
- Yeo, Dawn S Y,Srinivasan, Rajavel,Uttamchandani, Mahesh,Chen, Grace Y J,Zhu, Qing,Yao, Shao Q
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p. 2870 - 2871
(2007/10/03)
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- O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium salts as efficient reagents in active ester synthesis
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The new uronium salts O-succinimidyl-1,3-dimethyl-1,3-trimethyleneuronium hexafluorophosphate (HSDU) and tetrafluoroborate (TSDU) have been prepared from 1,3-dimethylpropyleneurea (DMPU) and employed in the synthesis of N-hydroxysuccinimide-derived active esters. High yields were obtained at room temperature in short reaction times and no racemization was observed.
- Bailén, Miguel A,Chinchilla, Rafael,Dodsworth, David J,Nájera, Carmen
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p. 1661 - 1664
(2007/10/03)
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- Combinatorial synthesis through disulfide exchange: Discovery of potent psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA)
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Psammaplin A is a symmetrical bromotyrosine-derived disulfide natural product isolated from the Psammaplysilla sponge, which exhibits in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Inspired by the structure of this marine natural product, a combinatorial scrambling strategy for the construction of heterodimeric disulfide analogues was developed and applied to the construction of a 3828-membered library starting from 88 homodimeric disulfides. These psammaplin A analogues were screened directly against various gram positive bacterial strains leading to the discovery of a series of potent antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA). Among the most active leads derived from these studies are compounds 104, 105, 113, 115, 123, and 128. The present, catalytically-induced, disulfide exchange strategy may be extendable to other types of building blocks bearing thiol groups facilitating the construction of diverse discovery-oriented combinatorial libraries.
- Nicolaou,Hughes, Robert,Pfefferkorn, Jeffrey A.,Barluenga, Sofia,Roecker
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p. 4280 - 4295
(2007/10/03)
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- Synthesis of N-alkoxycarbonyl-3-substituted tetramic acids and functionalized enols via C-acylation reactions of active methylene compounds with N-hydroxysuccinimide esters of N-alkoxycarbonyl-α-amino acids
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The N-hydroxysuccinimide esters of N-alkoxycarbonyl-α-amino acids react with active methylene compounds (malonic and acyl acetic esters), under basic conditions, to produce N-alkoxycarbonyl-3-substituted tetramic acids 7-17; in the case of the N-hydroxysuccinimide ester of L-alanine, the corresponding optically active tetramic acids 15 and 16 are obtained. In addition, the C-acylation reactions of cyanoacetic esters furnishes the functionalized enols 18-23 in very good yields. Spectral data and physical characteristics for all compounds are reported.
- Detsi, Anastasia,Micha-Screttas, Maria,Igglessi-Markopoulou, Olga
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p. 2443 - 2449
(2007/10/03)
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- New peptidyl-anthraquinones: Synthesis and DNA binding
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Aminoacyl-hydroxy-anthraquinones bearing glicyl, valyl, lysyl and tryptophanyl residues in the side-chain were synthesized as new potential DNA-directed drugs. These compounds bind very tightly to double-stranded DNA by intercalating their planar portion into the nucleic acid and further stabilizing the complex through electrostatic contacts with the backbone phosphates. All protonated groups in the side-chains participate in the latter process. The free energy of DNA-binding corrected for the electrostatic contribution is similar for the lysyl and glicyl derivatives, which points to a common geometry of intercalation.
- Zagotto, Giuseppe,Mitaritonna, Giovanni,Sissi, Claudia,Palumbo, Manlio
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p. 2135 - 2141
(2007/10/03)
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- Peptides modified by the phosphine group for marking with 99M TC and 186-188 RE or paramagnetic agents
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The peptides described are modified with the phosphine group and are useful for marking with 99m Tc and 186-188 Re or paramagnetic agents for use in diagnosis and radiotherapy; in particular chelating compounds having the co-ordinating sets PN2 X, where X is --S, --O, COO--, PN3, P2 N3 and P2 N2 are described.
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- Stereochemical requirements for β-hairpin formation: Model studies with four-residue peptides and depsipeptides
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Spectroscopic and crystallographic data are present for a series of tetrapeptides and analogous depsipeptides that can form a minimal β-hairpin (two intramolecular hydrogen bonds). These model compounds have been used to test the hypothesis that 'mirror image' β-turns promote β-hairpin formation. This hypothesis was inspired by a statistical survey of β-hairpins in globular proteins (Sibanda, B.L.; Thornton, J.M. Nature 1985, 316, 170), which showed that mirror image β-turns (type I' and type II'), although rare in general, are very commonly associated with β-hairpins containing a two-residue loop between the strand segments. Each of our four-residue molecules contains proline at the second position, to promote a central β-turn. The β-turn is induced to be either 'common' or 'mirror-image', relative to the outer residues, by choice of residue configuration (L vs D). In methylene chloride, end-capped tetrapeptide Ac-L-Val-D-Pro-D-Ala-L-Leu-NMe2 folds largely into the β-hairpin conformation, while the diastereomer Ac-L-Val-L-Pro-L-Ala-L-Leu-NMe2 displays little or no β-hairpin folding. For each diastereomer, the hydrogen-bonded driving force for β-hairpin folding is identical, and the dramatic difference in folding behavior therefore reflects a variation in the intrinsic conformational properties of the diastereomeric backbones. Similar behavior is seen for the diastereomeric peptide pair Ac-L-Val-D-Pro-Gly-L-Leu-NMe2 vs Ac-L-Val-L-Pro-Gly-L-Leu-NMe2, and for the analogous depsipeptides with a lactic acid or glycolic acid residue at the third position. Thus, our results show not only that mirror-image Pro-X turns strongly promote β-hairpin folding, but also that common β-turns strongly discourage formation of a β-hairpin with a two-residue loop.
- Haque, Tasir S.,Little, Jennifer C.,Gellman, Samuel H.
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p. 6975 - 6985
(2007/10/03)
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- Peptides modified by the phosphine group for marking with 99mTC and 186-188Re or paramagnetic agents
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The peptides described are modified with the phosphine group and are useful for marking with 99mTc and 186-188Re or paramagnetic agents for use in diagnosis and radiotherapy; in particular chelating compounds having the co-ordinating sets PN2X, where X is -S, -O, COO-, PN3, P2N3and P2N2are described.
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- Structural and thermodynamic characterization of temperature-dependent changes in the folding pattern of a synthetic triamide
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Variable-temperature 1H NMR and IR studies of triamide 1 and related compounds indicate that 1 undergoes dramatic temperature-dependent conformational changes in relatively nonpolar solvents (methylene chloride and chloroform). The folding pattern favored at low temperatures in these chlorocarbons (1c) contains a single C=O?H-N hydrogen bond in a nine-membered ring, while a folding pattern containing only a six-membered-ring C=O?N-H interaction (1a) is favored at higher temperatures. Dimethyl sulfoxide, a very strong hydrogen-bond-accepting solvent, disrupts all internal hydrogen bonding in 1. Acetonitrile appears to disrupt the six-membered-ring hydrogen bond selectively and to promote nine-membered-ring interaction at room temperature, relative to chlorocarbon solvents. By treating the behavior of 1 as a two-state system, in which folding pattern 1c is considered to be the "native state" and all other folding patterns comprise the "denatured state", we have been able to carry out van't Hoff analyses of the temperature-dependent conformational changes. In methylene chloride, the native state is enthalpically preferred by 1.9-2.5 kcal/mol but entropically disfavored by 7.4-9.1 eu. Similar values are obtained in chloroform. This thermodynamic characterization demonstrates that, even in a relatively nonpolar environment, the relative enthalpic stabilities of alternative folding patterns cannot be predicted simply by maximizing the pairing of hydrogen-bond donors and acceptors.
- Dado, Gregory P.,Gellman, Samuel H.
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p. 4228 - 4245
(2007/10/02)
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- Process for synthesizing active esters of carboxylic acids
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The invention relates to a new process for preparing active esters or carboxylic acids, which consists in reacting a carboxylic acid, in the presence of an agent for binding hydrohalic acid, with a carbonate of formula: STR1 in which R1 denotes either a radical of formula STR2 in which R3 and R4, which may be identical or different, are not hydrogen atoms and denote organic radicals which may be substituted or unsubstituted and saturated or unsaturated, and may be or may not be bound to a polymer, and which can be joined together to form a hetero-cyclic system with the nitrogen atom, or a substituted or unsubstituted aryl radical which may or may not be bound to a polymer, R2 denotes a hydrogen atom, an aliphatic or cycloaliphatic radical which may be substituted or unsubstituted and saturated or unsaturated, or a substituted or unsubstituted aromatic radical, and X denotes a halogen atom. This process is especially useful for the synthesis of active esters of N-protected amino acids. The invention also relates to the new carbonates described above and the method of producing them, which consists in reacting an alpha-halogenated chloroformate of formula: with an alcohol of formula R1 OH in an inert solvent medium of the presence of an organic or inorganic base.
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- Novel Preparation of N-Protected Amino Acid Active Esters Using 1,2,2,2-Tetrachloroethyl Carbonates
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1,2,2,2-Tetrachloroethyl chloroformate reacts with substituted phenols or N-hydroxy imides to yield crystalline and stable mixed aryl or oximido tetrachloroethyl carbonates.When allowed to react with an N-protected amino acid derivative, these compounds proved to be efficient for the syntheses of the corresponding active esters.A series of active esters including p-nitrophenol, trichlorophenol, pentafluorophenol, and N-hydroxysuccinimide derivatives were prepared by this new procedure.
- Jaoudai, Mahmoud,Martinez, Jean,Castro, Bertrand
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p. 2364 - 2367
(2007/10/02)
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- LE CHLOROFORMIATE D'ISOPROPENYLE (IPCF) EN CHIMIE DES AMINO-ACIDES ET DES PEPTIDES - III SYNTHESE D'ESTERS ACTIFS D'AMINO ACIDES N-PROTEGES
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Isopropenyl chloroformate (IPCF) was used for preparation of mixed carbonates (Aryl and isopropenyl) which are very suitable reagents for active ester synthesis of amino acid derivatives (Boc derivatives in particular).
- Jaouadi, M.,Selve, C.,Dormoy, J. R.,Castro, B.,Martinez, J.
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p. 1721 - 1722
(2007/10/02)
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- FORMATION CONSTANTS OF SILVER(I) COMPLEXES OF SOME SULPHUR-CONTAINING DIPEPTIDES AND VALYLVALINE
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Formation constants at 25 deg C and l = 0.10 mol dm-3 (KNO3) have been determined for the complexes of AgI with a range of nine dipeptides which incorporate side-chains containing one (glycylmethionine and methionylglycine) or two sulphur donor atoms.In the latter case dipeptides formed from amino acids of the same and of different chiralities were studied (e.g.L-methionyl-L-methionine and L-methionyl-D-methionine).The results are compared with those for valylvaline.Values for the formation constants are interpreted in terms of the preferred conformations of the dipeptides, and the tendency for AgI to bond to S-donor atoms or to adopt linear co-ordination through the formation of dimeric complexes.
- Lyons, Anthony Q.,Pettit, Leslie D.
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p. 2305 - 2308
(2007/10/02)
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