- MACROCYCLIZATION OF PEPTIDOMIMETICS
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The invention provides an improved method of macrocyclization of peptidomimetics, as measured by isolated yields and product distribution, which comprises substitution of one or more of the backbone amide C=O bonds with a turn-inducing motif. The method is general with enhancements seen across a range of ring sizes (e.g. tri-, tetra-, penta- and hexapeptides). Specifically, the invention provides a peptidomimetic macrocycle comprising a carbonyl bioisosteric turn-inducing element having the structure: (I) wherein X is a heteroatom; and wherein R1 to R6 are each independently selected from alkyl, aryl, heteroaryl and H.
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Page/Page column 36; 38-39
(2019/10/19)
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- Metal-free transesterification catalyzed by tetramethylammonium methyl carbonate
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Environmentally benign metal-free tetramethylammonium methyl carbonate is effective as a catalyst for the chemoselective, scalable, and reusable transesterification of various esters and alcohols in common organic solvents. In situ-generated highly active species, tetramethylammonium alkoxides, can greatly avoid self-decomposition at ≤110 °C, and are reusable. In particular, chelating substrates, such as amino alcohols, diols, triols, sugar derivatives, alkaloids, α-amino acid esters, etc., which deactivate conventional metal salt catalysts, can be used. A 100 gram scale biodiesel production was also demonstrated.
- Hatano, Manabu,Tabata, Yuji,Yoshida, Yurika,Toh, Kohei,Yamashita, Kenji,Ogura, Yoshihiro,Ishihara, Kazuaki
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supporting information
p. 1193 - 1198
(2018/03/27)
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- Michael Acceptor-Based Peptidomimetic Inhibitor of Main Protease from Porcine Epidemic Diarrhea Virus
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Porcine epidemic diarrhea virus (PEDV) causes high mortality in pigs. PEDV main protease (Mpro) plays an essential role in viral replication. We solved the structure of PEDV Mpro complexed with peptidomimetic inhibitor N3 carrying a Michael acceptor warhead, revealing atomic level interactions. We further designed a series of 17 inhibitors with altered side groups. Inhibitors M2 and M17 demonstrated enhanced specificity against PEDV Mpro. These compounds have potential as future therapeutics to combat PEDV infection.
- Wang, Fenghua,Chen, Cheng,Yang, Kailin,Xu, Yang,Liu, Xiaomei,Gao, Fan,Liu, He,Chen, Xia,Zhao, Qi,Liu, Xiang,Cai, Yan,Yang, Haitao
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supporting information
p. 3212 - 3216
(2017/04/21)
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- Small-molecule inhibitor against MERS-CoV main protease, and preparation method and application thereof
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The invention provides a small-molecule inhibitor against MERS-CoV main protease. The small-molecule inhibitor is designed on the basis of the crystal structure of main protease of the novel coronavirus MERS-CoV. The invention also provides a synthetic method for the small-molecule inhibitor and application of the small-molecule inhibitor in preparation of drugs used for preventing and treating MERS-CoV infections. The small-molecule inhibitor against MERS-CoV main protease can substantially inhibit the activity of main protease of the MERS coronavirus, has good inhibitory activity to main protease of coronaviruses like SARS and MHV, and presents good application prospects in preparation of drugs used for preventing or treating coronavirus infections.
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Paragraph 0128; 0129; 0134; 0135
(2016/10/10)
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- In situ deprotection and incorporation of unnatural amino acids during cell-free protein synthesis
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The S30 extract from E. coli BL21 Star (DE3) used for cell-free protein synthesis removes a wide range of α-amino acid protecting groups by cleaving α-carboxyl hydrazides; methyl, benzyl, tert-butyl, and adamantyl esters; tert-butyl and adamantyl carboxamides; α-amino form-, acet-, trifluoroacet-, and benzamides and sidechain hydrazides and esters. The free amino acids are produced and incorporated into a protein under standard conditions. This approach allows the deprotection of amino acids to be carried out in situ to avoid separate processing steps. The advantages of this approach are demonstrated by the efficient incorporation of the chemically intractable (S)-4-fluoroleucine, (S)-4,5- dehydroleucine, and (2S,3R)-4-chlorovaline into a protein through the direct use of their respective precursors, namely, (S)-4-fluoroleucine hydrazide, (S)-4,5-dehydroleucine hydrazide, and (2S,3R)-4-chlorovaline methyl ester. These results also show that the fluoroand dehydroleucine and the chlorovaline are incorporated into a protein by the normal biosynthetic machinery as substitutes for leucine and isoleucine, respectively. Copyright
- Arthur, Isaac N.,Hennessy, James E.,Padmakshan, Dharshana,Stigers, Dannon J.,Lesturgez, Stéphanie,Fraser, Samuel A.,Liutkus, Mantas,Otting, Gottfried,Oakeshott, John G.,Easton, Christopher J.
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supporting information
p. 6824 - 6830
(2013/06/26)
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- N-aminosulfamide peptide mimic synthesis by alkylation of aza-sulfurylglycinyl peptides
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N-Aminosulfamides are peptidomimetics in which the CαH and the carbonyl of an amino acid residue are both respectively replaced by a nitrogen atom and a sulfonyl group. Aza-sulfurylglycinyl tripeptide analogs were effectively synthesized from amino acid building blocks by condensations of N-protected amino hydrazides and p-nitrophenylsulfamidate esters. The installation of N-alkyl chains and access to other aza-sulfuryl amino acid residues were effectively achieved by chemoselective alkylation.
- Turcotte, Stephane,Bouayad-Gervais, Samir H.,Lubell, William D.
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supporting information; body text
p. 1318 - 1321
(2012/05/20)
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- COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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The present invention relates to derivatized cyclofructan compounds, compositions comprising derivatized cyclofructan compounds, and methods of using compositions comprising derivatized cyclofructan compounds for chromatographic separations of chemical species, including enantiomers. Said compositions may comprise a solid support and/or polymers comprising derivatized cyclofructan compounds.
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Page/Page column 45-49; 60
(2010/12/31)
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- A class of novel conjugates of substituted purine and Gly-AA-OBzl: Synthesis and evaluation of orally analgesic activity
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Aimed at the chemotherapy of chronic pain two kinds of analgesic pharmacophores, substituted purine and Gly-AA-OBzl, were coupled via a five-step-reaction procedure and 19 novel conjugates N-[2-chloro-9- (tetrahydropyran-2-yl)-9H-purin-6-yl]-N-cyclopropylglycylamino acid benzylesters were provided. On mouse-tail flick model their in vivo analgesic activities were assayed. The results indicate that introducing Gly-OC2H 5 into the 6-position of the substituted purine leads to ambiguous increase of the analgesic activity, while introducing Gly-AA-OBzl into this position leads to significant increase of the analgesic activity.
- Kang, Guifeng,Zhao, Ming,Zhang, Xiaoyi,Peng, Li,Li, Chunbo,Mao, Wei,Ye, Weidong,Peng, Shiqi
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supporting information; experimental part
p. 6157 - 6160
(2010/12/19)
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- Synthesis and RNase A inhibition study of C2-symmetric bis-isochromenyl sulfones
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A new class of C2-symmetric bis-isochromene derivatives with 3,3′-linkage has been synthesized from bis-propargyl sulfones. The method involves treatment of the sulfones with triethylamine to form the isochromene derivatives presumably via the intramolecular Michael addition to the intermediate bis-allenic sulfones. Interestingly, the product expected from the Garratt-Braverman pathway was not obtained. The bis-isochromene 7d displayed RNase A inhibition activity, much stronger than the isochromene 8 and bis-isocoumarin 9.
- Mitra, Tapobrata,Dutta, Sansa,Basak, Amit
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supporting information; experimental part
p. 2828 - 2831
(2010/07/06)
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- MACROCYCLIC ANTAGONISTS OF THE MOTILIN RECEPTOR FOR TREATMENT OF GASTROINTESTINAL DYSMOTILITY DISORDERS
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The present invention provides conformationally-defined macrocyclic compounds that bind to and/or are functional modulators of the motilin receptor including subtypes, isoforms and/or variants thereof. These macrocyclic compounds, at a minimum, possess adequate pharmacological properties to be useful as therapeutics for a range of disease indications. In particular, these compounds are useful for treatment and prevention of disorders characterized by hypermotilinemia and/or gastrointestinal hypermotility, including, but not limited to, diarrhea, cancer treatment-related diarrhea, cancer-induced diarrhea, chemotherapy-induced diarrhea, radiation enteritis, radiation-induced diarrhea, stress-induced diarrhea, chronic diarrhea, AIDS-related diarrhea, C. difficile associated diarrhea, traveller's diarrhea, diarrhea induced by graph versus host disease, other types of diarrhea, dyspepsia, irritable bowel syndrome, chemotherapy-induced nausea and vomiting (emesis) and post-operative nausea and vomiting and functional gastrointestinal disorders. In addition, the compounds possess utility for the treatment of diseases and disorders characterized by poor stomach or intestinal absorption, such as short bowel syndrome, celiac disease and cachexia. The compounds also have use for the treatment of inflammatory diseases and disorders of the gastrointestinal tract, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease and pancreatitis. Accordingly, methods of treating such disorders and pharmaceutical compositions including compounds of the present invention are also provided.
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Page/Page column 45
(2010/04/30)
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- Esterification of unprotected a-Amino acids in ionic liquids as the reaction media
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Ionic liquid 1,3-dimethylimidazolium methanesulfonate was used to prepare a-amino acids benzylic esters from unprotected amino acids and benzyl chloride. Esterification of several amino acids was achieved with satisfactory yields: by-products can be removed by a simple work-up procedure to afford the pure product. The described method is simple, mild, rapid and save.
- Biondini, Daniele,Brinchi, Lucia,Germani, Raimondo,Goracci, Laura,Savelli, Gianfranco
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experimental part
p. 39 - 44
(2010/08/22)
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- Study on synthesis, characteristics and catalysis properties of novel chiral metal complexes catalysts for 1,3-dipolar cycloaddition reactions of nitrone with electron-rich alkene
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As a new class of potential catalysts for 1,3-dipolar cycloaddition reactions, fourteen L-amino acid Schiff base Cu(II) and Ti(IV) complexes were synthesized, characterized, and evaluated for their catalytic activities in the reaction between C, N-diphenylnitrone and electron-rich ethyl vinyl ether under both homogeneous and in situ conditions. The methods for preparation and utilization of the catalysts were elucidated in detail, and the results of the catalytic reactions were described and discussed as well. Excellent reaction results were found in the presence of some catalysts (20 mol%) with > 90% endo-isoazolidines produced, compared with predominantly exo-isoazolidine produced without a catalyst. In addition, the reaction rate is found to be enhanced remarkably by a Cu(II) complex Schiff base catalyst at room temperature.
- You, Jun,Liu, Bo,Wang, Yi
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experimental part
p. 1010 - 1017
(2010/08/13)
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- PEPTIDIC COMPOUNDS
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The present invention provides a compound of formula (I), (II), (III) and (IV) as defined herein and pharmaceutically acceptable derivatives thereof. The present invention further provides use of the compounds of the present invention in the treatment of bacterial infection and in the treatment of HIV infection. Also provided are pharmaceutical compositions comprising the compounds of the present invention.
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Page/Page column 31
(2008/06/13)
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- Methods and compositions for treating amyloid-related diseases
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Methods, compounds, pharmaceutical compositions and kits are described for treating or preventing amyloid-related disease.
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Page/Page column 138
(2010/11/24)
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- Synthesis and cytotoxic activities of β-carboline amino acid ester conjugates
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β-Carboline represents a class of compounds with potent anti-tumor activity by intercalating with DNA. To further enhance the cytotoxic potency and bioavailability of β-carboline, a series of novel β-carboline amino acid ester conjugates were designed and synthesized, and the cytotoxic activities of these compounds were tested using a panel of human tumor cell lines. In addition, the membrane permeability of these compounds was evaluated in vitro using a Caco-2 cell monolayer model. The β-carboline amino acid ester conjugates demonstrated improved cytotoxic activity compared to the parental β-carbolines. In particular, the Lys/Arg conjugates were the most potent analogs with an IC50 value of 4 and 1 μM against human cervical carcinoma cells. The low interaction energy of Arg conjugate based on molecular modeling may contribute to its enhanced cytotoxicity. Taken together, this study provided new insights into structure-activity relationships in the β-carboline amino acid ester conjugates and identified the β-carboline Lys/Arg conjugates as promising lead compounds for further in vivo biological and molecular evaluation.
- Zhao, Ming,Bi, Lanrong,Wang, Wei,Wang, Chao,Baudy-Floc'h, Michele,Ju, Jingfang,Peng, Shiqi
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p. 6998 - 7010
(2007/10/03)
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- Effect of PNA backbone modifications on cyanine dye binding to PNA-DNA duplexes investigated by optical spectroscopy and molecular dynamics simulations
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Optical spectroscopy and molecular dynamics simulations have been used to study the interaction between a cationic cyanine dye and peptide nucleic acid (PNA)-DNA duplexes. This recognition event is important because it leads to a visible color change, signaling successful hybridization of PNA with a complementary DNA strand. We previously proposed that the dye recognized the minor groove of the duplex, using it as a template for the assembly of a helical aggregate. Consistent with this, we now report that addition of isobutyl groups to the PNA backbone hinders aggregation of the dye when the substituents project into the minor groove but have a weaker effect if directed out of the groove. UV-Visible and circular dichroic spectroscopy were used to compare aggregation on the different PNA-DNA duplexes, while molecular dynamics simulations were used to confirm that the substituents block the minor groove to varying degrees, depending on the configuration of the starting amino acid. In addition to a simple steric blockage effect of the substituent, the simulations suggest that directing the isobutyl group into the minor groove causes the groove to narrow and the duplex to become more rigid, structural perturbations that are relevant to the growing interest in backbone-modified PNA for applications in the biological and materials sciences.
- Dilek, Isil,Madrid, Marcela,Singh, Rojendra,Urrea, Christian P.,Armitage, Bruce A.
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p. 3339 - 3345
(2007/10/03)
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- Restricted conformation analogues of an anthelmintic cyclodepsipeptide
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Six analogues of the anthelmintic cyclodepsipeptide PF1022A were prepared, each containing a small ring fused to the macrocycle to restrict the number of conformations the larger ring can adopt. It was anticipated that such conformational changes could lead to enhanced biological activity and selectivity. The analogues form two series of three members each. In one series, a carbon-based molecular bridge joins the methyl of a leucine residue with the methyl of its closest lactic acid residue to form five-, six-, and seven-membered lactam rings. In the second series, a leucine residue is replaced with five-, six-, and seven-membered nitrogen heterocycles. Decreasing the size of the small ring in the lactam series increasingly distorts the macrocycle and consistently decreases activity relative to PF1022A. In the leucine series, a similar trend is observed. Molecular modeling of PF1022A along with the analogues described herein suggests that the ability to exist in a highly symmetrical conformational state is a necessary condition for biological activity.
- Dutton, Fred E.,Lee, Byung H.,Johnson, Sandra S.,Coscarelli, Eileen M.,Lee, Pil H.
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p. 2057 - 2073
(2007/10/03)
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- Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by β-glucuronidase
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The first synthesis of a prodrug of HLA-A2.1 associated antigenic influenza peptide 2a was accomplished. Two methods for synthesis of prodrugs of antigenic peptides activated by β-glucuronidase and comprising a self-immolative 3-nitrobenzyloxycarbonyl moiety were investigated. Reaction of β-glucuronic acid glycoside of 4-hydroxy-3-nitrobenzyl alcohol (3) with N,N′-disuccinimidyl carbonate (DSC) followed by conjugation with AlaOMe, Gly, Thr, Phe-Leu, and Leu-Arg gave carbamates 4a-4f. Deacetylation of 4b and 4e with MeONa/MeOH gave β-glucuronides 5b and 5e. Compound 5e was converted to β-glucuronic acid conjugate 6e by the action of pig liver esterase (PLE). Compound 6e is a substrate for β-glucuronidase. Method of a direct introduction of the prodrug residue into antigenic nonapeptide GILGFVFTL (2b) failed. Alternately, glycine conjugate 5b was activated to pentafluorophenyl ester 10. Model coupling of 10 with Phe-Leu gave tripeptide conjugate ester 11a which was hydrolyzed by PLE to uronic acid 12. Condensation of 10 with octapeptide ILGFVFTL (9) gave prodrug precursor 11b. Octapeptide 9 was prepared by de novo synthesis using a racemization-free fragment coupling method. Ester hydrolysis with Ba(OH)2/MeOH gave the target prodrug 2a which is a substrate for β-glucuronidase. Prodrug 2a does not bind to HLA-A2.1 of T2 human cells defective in major histocompatibility complex I (MHC I)-associated peptide processing. Addition of β-glucuronidase restored the binding to the level observed with parent nonapeptide 2b although higher concentrations of prodrug 2a and enzyme were necessary.
- Rawale, Sharad,Hrihorczuk, Lew M.,Wei, Wei-Zen,Zemlicka, Jiri
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p. 937 - 943
(2007/10/03)
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- Solution-phase automated synthesis of tripeptide derivatives
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An improved general method for automated synthesis of tripeptides was developed, in which methanesulfonic acid (MSA) was used in place of trifluoroacetic acid (TFA), thus making it possible to avoid, 1) corrosion of the apparatus by strong acid vapor, 2) formation of emulsions, and 3) use of the restricted solvent, dichloromethane. As an application of the automated synthesis apparatus, 216 fragment tripeptide derivatives were synthesized systematically using the MSA method, in excellent yield and with increased efficiency.
- Kuroda,Hattori,Kitada,Sugawara
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p. 1138 - 1146
(2007/10/03)
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- Application of a unique automated synthesis system for solution-phase peptide synthesis
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An automated synthesis system, which is suitable for repetitive syntheses using similar reaction procedures, was used to synthesize systematically a library of all possible dipeptides (25) and tripeptides (125) from 5 protected amino acids. The apparatus has also been applied to the automated synthesis of 10 fragment tripeptide derivatives that are constituents of the hormone PACAP-27. The measured molecular optical rotation values of the library of 125 tripeptides were found to correlate well with calculated values obtained by summation of the molecular optical rotation values for the constituent amino acids.
- Sugawara,Kobayashi,Okamoto,Kitada,Fujino
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p. 1272 - 1280
(2007/10/02)
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- Biodegradable microspheres. 16. Synthesis of primaquine-peptide spacers for lysosomal release from starch microparticles
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Classical procedures of peptide synthesis were applied to synthesize four groups of compounds, and analytical methods were developed for each of them. Two of the groups are tetrapeptide derivatives of the antileishmanial drug primaquine (PQ), with general structure NH2-X-Leu-Ala-Y-PQ. In the first group, Leu, Tyr, Lys, and Asp were used in the Y position, while X was Ala. In the second group, Ala, Tyr, Lys, and Asp were used in the X position, while Y was Leu. The derivatives are intended to be coupled, via their free α-amino group, to polyacryl starch microparticles, lysosomotropic drug carriers developed in our laboratory. Thus, a systematic study of the significance of the varying amino acid composition of the tetrapeptide spacer arm for the rate of lysosomal enzymatic release of PQ can be possible. A third group, composing ε-aminocaproic acid-PQ derivatives which lack a free α-amino group, was synthesized. This was done to study the importance of enzymes, other than aminopeptidases, during lysosomal degradation of these derivatives. To allow HPLC analysis of the pattern of degradation of tetrapeptide-PQ derivatives, some shorter peptide-PQ derivatives (group four) were prepared as well.
- Borissova,Lammek,Stjarnkvist,Sjoholm
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p. 249 - 255
(2007/10/02)
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- The synthesis of pure Amadori rearrangement products
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The term "Maillard reaction" is used to describe a complex set of reactions in foods leading to flavour generation and non-enzymatic browning.The first step in this process is the so-called Amadori rearrangement: a reducing saccharide and a peptide fragment react to form an Amadori Rearrangement Product (ARP).To be able to do model studies on flavour generation, gram amounts of pure ARP are required.In the present study, glucose-derived ARPs were synthesised from specifically protected and activated starting compounds.After deprotection and purification, pure ARPs were obtained.This is the first time that ARPs of dipeptides have been isolated.
- Noomen, S. N.,Breel, G. J.,Winkel, C.
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p. 321 - 324
(2007/10/02)
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- Method for treating inflammation and compounds and compositions suitable for use therein
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The present invention relates to a method of treating an inflammatory condition, and to compounds and composition suitable for use in such a method, which compounds have the Formula: STR1 wherein: X is methylene, ethylene, ethyleneoxy, or oxygen; Q is STR2 where C' is a residue of a lipophilic amino acid, and Y is --CO2 H, --CH2 OH, --CONR1 R2, or --CO2 R1 where R1 and R2 hydrogen, alkyl, or aryl; R3 and R4 are, independently, hydrogen, alkyl or aryl; and A and B are, independently, hydrogen, fused phenyl, alkyl, aryl, alkaryl, aralkyl, alkoxy, alkoxyalkyl, halogen, or nitro; or pharmaceutically acceptable salts thereof.
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- Enzymes in organic synthesis: Use of subtilisin and a highly stable mutant derived from multiple site-specific mutations
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A subtilisin mutant (subtilisin 8350) derived from subtilisin BPN' via six-specific mutations (Met50Phe, Gly169Ala, Asn76Asp, Gln206Cys, Tyr217Lys, and Asn218Ser) was found to be 100 times more stable than the wild-type enzyme in aqueous solution at room temperature and 50 times more stable than the wild type in anhydrous dimethylformamide. Kinetic studies using ester, thio ester, and amide substrates, and the transition-state analogue inhibitor Boc-Ala-Val-Phe-CF3, indicate the both the wild-type and the mutant enzymes have very similar specificities and catalytic properties. The inhibition constant (K(i)) = 5.0 μM) for the wild-type enzyme is approximately 5 times that of the mutant enzyme (K(i)) = 1.1 μM), suggesting that the mutant enzyme binds the reaction transition state more strongly than the wild-type enzyme. This result is consistent with the observed rate constants for the corresponding ester and amide substrates; i.e. the k(cat)/k(m) values for the mutant are larger than those for hhe wild-type enzyme. Application of the mutant enzyme and the wild-type enzyme to organic synthesis has been demonstrated in the regioselective acylation of nucleosides in anhydrous dimethylformamide (with 65-100% regioselectivity at the 5'-position), in the enantioselective hydrolysis of N-protected and unprotected common and uncommon amino acid esters in water (with 85-98% enantioselectivity for the L-isomer), and in the synthesis of di- and oligopeptides via aminolysis of N-protected amino acid and peptide esters. The enzymatic peptide synthesis was carried out under high concentrations of DMF (~50%) to improve substrate solubility and to minimize enzymatic peptide cleavage. Low enantioselectivity was observed in the enzymatic transformation of non-amino acid alcohols and acids.
- Wong,Chen,Hennen,Bibbs,Wang,L iu,Pantoliano,Whitlow,Bryan
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p. 945 - 953
(2007/10/02)
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