- Expected and unforeseen reactions of 2,3,3-trimethyl-1λ6-isothiazolidine-1,1,4-trione and their spiro derivative
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Herein, we present a full account of our studies with respect to the reactivity of insufficiently explored 1λ6-isothiazolidine-1,1,4-triones (so-called β-keto-γ-sultams). This heterocyclic system possesses two reaction centers: the EWG-activate
- Popova, Maria V.,Dobrydnev, Alexey V.,Dyakonenko, Viktoriya V.,Konovalova, Irina S.,Shishkina, Svitlana V.,Volovenko, Yulian M.
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- Preparation and NMR spectra of substituted 2-(4-nitrophenyl)imidazolinones
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A series of 11 substituted 2-(4-nitrophenyl)imidazolinones have been prepared by base catalyzed cyclizations of substituted 2-(4-nitrobenzoylamino)alkanamides. At higher methoxide concentrations the cyclization can be accompanied by reduction of nitro group to azoxy group. All the substances prepared have been identified by 1H and 13C NMR spectra.
- Sedlak, Milos,Halama, Ales,Kavalek, Jaromir,Machacek, Vladimir,Mitas, Petr,Sterba, Vojeslav
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- Stapling of a 310-helix with click chemistry
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Short peptides are important as lead compounds and molecular probes in drug discovery and chemical biology, but their well-known drawbacks, such as high conformational flexibility, protease lability, poor bioavailability and short half-lives in vivo, have prevented their potential from being fully realized. Side chain-to-side chain cyclization, e.g., by ring-closing olefin metathesis, known as stapling, is one approach to increase the biological activity of short peptides that has shown promise when applied to 310-and α-helical peptides. However, atomic resolution structural information on the effect of side chain-to-side chain cyclization in 310-helical peptides is scarce, and reported data suggest that there is significant potential for improvement of existing methodologies. Here, we report a novel stapling methodology for 310-helical peptides using the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction in a model aminoisobutyric acid (Aib) rich peptide and examine the structural effect of side chain-to-side chain cyclization by NMR, X-ray diffraction, linear IR and femtosecond 2D IR spectroscopy. Our data show that the resulting cyclic peptide represents a more ideal 310-helix than its acyclic precursor and other stapled 310-helical peptides reported to date. Side chain-to-side chain stapling by CuAAC should prove useful when applied to 3 10-helical peptides and protein segments of interest in biomedicine.(Figure Presented)
- Jacobsen, yvind,Maekawa, Hiroaki,Ge, Nien-Hui,Goerbitz, Carl Henrik,Rongved, Pal,Ottersen, Ole Petter,Amiry-Moghaddam, Mahmood,Klaveness, Jo
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- Influence of the C-terminal substituent on the crystal-state conformation of Adm peptides
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The bis-functionalized diamondoid α-amino acid 2-aminoadamantane-2-carboxylic acid (Adm) has been used as the building block of four Nα-formyl homo-dipeptide alkylamide sequences via a solution-phase Ugi multicomponent reaction approach. The conformers of these peptides have been determined in the crystalline state by X-ray diffraction to distinguish the influences of the C-terminal substituent. One of the Adm peptides folds into an open and a hydrogen-bonded γ-turn geometry. Moreover, 3D-structures have been observed featuring two consecutive γ-turns in an incipient γ-helical structure, a significantly distorted nonhelical β-turn, as well as an S-shaped conformation with opposite helical screw senses. A significant topological variety is thus exhibited by the -Adm-Adm- sequences contingent on their C-terminal substituents, illustrating both the broad conformational potential and the need for further characterization of this sterically bulky residue in explorations of its ?, ψ space.
- Mir, Fatemeh M.,Crisma, Marco,Toniolo, Claudio,Lubell, William D.
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- Conformation-specific spectroscopy of capped, gas-phase Aib oligomers: Tests of the Aib residue as a 310-helix former
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The conformational preferences of a series of capped peptides containing the helicogenic amino acid aminoisobutyric acid (Aib) (Z-Aib-OH, Z-(Aib)2-OMe, and Z-(Aib)4-OMe) are studied in the gas phase under expansion-cooled conditions. Aib oligomers are known to form 310-helical secondary structures in solution and in the solid phase. However, in the gas phase, accumulation of a macrodipole as the helix grows could inhibit helix stabilization. Implementing single-conformation IR spectroscopy in the NH stretch region, Z-Aib-OH and Z-(Aib)2-OMe are both observed to have minor conformations that exhibit dihedral angles consistent with the 310-helical portion of the Ramachandran map (φ, ψ = -57°, -30°), even though they lack sufficient backbone length to form 10-membered rings which are a hallmark of the developed 310-helix. For Z-(Aib)4-OMe three conformers are observed in the gas phase. Single-conformation infrared spectroscopy in both the NH stretch (Amide A) and CO stretch (Amide I) regions identifies the main conformer as an incipient 310-helix, having two free NH groups and two C10 H-bonded NH groups, labeled an F-F-10-10 structure, with a calculated dipole moment of 13.7 D. A second minor conformer has an infrared spectrum characteristic of an F-F-10-7 structure in which the third and fourth Aib residues have φ, ψ = 75°, -74° and -52°, 143°, Ramachandran angles which fall outside of the typical range for 310-helices, and a dipole moment that shrinks to 5.4 D. These results show Aib to be a 310-helix former in the gas phase at the earliest stages of oligomer growth.
- Gord, Joseph R.,Hewett, Daniel M.,Hernandez-Castillo, Alicia O.,Blodgett, Karl N.,Rotondaro, Matthew C.,Varuolo, Adalgisa,Kubasik, Matthew A.,Zwier, Timothy S.
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- [N-methyl-11C]MeAIB, a Tracer for System A Amino Acid Transport: Preparation from [11C]Methyl Triflate and HPLC Metabolite Analysis of Plasma Samples After Intravenous Administration in Man
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MeAIB, α-methylamino-isobutyric acid, is an achiral synthetic ammo acid which is a highly selective substrate for the A-type, or alanine-preferring, amino acid transport system. [N-methyl-11C]MeAIB ([11C]MeAIB) was prepared by reaction of [11C]methyl triflate with AIB methyl ester, generated in situ from its corresponding hydrochloride, followed by hydrolysis of the ester function with aqueous NaOH. After HPLC-purification, the product was obtained in a 60-70 percent decay corrected yield counted from [11C]methyl triflate. The total synthesis time was 32-37 min and the radiochemical purity of the product higher than 98 percent. HPLC analysis of plasma samples taken 5-30 min after the administration of [11C]MeAlB to man showed that more than 95 percent of the total radioactivity in the plasma consisted of unchanged [11C]MeAIB. The simple preparation and the high metabolic stability of [11C]MeAlB makes this novel tracer a potential candidate for positron emission tomography investigations for the system A amino acid transport system in vivo.
- Nagren, Kjell,Sutinen, Eija,Jyrkkio, Sirkku
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- N-(tert-Butoxycarbonyl)-α-aminoisobutyryl-α-aminoisobutyric acid methyl ester: Two polymorphic forms in the space group P21/n
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The title compound (systematic name: methyl 2-{2-[(tertbutoxycarbonyl) amino]-2-methylpropanamido}-2-methylpropanoate), C14H 26N2O5, (I), crystallizes in the monoclinic space group P21/n in two polymorphic forms, each with one molecule in the asymmetric unit. The mol-ecular conformation is essentially the same in both polymorphs, with the α-amino-isobutyric acid (Aib) residues adopting φ and ψ values characteristic of α-helical and mixed 310- and α-helical conformations. The helical handedness of the C-terminal residue (Aib2) is opposite to that of the N-terminal residue (Aib1). In contrast to (I), the closely related peptide Boc-Aib-Aib-OBn (Boc is tert-butoxycarbonyl and Bn is benzyl) adopts an αL-PII backbone conformation (or the mirror image conformation). Compound (I) forms hydrogen-bonded para-llel β-sheet-like tapes, with the carbonyl groups of Aib1 and Aib2 acting as hydrogen-bond acceptors. This seems to represent an unusual packing for a protected dipeptide containing at least one ,-disubstituted residue.
- Gebreslasie, Hadgu Girmay,Jacobsen, yvind,Goerbitz, Carl Henrik
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- A Transannular Rearrangement Reaction of a Pyrroloindoline Diketopiperazine
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Oxaline, glandicoline, and meleagrin contain a unique triazaspirocyclic structure. Attracted by their biological activities, we attempted a novel strategy, mimicking a proposed biosynthetic pathway for glandicoline B in Penicillium chrysogenum and Penicil
- Yan, Qiao,Carroll, Patrick J.,Gau, Michael R.,Winkler, Jeffrey D.,Joullié, Madeleine M.
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Read Online
- Microwave-Assisted Ruthenium- and Rhodium-Catalyzed Couplings of α-Amino Acid Ester-Derived Phosphinamides with Alkynes
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Two different types of new phosphinamide α-amino ester derivatives have been prepared in moderate to high yields via ruthenium(II) and rhodium(III)-catalyzed ortho-C?H functionalization under microwave irradiation. Specifically, the ortho-alkenylated phosphinamides were produced through coupling of phosphinamides containing an α-substituted or α,α-disubstituted α-amino ester with internal alkynes under ruthenium catalysis. In contrast, Ru and the more effective Rh-catalyzed coupling of the α-unsubstituted glycine ester phosphinamide with alkynes resulted in formation of oxidative annulation products, phosphaisoquinolin-1-ones. The developed methods feature the use of easily accessible starting materials, short reaction time, exclusive E-stereoselectivity (for ortho-alkenylation) and good functional group tolerance. The alkenylation reaction was readily scaled up to gram scale. Furthermore, the obtained alkenylated phosphinamide could be transformed into P-containing dipeptides through hydrolysis of the ester group in the catalysis product and subsequent condensation with an α-amino ester.
- Li, Xue-Hong,Gong, Jun-Fang,Song, Mao-Ping
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supporting information
(2021/12/23)
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- Transition Metal-Free N-Arylation of Amino Acid Esters with Diaryliodonium Salts
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A transition metal-free approach for the N-arylation of amino acid derivatives has been developed. Key to this method is the use of unsymmetric diaryliodonium salts with anisyl ligands, which proved important to obtain high chemoselectivity and yields. The scope includes the transfer of both electron deficient, electron rich and sterically hindered aryl groups with a variety of different functional groups. Furthermore, a cyclic diaryliodonium salt was successfully employed in the arylation. The N-arylated products were obtained with retained enantiomeric excess.
- Kervefors, Gabriella,Kersting, Leonard,Olofsson, Berit
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supporting information
p. 5790 - 5795
(2021/03/08)
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- AZOLE DERIVATIVE, AGRICULTURAL AND HORTICULTURAL CHEMICAL AND INDUSTRIAL MATERIAL PROTECTIVE AGENT
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PROBLEM TO BE SOLVED: To provide a plant disease-controlling agent which has low toxicity to humans and animals and excellent handling safety and exhibits an excellent controlling effect on a wide range of plant diseases and a high antifungal activity aga
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Paragraph 0153
(2020/12/05)
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- Benzoazepine-Fused Isoindolines via Intramolecular (3 + 2)-Cycloadditions of Azomethine Ylides with Dinitroarenes
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Aminobenzaldehydes bearing a pendant 3,5-dinitrophenyl group react thermally with N-substituted α-amino acids to form unprecedented benzoazepine-fused isoindolines. The reaction proceeds via a dearomatization/rearomatization sequence involving an intramolecular (3 + 2)-cycloaddition between the in situ formed azomethine ylide and the dinitroarene. Various glycine derivatives are tolerated as well as branched substrates based on cyclic, α-mono-, and α,α-disubstituted amino acids, giving single diastereomers in many cases. The method is scalable and gives products with a nitro group ready for further manipulation.
- Wales, Steven M.,Rivinoja, Daniel J.,Gardiner, Michael G.,Bird, Melissa J.,Meyer, Adam G.,Ryan, John H.,Hyland, Christopher J. T.
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supporting information
p. 4703 - 4708
(2019/06/27)
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- Oxidative Damage in Aliphatic Amino Acids and Di- and Tripeptides by the Environmental Free Radical Oxidant NO3?: the Role of the Amide Bond Revealed by Kinetic and Computational Studies
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Kinetic and computational data reveal a complex behavior of the important environmental free radical oxidant NO3? in its reactions with aliphatic amino acids and di- and tripeptides, suggesting that attack at the amide N-H bond in the peptide backbone is a highly viable pathway, which proceeds through a proton-coupled electron transfer (PCET) mechanism with a rate coefficient of about 1 × 106 M-1 s-1 in acetonitrile. Similar rate coefficients were determined for hydrogen abstraction from the α-carbon and from tertiary C-H bonds in the side chain. The obtained rate coefficients for the reaction of NO3? with aliphatic di- and tripeptides suggest that attack occurs at all of these sites in each individual amino acid residue, which makes aliphatic peptide sequences highly vulnerable to NO3?-induced oxidative damage. No evidence for amide neighboring group effects, which have previously been found to facilitate radical-induced side-chain damage in phenylalanine, was found for the reaction of NO3? with side chains in aliphatic peptides.
- Nathanael, Joses G.,Wille, Uta
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p. 3405 - 3418
(2019/03/11)
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- Peptides
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A peptide which can adopt a 310-helical conformation in which the side chains of two amino acid residues in the peptide backbone are linked by a group comprising an aromatic 5-membered ring.
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Page/Page column 37
(2016/02/03)
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- INHIBITORS OF HEPATITIS C VIRUS POLYMERASE
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The present invention provides, among other things, compounds represented by the general Formula I: (I) and pharmaceutically acceptable salts thereof, wherein L and A (and further substituents) are as defined in classes and subclasses herein and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection.
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Paragraph 409; 410; 412
(2016/10/11)
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- Electron transfer-induced coupling of haloarenes to styrenes and 1,1-diphenylethenes triggered by diketopiperazines and potassium tert-butoxide
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The coupling of haloarenes to styrenes and 1,1-diarylethenes has been achieved with potassium tert-butoxide in the presence of N,N'-dialkyldiketopiperazines. In contrast to previously reported reactions where phenanthroline has been used to mediate the reactions, the use of diketopiperazines can lead to either 1,1,2-triarylethenes or 1,1,2-triarylethanes, depending on the conditions used.
- Doni, Eswararao,Zhou, Shengze,Murphy, John A.
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p. 1755 - 1774
(2015/02/05)
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- A COMPOUND FOR INHIBITING 11B-HYDROXY STEROID DEHYDROGENASE 1, AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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Disclosed are a novel compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition including the same for inhibiting human 11-β-hydroxy steroid dehydrogenase type 1 (11β-HSD1). The disclosed compound and the pharmaceutical composition including the same for inhibiting human 11-β-hydroxy steroid dehydrogenase type 1 (11β-HSD1) are excellent in activity and solubility, and is more efficient in formulation and transfer.
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Paragraph 0513-0514; 0568-0569; 0599-0600; 0658-0660
(2014/08/06)
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- Mechanochemical preparation of hydantoins from amino esters: Application to the synthesis of the antiepileptic drug phenytoin
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The eco-friendly preparation of 5- and 5,5-disubstituted hydantoins from various amino ester hydrochlorides and potassium cyanate in a planetary ball-mill is described. The one-pot/two-step protocol consisted in the formation of ureido ester intermediates, followed by a base-catalyzed cyclization to hydantoins. This easy-handling mechanochemical methodology was applied to a large variety of α- and β-amino esters, in smooth conditions, leading to hydantoins in good yields and with no need of purification steps. As an example, the methodology was applied to the "green" synthesis of the antiepileptic drug Phenytoin, with no use of any harmful organic solvent.
- Konnert, Laure,Reneaud, Benjamin,De Figueiredo, Renata Marcia,Campagne, Jean-Marc,Lamaty, Frdric,Martinez, Jean,Colacino, Evelina
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p. 10132 - 10142
(2015/02/19)
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- Identifying the roles of amino acids, alcohols and 1,2-diamines as mediators in coupling of haloarenes to arenes
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Coupling of haloarenes to arenes has been facilitated by a diverse range of organic additives in the presence of KOtBu or NaOtBu since the first report in 2008. Very recently, we showed that the reactivity of some of these additives (e.g., compounds 6 and 7) could be explained by the formation of organic electron donors in situ, but the role of other additives was not addressed. The simplest of these, alcohols, including 1,2-diols, 1,2-diamines, and amino acids are the most intriguing, and we now report experiments that support their roles as precursors of organic electron donors, underlining the importance of this mode of initiation in these coupling reactions.
- Zhou, Shengze,Doni, Eswararao,Anderson, Greg M.,Kane, Ryan G.,Macdougall, Scott W.,Ironmonger, Victoria M.,Tuttle, Tell,Murphy, John A.
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supporting information
p. 17818 - 17826
(2015/02/19)
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- A COMPOUND FOR INHIBITING 11BETA-HYDROXY STEROID DEHYDROGENASE 1, AND A PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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Disclosed are a novel compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition including the same for inhibiting human 11-beta-hydroxy steroid dehydrogenase type 1 (11beta-HSD1). The disclosed compound and the pharmaceutical composition including the same for inhibiting human 11-beta-hydroxy steroid dehydrogenase type 1 (11beta-HSD1) are excellent in activity and solubility, and is more efficient in formulation and transfer.
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Paragraph 936-938
(2013/03/26)
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- Method for the efficient synthesis of highly-substituted oxetan- and azetidin-, dihydrofuran- and pyrrolidin-3-ones and its application to the synthesis of (±)-pseudodeflectusin
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Highly substituted four- and five-membered heterocycles were prepared starting with O,P- and N,P-acetals by using a one-pot method involving base induced cyclization and a Horner-Wadsworth-Emmons (HWE) olefination reaction. Divergent synthesis of various heterocycles was achieved by using this method and transformations of the alkenyl group in the products of these processes were exemplified. Finally, a short and efficient synthesis of (±)- pseudodeflectusin based on the new methodology was achieved.
- Maegawa, Tomohiro,Otake, Kazuki,Hirosawa, Keiichi,Goto, Akihiro,Fujioka, Hiromichi
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supporting information
p. 4798 - 4801
(2013/01/15)
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- Molecular assembly composed of a dendrimer template and block polypeptides through stereocomplex formation
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A 2nd generation polyamideamine (PAMAM) dendrimer bearing right-handed helices to its eight terminals was shown to accommodate eight left-handed helices via stereocomplex formation to generate molecular assemblies of disk structure with 13-14 nm diameter and 6 nm thickness.
- Matsui, Hisato,Ueda, Motoki,Makino, Akira,Kimura, Shunsaku
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supporting information; scheme or table
p. 6181 - 6183
(2012/07/28)
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- IMIDAZOLIDINEDIONE DERIVATIVES
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The invention provides a compound of formula (Ia), and pharmaceutically acceptable salts thereof. The invention also provides use of the compounds or salts as modulators of Kv3.1 and/or Kv3.2, and in the treatment of diseases or disorders where a modulator of Kv3.1 and/or Kv3.2 is required, such as depression and mood disorders, hearing disorders, schizopherenea, substance abuse disorders, sleep disorders or epilepsy.
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Page/Page column 82
(2011/06/26)
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- PROCESS FOR THE PREPARATION OF ANAGRELIDE AND ANALOGUES
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The present invention relates to a novel process for producing quinazoline compounds which are useful in therapy. More specifically, the compounds produced by the process of the invention are useful in the treatment of a number of cardiovascular diseases.
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Page/Page column 21
(2010/08/05)
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- Discovery of a novel sulfonamide-pyrazolopiperidine series as potent and efficacious γ-secretase inhibitors (Part II)
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Significant improvement in metabolic stability on the pyrazolopiperidine scaffold over the original series were achieved and this stability improvement translated in an improved in vivo efficacy.
- Ye, Xiaocong M.,Konradi, Andrei W.,Smith, Jenifer,Aubele, Danielle L.,Garofalo, Albert W.,Marugg, Jennifer,Neitzel, Marty L.,Semko, Chris M.,Sham, Hing L.,Sun, Minghua,Truong, Anh P.,Wu, Jing,Zhang, Hongbin,Goldbach, Erich,Sauer, John-Michael,Brigham, Elizabeth F.,Bova, Michael,Basi, Guriqbal S.
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scheme or table
p. 3502 - 3506
(2010/08/07)
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- SUBSTITUTED IMIDAZOLONE DERIVATIVES, PREPARATIONS AND USES
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The present invention relates to polysubstituted imidazolone derivatives, to the pharmaceutical compositions comprising them and to the therapeutic uses thereof in the human and animal health fields. The present invention also relates to a process for preparing these derivatives.
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Page/Page column 37
(2010/02/16)
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- Facile synthesis of β-amino disulfides, cystines, and their direct incorporation into peptides
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Herein, we report a simple and efficient methodology for the synthesis of β-amino disulfides by regioselective ring opening of sulfamidates with benzyltriethylammonium tetrathiomolybdate [BnNEt3] 2MoS4. Stability and reactivity of different protecting groups under the reaction conditions have been discussed. This methodology has also been extended to serine and threonine derived sulfamidates to furnish cystine and 3,3′-dimethyl cystine derivatives. Georg Thieme Verlag.
- Nasir Baig,Kanimozhi, Catherine K.,Sudhir, V. Sai,Chandrasekaran, Srinivasan
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scheme or table
p. 1227 - 1232
(2009/09/06)
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- 6-Hydrazinopurine 2′-methyl ribonucleosides and their 5′-monophosphate prodrugs as potent hepatitis C virus inhibitors
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A series of 6-hydrazinopurine 2′-methyl ribonucleosides was synthesized and tested for its inhibitory activity against the hepatitis C virus (HCV). The lack of antiviral activity of these nucleosides was associated with a poor affinity for adenosine kinase, which prompted us to synthesize several of their 5′-monophosphate prodrugs. Some of these prodrugs exhibited more than 1000-fold improvement in anti-HCV activity when compared to their parent nucleosides (EC50 of 24 nM vs 92 μM for the parent).
- Gunic, Esmir,Chow, Suetying,Rong, Frank,Ramasamy, Kanda,Raney, Anneke,Yunzhi Li, David,Huang, Jingfan,Hamatake, Robert K.,Hong, Zhi,Girardet, Jean-Luc
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p. 2456 - 2458
(2008/02/03)
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- PS-IIDQ: a supported coupling reagent for efficient and general amide bond formation
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Polystyrene-IIDQ, a polymer-supported coupling reagent, was synthesized in three steps from Merrifield resin in 86% overall conversion. This reagent efficiently coupled carboxylic acids to amines in good yields and high purities, required no pre-activation step, and was tolerant of the order of reagent addition. PS-IIDQ was observed to be more efficient than polymer-supported carbodiimides (PS-EDC and PS-DCC) and gave higher yields than HATU for general amide bond formation, including the coupling of anilines and hindered substrates. When evaluated with five carboxylic acids and nine amines (including anilines and secondary amines) PS-IIDQ gave an average isolated yield of 73%.
- Valeur, Eric,Bradley, Mark
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p. 8855 - 8871
(2008/02/11)
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- Ammonium chloride promoted three-component synthesis of 5-iminooxazoline and its subsequent transformation to macrocyclodepsipeptide
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(Chemical Equation Presented) A three-component reaction of an α,α-disubstituted α-isocyanoacetamide, an aldehyde and an amino alcohol afforded the 5-iminooxazoline, which, upon saponification, cyclized under acidic conditions to provide the macrocyclodepsipeptide in good overall yield.
- Pirali, Tracey,Tron, Gian Cesare,Masson, Geraldine,Zhu, Jieping
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p. 5275 - 5278
(2008/09/18)
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- Studies of β-turn opening with model peptides containing non-coded α-amino isobutyric acid
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Single crystal X-ray diffraction studies show that among the three terminally protected model tripeptides I-III, Boc-Ile-Aib-Xx-OMe (Xx in peptide I: Val; II: Leu; III: Phe) with a centrally placed non-coded amino acid Aib (Aib: α-amino isobutyric acid), peptide I displays a conformational preference for β-turn, peptide II forms a hydrated β-turn representing the solvent mediated intermediate for the interconversion between β-turn and β-strand and peptide III adopts a completely unfolded β-strand like structure. By varying the steric bulk of the third residue, Xx(3), various conformations related to the structural interconversion between the β-turn and β-strand have been isolated. The peptide conformations in the solution phase have been probed by solvent dependent NMR titration and CD spectroscopy. Morphological studies with scanning electron microscopy (SEM) reveal that among the three peptides only peptide III can form filamentous fibrils in the solid state.
- Dutt, Anita,Dutta, Arpita,Mondal, Raju,Spencer, Elinor C.,Howard, Judith A.K.,Pramanik, Animesh
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p. 10282 - 10289
(2008/02/13)
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- Ultrasound accelerated synthesis of proteinogenic and α,α- dialkylamino acid ester salts
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A simple and efficient sonochemical esterification of proteinogenic as well as cyclic α,α-dialkyl amino acid methyl and ethyl ester hydrochloride salts employing thionyl chloride and alcohol has been reported. All the amino acid esters made have been obtained in good yield (94-98%) as pure compounds.
- Kantharaju,Babu, Vommina V. Suresh
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p. 1942 - 1944
(2007/10/03)
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- Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives
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We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.
- McGuigan, Christopher,Hassan-Abdallah, Alshaimaa,Srinivasan, Sheila,Wang, Yikang,Siddiqui, Adam,Daluge, Susan M.,Gudmundsson, Kristjan S.,Zhou, Huiqiang,McLean, Ed W.,Peckham, Jennifer P.,Burnette, Thimysta C.,Marr, Harry,Hazen, Richard,Condreay, Lynn D.,Johnson, Lance,Balzarini, Jan
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p. 7215 - 7226
(2007/10/03)
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- CHEMICAL COMPOUNDS
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Phosphoramidate derivatives of nucleotides and their use in the treatment of cancer are described. The base moieties of, for example, each of deoxyuridine, cytarabine, gemcitabine and citidine may be substituted at the 5-position. The phosphoramidate moiety has attached to the P atom an aryl-O moiety and an α-amino acid moiety. The α-amino acid moiety may correspond to or be derived from either a naturally occurring or a non-naturally occurring amino acid.
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Page/Page column 21
(2010/02/10)
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- Relationship between the hydrophobicity of dipeptides and the Michaelis-Menten constant Km of their hydrolysis by carboxypeptidase-Y and carboxypeptidase-A
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The enzymatic hydrolysis of dipeptides by carboxypeptidase-Y and carboxypeptidase-A was investigated. In the enzymatic hydrolysis of the dipeptides, a good linear relationship (r = 0.997 and 0.999) was found between the Michaelis-Menten constant (Km) and the hydrophobicity of the substrates evaluated from relative elution volume in reversed-phase HPLC. The correlation suggests that the hydrophobicity of the C-terminal amino acid is a major factor in governing the stability of the enzyme-substrate complex. The difference in the slope of the linear-regression lines seems to reflect the degree of relative hydrophobicity of the binding pockets in carboxypeptidase-Y and carboxypeptidase-A.
- Kanosue, Yoshifumi,Kojima, Satoshi,Hiraga, Yoshikazu,Ohkata, Katsuo
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p. 1187 - 1193
(2007/10/03)
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- Small cyclic disulfide peptides: Synthesis in preparative amounts and characterization by means of NMR and FT-IR spectroscopy
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Two cyclic disulfide-bridged tetrapeptides [cyclo(Boc-Cys-Pro-Aib-Cys-OMe) and cyclo(Boc-Cys-Pro-Phe-Cys-OMe)] were prepared in high yield and purity. The use of double-walled reaction flasks, which were attached to an external cryostat, gave perfect temperature control of the reaction. The acetamidomethyl and trityl group were used for the protection of the thiol groups of Cys. Disulfide bond formation was obtained by cleavage of the protection groups and subsequent oxidation of the free thiols with iodine under high dilution conditions in one step. The obtained cyclic peptides were checked for purity by analytical HPLC, and identified by NMR spectroscopy and a variety of standard analytical methods (IR, m. p., FAB-MS, ELA, TLC). Conformational properties of the peptides were derived from one- and two-dimensional NMR experiments. Temperature-dependent NMR and FT-IR experiments allowed for the determination of the degree of inter- and intramolecular hydrogen bonding of the cyclic tetrapeptides. The results from the temperature-dependent NMR experiments are in good agreement with the observed dynamics of the peptides in the amide I and II region, which were determined by means of temperature-dependent FT-IR spectroscopy using the ATR technique. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Kolano, Christoph,Gomann, Klaus,Sander, Wolfram
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p. 4167 - 4176
(2007/10/03)
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- Influence of solvent viscosity on the rate of hydrolysis of dipeptides by carboxypeptidase Y
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The influence of solvent viscosity on the rate of enzymatic hydrolysis of a series of dipeptides (Z-Phe-Gly, Z-Phe-Sar, Z-Phe-Ala, Z-Phe-NMeAla, Z-Phe-Aib and Z-Phe-Pro) by carboxypeptidase Y was investigated. The effect of solvent viscosity on the enzymatic hydrolysis revealed that whereas all Kcat values decreased with viscosity, those of the N-alkyl peptides decreased more than those of the N-H peptides. The kinetic behaviour implies the involvement of conformational changes of the enzyme in terms of the 'induced-fit' process. Copyright
- Kanosue, Yoshifumi,Kojima, Satoshi,Ohkata, Katsuo
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p. 448 - 457
(2007/10/03)
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- Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents
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This invention relates to 2-arylimino heterocycles, including 2-arylimino-1,3-thiazolidines, 2-arylimino-2,3,4,5-tetrahydro-1,3-thiazines, 2-arylimino-1,3-thiazolidin-4-ones, 2-arylimino-1,3-thiazolidin-5-ones, and 2-arylimino-1,3-oxazolidines, and their use in modulating progesterone receptor mediated processes, and pharmaceutical compositions for use in such therapies.
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Page column 138
(2010/02/05)
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- Process for the preparation of matrix metalloproteinase inhibitors
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The instant invention provides a process for the synthesis of matrix metalloproteinase inhibitors.
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- NOVEL THIAZINE OR PYRAZINE DERIVATIVES
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An object of the present invention is to synthesize novel compounds having 3-oxo-3, 4-dihydro-2H-1, 4-thiazine or 2-oxo-1, 2, 3, 4-tetrahydropyrazine as a main skeleton. The present invention relates to compounds represented by the following general formula [I] and salts thereof. In the formula, X is S or R6-(A2)n-N, R1 and R2 are H, alkyl, cycloalkyl or aryl, R3 and R4 are H, alkyl, cycloalkyl, aryl or aromatic heterocycles, R5 is H, alkyl, cycloalkyl, aryl or -A3-A4-R7, R6 is H, alkyl, cycloalkyl, OH, alkoxy, aryl, aryloxy or an aromatic heterocycle, R7 is H, alkyl, OH, alkoxy, aryl, aryloxy, amino, alkylamino, arylamino, an aromatic heterocycle or a nonaromatic heterocycle, A1 is alkylene, A2 is carbonyl or sulfonyl, A3 is alkylene, and A4 is carbonyl or oxalyl.
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- The first water-soluble 310-helical peptides
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Two water-soluble 310-helical peptides are synthesized and fully characterized for the first time. The sequence of these terminally blocked heptamers comprises two residues of the Cα-trisubstituted α-amino acid 2-amino-3-[1-(1,4,7 triazacyclononyl)]propanoic acid and five residues of a Cα-tetrasubstituted α-amino acid (either α-aminoisobutyric acid or isovaline). Using CD and NMR techniques we were able to show that both heptapeptides are well structured in water, and that the type of conformation adopted is indeed the ternary 310-helix.
- Formaggio, Fernando,Crisma, Marco,Rossi, Paola,Scrimin, Paolo,Kaptein, Bernard,Broxterman, Quirinus B.,Kamphuis, Johan,Toniolo, Claudio
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p. 4498 - 4504
(2007/10/03)
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- RETROVIRAL PROTEASE INHIBITORS
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Urea-containing hydroxyethylamine peptide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
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- N-bis-silylation of α-amino acids: "benzostabases" as amino protecting group
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N-Bis-trimethylsilylation of α-amino acids using the powerful trimethylsilyl triflate reagent is difficult, and is rendered impossible in the case of bulky side-chains (valine). However, favorable entropy changes resulting from a cyclization reaction allow the formation of "benzostabase" N-diprotections regardless of the side-chain bulk.
- Cavelier-Frontin, Florine,Jacquier, Robert,Paladino, Joseph,Verducci, Jean
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p. 9807 - 9822
(2007/10/02)
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- HETEROCYCLES FROM NITRILE IMINES. PART IV. CHIRAL 4,5-DIHYDRO-1,2,4-TRIAZIN-6-ONES
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The reaction of nitrile imines (II) with α-amino esters (III) proceeds with no detectable racemization and constitutes a convenient synthetic route to 4,5-dihydro-1,2,4-triazin-6-ones (IV).Permangamate oxidation of heterocycles (IV) affords the corresponding 1,2,4-triazin-6-ones (V).The reaction of (II) with β-amino esters gives the respective acyclic amidrazone adducts (VI).
- El-Abadelah, Mustafa M.,Hussein, Ahmad Q.,Thaher, Bassam A.
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p. 1879 - 1895
(2007/10/02)
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- Carboxy, carboalkoxy and carbamile substituted isonitrile radionuclide complexes
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A coordination complex comprising a radionuclide selected from the class consisting of radioactive isotopes of Tc, Ru, Co, Pt and Re and an isonitrile ligand of the formula: where X is a lower alkyl group having 1 to 4 carbon atoms, wherein R is selected from the group consisting of COOR1 and CONR2 R3 where R1 can be H, a pharmaceutically acceptable cation, or a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, R2, and R3 can be H, or a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms, and R2 and R3 can be the same or different is disclosed. Kits that can be used to form these complexes are also disclosed.
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- Peptide Sweeteners. 6. Structural Studies on the C-Terminal Amino Acid of L-Aspartyl Dipeptide Sweeteners
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Stereochemical and structural aspects of the variations in the C-terminal residue of L-aspartyl-L-phenylalanine methyl ester have been investigated.Novel configurational analogues such as L-aspartyl-D-alanine benzyl ester and L-aspartyl-D-α-aminobutyric acid benzyl ester were found to be sweet.In addition, chiral and achiral α,α-dialkylglycine and α-aminocycloalkanecarboxylic acids were incorporated into the dipeptides.The L-aspartic acid based dipeptide derivatives of α-aminoisobutyric acid methyl ester, α-aminocyclopropanecarboxylic acid methyl ester, α-aminocyclobutanecarboxylic acid methyl ester, and α-aminocyclopentanecarboxylic acid methyl ester are sweet.Dipeptides with α-aminocyclohexanecarboxylic acid methyl ester and α-aminocycloheptanecarboxylic acid methyl ester are bitter, whereas the analogues with α-aminocyclooctanecarboxylic acid methyl ester, α,α-diethylglycine methyl ester, and α-aminoisobutyric acid benzyl ester are tasteless.Aspects on chirality and effective volume of the C-terminal residue are discussed and correlated with taste.
- Tsang, Joseph W.,Schmied, Bernhard,Nyfeler, Rolf,Goodman, Murray
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p. 1663 - 1668
(2007/10/02)
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- SYNTHESE VON 2-METHYLALANIN-PEPTIDEN, DIE pH-ABHAENGIGKEIT IHRER 13C-NMR-SPECTREN UND EINE NEUE METHODE ZUR AUSWERTUNG UEBER CS-DIAGRAMME
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The uncommon amino-acid 2-methylalanine (α-aminoisobutiryc acid, Aib) was investigated by 13C-NMR.The chemical shifts of amino- or carboxy-protected derivates of Aib and of protected oligopeptides are discussed with respect to neighbouring groups and amino acids.The pH-dependence of the 13C-NMR spectra of Aib, Aib-Ala, Ala-Aib, Aib-Ala-Aib and Aib-Ala-Aib-Ala-Aib was studied.Using these examples, a new and advantageous method is demonstrated for the first time for the evaluation of NMR titration curves, which uses so-called chemical shift diagrams (CS diagrams).
- Leibfritz, Dieter,Haupt, Erhard,Dubischar, Norbert,Lachmann, Heinrich,Oekonomopulos, Raymond,Jung, Guenther
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p. 2165 - 2182
(2007/10/02)
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- Improved Synthesis of chlamydocin: Cyclization Studies of Tetrapeptides Containing Five α-Substituents
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A complete search for the optimal conditions for preparing cycling tetrapeptide 2 was carried out.In this study all four possible sequences of the linear tetrapeptide precursors were synthesized and cyclized.The results establish that one linear sequence is especially favorable for synthesizing the peptide ring system in chlamydocin (1).
- Pastuszak, Jacek,Gardner, Joseph H.,Singh, Jasbir,Rich, Daniel H.
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p. 2982 - 2987
(2007/10/02)
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- N-chloro-amino acid derivatives activity
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There is provided, a novel class of compounds exhibiting antibacterial activity, said compounds having the formula: EQU1 wherein X and Y each represent a member which may be the same or different selected from the group consisting of H and Cl with the pri
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