- Synthesis of N-[(tert-Butoxy)carbonyl]-3-(9,10-dihydro-9-oxoacridin-2-yl)-L-alanine, a New Fluorescent Amino Acid Derivative
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A simple synthesis of a new, highly fluorescent amino acid and of its protected derivative useful in peptide studies is described. The obtained derivative, N-[(tert-butoxy)carbonyl]-3-(9,10-dihydro-9-oxoacridin-2-yl)-L-alanine (6), shows intense long-wave absorption (above 360 nm) and emission (above 400 nm). The quantum yield of fluorescence of the investigated compound is very high, so it can serve as a sensitive analytical probe useful, e.g., in analysis of peptide conformations.
- Szymanska, Aneta,Wegner, Katarzyna,Lankiewicz, Leszek
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- Synthesis and characterization of novel benzothiazole amide derivatives and screening as possible antimitotic and antimicrobial agents
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Abstract: A new series of benzothiazole amide derivatives (9a–l) were synthesized and characterized by Fourier-transform infrared (FT-IR), mass, and 1H and 13C nuclear magnetic resonance (NMR) spectroscopic techniques. The antimitotic activity of the newly synthesized compounds was determined by the Allium assay method, from which mitotic index values were calculated. Here, 9g (14.0?%) and 9l (14.5?%) showed mitotic index values most comparable to that of standard drug (14.4?%), while the remaining compounds showed lower mitotic index values; hence, these compounds inhibit the regular cell division process and are the most promising antimitotic agents. Based on the structural activity relationship, the maximum percentage inhibition was observed for compounds containing electron-withdrawing group, revealing enhanced antimitotic activity, while compounds with electron-donating groups such as furan (9g) and methyl (9l) were comparable to standard. The newly synthesized compounds were also screened for antimicrobial activity, with some of them showing remarkable activity. Graphical Abstract: [Figure not available: see fulltext.]
- Bhat, Mahesh,Belagali,Hemanth Kumar,Mahadeva Kumar
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- NITRATION
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The present invention relates to a process for preparing a nitrated compound, comprising the step of reacting a compound (A) comprising at least one substituted or unsubstituted aromatic or heteroaromatic ring, wherein said heteroaromatic ring comprises at least one heteroatom selected from the group consisting of oxygen, sulfur, phosphor, selenium and nitrogen, with a compound of formula (I) wherein Y is selected from the group consisting of hydrogen and nitro.
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Page/Page column 36; 41; 46; 64; 45; 75-76
(2020/05/28)
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- Deuterium-substituted 3-(methylsulfonyl)-L-phenylalanine derivative and medicine composition, medicine preparation and application thereof
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The invention provides a deuterium-substituted 3-(methylsulfonyl)-L-phenylalanine derivative and a medicine composition, a medicine preparation and application thereof. The deuterium-substituted 3-(methylsulfonyl)-L-phenylalanine derivative has a structure shown in a formula I. A compound provided by the invention and the derivative thereof have good LFA-1 antagonistic activity, excellent pharmacodynamics property and lower toxicity. The formula I is shown in the description, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20 and R21 are respectively and independently hydrogen or deuterium, and at least contain one deuterium; R is hydrogen.
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Paragraph 0036; 0108; 0109
(2017/08/31)
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- Synthesis, characterization, and biological study of phenylalanine amide derivatives
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In the present study, a series of amide derivatives of 4-nitro-l-phenylalanine were synthesized with good yield from 4-nitro-l-phenylalanine and substituted anilines using propylphosphonic anhydride (T3P) as coupling reagent and were characterized through the IR, LC–MS, 1H and 13C NMR spectral studies. The isolated products were screened for antimicrobial and antioxidant activities. Some of the compounds showed Microsporum gypsuem activity or were active against Candida albicans, also a few of compounds showed antibacterial activities. The resultant compounds screened for anti-oxidant activity, which showed good activity for DPPH scavenging and ABTS assay methods and others had moderately activity. Some amide compounds act as metal chelating ligands with Fe2+ ions. Graphical abstract: [Figure not available: see fulltext.]
- Bhat, Mahesh,Belagali,Rajesh Shastry,Ravishankar Rai
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p. 2001 - 2008
(2016/10/21)
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- Cyclic side-chain-linked opioid analogs utilizing cis- and trans-4-aminocyclohexyl-d-alanine
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Cyclization of linear sequences is a well recognized tool in opioid peptide chemistry for generating analogs with improved bioactivities. Cyclization can be achieved through various bridging bonds between peptide ends or side-chains. In our earlier paper we have reported the synthesis and biological activity of a cyclic peptide, Tyr-c[d-Lys-Phe-Phe-Asp]NH2 (1), which can be viewed as an analog of endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2). Cyclization was achieved through an amide bond between side-chains of d-Lys and Asp residues. Here, to increase rigidity of the cyclic structure, we replaced d-Lys with cis- or trans-4-aminocyclohexyl-d-alanine (d-ACAla). Two sets of analogs incorporating either Tyr or Dmt (2′,6′-dimethyltyrosine) residues in position 1 were synthesized. In the binding studies the analog incorporating Dmt and trans-d-ACAla showed high affinity for both, μ- and δ-opioid receptors (MOR and DOR, respectively) and moderate affinity for the κ-opioid receptor (KOR), while analog with Dmt and cis-d-ACAla was exceptionally MOR-selective. Conformational analyses by NMR and molecular docking studies have been performed to investigate the molecular structural features responsible for the noteworthy MOR selectivity.
- Piekielna, Justyna,Gentilucci, Luca,De Marco, Rossella,Perlikowska, Renata,Adamska, Anna,Olczak, Jacek,Mazur, Marzena,Artali, Roberto,Modranka, Jakub,Janecki, Tomasz,T?mb?ly, Csaba,Janecka, Anna
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p. 6545 - 6551
(2015/02/19)
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- Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites
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In order to identify compounds selective for the GluK1 and GluK3 subtypes of kainate receptors we have designed and synthesized a series of (S)-2-amino-3-((2-carboxyethyl)phenyl)propanoic acid analogs with hydrogen bond donating and accepting substituents on the aromatic ring. Based on crystal structures of GluK1 in complex with related ligands, the compounds were designed to explore possible interactions with non-conserved residues outside the glutamate ligand binding site and challenge the water binding network. Apart from obtaining GluK1 selective antagonists one analog with a phenyl-substituted urea (compound 31) showed some preference for GluK3 over GluK1-receptors. Docking studies indicate that this preference may be attributed to contacts between the NH of the urea substituent and non-conserved Ser741 and Ser761 residues.
- Sk?ld, Niklas,Nielsen, Birgitte,Olsen, Jacob,Han, Liwei,Olsen, Lars,Madsen, Ulf,Kristensen, Jesper L.,Pickering, Darryl S.,Johansen, Tommy N.
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p. 5368 - 5377
(2014/12/11)
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- Synthesis and?antiproliferative activities of?indolin-2-one?derivatives bearing amino acid moieties
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A convenient synthesis of indolin-2-ones substituted in the 3 position by an aminomethylene group bearing different amino acid moieties is described. Their antiproliferative activities were evaluated toward a panel of human solid tumor cell lines (PC 3, DLD-1, MCF-7, M4 Beu, A549, PA 1) and healthy cell lines (a murine fibroblast L929 and a human fibroblast primary culture).
- Sassatelli, Mathieu,Debiton, éric,Aboab, Bettina,Prudhomme, Michelle,Moreau, Pascale
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p. 709 - 716
(2007/10/03)
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- Amino (oxo) acetic acid protein tyrosine phosphatase inhibitors
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Compounds of formula (I) or therapeutically acceptable salts thereof, are protein tyrosine kinase PTP1B inhibitors. Preparation of the compounds, compositions containing the compounds, and treatment of diseases using the compounds are disclosed.
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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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- Asymmetric synthesis of conformationally restricted L-arginine analogues as active site probes of nitric oxide synthase
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Using the catalytic asymmetric sharpless carbamate aminohydroxylation, conformationally restricted L-arginine and L-homoarginine derivatives (5-8) were prepared in good enantiomeric excess to investigate the binding requirements of L-arginine-based compounds with nitric oxide synthase. The L- arginine derivatives (5 and 6) inhibited both the inducible and neuronal isoforms of nitric oxide synthase with little isoform selectivity (5, IC50 = 42 and 144 μM, 6, 8 and 12 μM, respectively). The guanidine-containing compound (5) did not act as a nitric oxide producing substrate for nitric oxide synthase. The ability of these compounds to interact with the enzyme supports the idea that L-arginine-based inhibitors bind to the enzyme in a folded conformation. The L-homoarginine derivatives (7 and 8) did not interact with the enzyme as either substrates or inhibitors. The two-carbon L-arginine homologue (9), prepared from L-phenylalanine, demonstrated the greatest isoform selective inhibition of the compounds examined (IC50(iNOS) = 19 and IC50(nNOS) = 147 μM, IC50(nNOS)/IC50i(NOS) = 7.7). These results suggest isoform selective inhibition may be related to the folded conformations required for binding of these higher L-arginine homologues.
- Atkinson,Moore,Tobin,King
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p. 3467 - 3475
(2007/10/03)
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- PEPTIDE DERIVATIVES AND ANGIOTENSIN IV RECEPTOR AGONIST
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Short-chain peptide derivatives acting on angiotensin IV receptor at low concentrations. Because of agonistically acting on angiotensin IV receptor, the novel peptide derivatives of the present invention represented by the following formula (1) are useful as remedies for various diseases in which angiotensin IV participates:
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- Stereochemical influence on the stability of radio-metal complexes in vivo. Synthesis and evaluation of the four stereoisomers of 2-(p- nitrobenzyl)-trans-CyDTPA
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Distinct differences in in vivo stability of the two diastereomeric C- Functionalized CyDTPA chelating agents, (CHX-A DTPA and CHX-B DTPA, both racemates), as recently reported prompted further investigation as to why differences in configuration produced striking effects on the in vivo stability of their yttrium complexes. To this end, the four individual component stereoisomers of CHX-A and CHX-B were synthesized and ability to bind yttrium was investigated both in vitro and in vivo.
- Wu,Kobayashi,Sun,Yoo,Paik,Gansow,Carrasquillo,Pastan,Brechbiel
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p. 1925 - 1934
(2007/10/03)
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- Pretargeting methods and compounds
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Methods, compounds, compositions and kits that relate to pretargeted delivery of diagnostic and therapeutic agents are disclosed. In particular, methods for radiometal labeling of biotin, as well as related compounds, are described. Articles of manufacture useful in pretargeting methods are also discussed.
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- Cholecystokinin B antagonists. Synthesis and quantitative structure-activity relationships of a series of C-terminal analogues of CI-988
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A study of structure-activity relationships of a series of 'dipeptoid' CCK-B receptor antagonists was performed in which variations of the phenyl ring were examined while the [(2-adamantyloxy)carbonyl]-α-methyl-R)-tryptophan moiety of the potent antagonist CI-988 was kept constant. Since the main focus of this study was phenyl substituent variation, series design techniques were employed to insure an adequate spread of physicochemical properties (lipophilic, steric, electronic), as well as positional substitution. A QSAR analysis on sets of 26 and 16 analogues revealed that CCK-B affinity was related to a combination of the overall size and, marginally, lipophilicity of the phenyl ring substituents (i.e., smaller groups were associated with increased potency with an optimum π near zero, respectively). Further exploration revealed that the dimensions and electronics of the para-phenyl substituent could be related to CCK-B affinity. Increased affinity was seen with short, bulky (branched) electron withdrawing groups. Analogs with small para-substituents appeared to be about 1000-fold CCK-B selective, indicating that selectivity for CCK-B binding is sensitive to phenyl ring substitution. The 4-F-phenyl dipeptoid, derived from this study, has extraordinary high affinity at the CCK-B receptor (IC50 = 0.08 nM) and was also very selective (940-fold CCK-B selective). Consistent with previous reports, (S)-configuration at the substituted phenethylamide center, a carboxylic acid and the presence of a phenyl ring were found to be associated with increased affinity at both CCK-A and CCK-B receptors.
- Augelli-Szafran, Corinne E.,Horwell, David C.,Kneen, Clare,Ortwine, Daniel F.,Pritchard, Martyn C.,Purchase, Terri S.,Roth, Bruce D.,Trivedi, Bharat K.,Hill, David,Suman-Chauhan, Nirmala,Webdale, Louise
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p. 1733 - 1745
(2007/10/03)
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- Development of active center-directed plasmin and plasma kallikrein inhibitors and studies on the structure-inhibitory activity relationship
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The molecule of trans-4-aminomethylcyclohexanecarbonylphenylalanine 4- carboxymethylanilide (8), which is a potent and selective inhibitor of plasma kallikrein, can be divided into three parts (P1, P1 and P2), each of which contains one of the rings. In order to study the role of each part in the manifestation of potent and selective inhibitory activity and the relationship between the structure and inhibitory activities toward plasmin, plasma kallikrein, urokinase and thrombin, each part was substituted with various other moieties to give many kinds of analogs and their inhibitory activities against the above enzymes were examined. Among them, trans-4- aminomethylcyclohexanecarbonyl-O-2-bromobenzyloxycarbonyltyrosine 4- acetylanilide (12) inhibited plasmin and plasma kallikrein with IC50 values of 2.3 x 10-7 M and 3.7 x 10-7 M, and K(i) values of 1.2 x 10-7 M and 1.3 x 10-7 M, respectively.
- Teno,Wanaka,Okada,Taguchi,Okamoto,Hijikata-Okunomiya,Okamoto
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p. 1079 - 1090
(2007/10/02)
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- Metal chelate protein conjugate
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A method of forming a novel metal chelate protein conjugate is described. Also described are metal chelates and precursor compounds to the metal chelates. The novel metal chelate protein conjugates are particularly useful in the diagnostic imaging of tumors and in tumor therapy.
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- Synthesis of highly μ and δ opioid receptor selective peptides containing a photoaffinity group
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A series of cyclic, conformationally constrained photolabile peptides related to the enkephalins and to somatostatin were designed and synthesized in an effort to develop highly selective and potent peptides for the δ and μ opioid receptors. The following new peptides were prepared and tested for their δ opioid receptor potency and selectivity in the guinea pig ileum assay, the mouse vas deferens assay, and the rat brain binding assay: H-Tyr-D-Pen-Gly-p-NH2Phe-D-Pen-OH (1, [p-NH2Phe4]DPDPE) and H-Tyr-D-Pen-Gly-p-N3Phe-D-Pen-OH (2, [p-N3Phe4]DPDPE). The following new peptides were prepared and tested for their μ opioid receptor potency and selectivity in the same assays: H-D-Phe-Cys-p-NH2Phe-D-Trp-Lys-Thr-Pen-Thr-NH2 (3, [p-NH2Phe3]CTP) and D-Phe-Cys-p-N3Phe-D-Trp-Lys-Thr-Pen-Thr-NH2 (4, [p-N3Phe3]CTP). The δ selective photoaffinity peptide 2 displayed both high affinity (IC50 = 9.5 nM) and good selectivity (IC50 μ/IC50 δ = 1053) as an agonist at δ opioid receptors in bioassays, and 2 also displayed moderate affinity (33 nM) and excellent selectivity (IC50 μ/IC50 δ = 110) for rat brain δ opioid receptors. The μ selective photoaffinity peptide 4 displayed very weak affinity (8% contraction at 300 nM) at μ opioid receptors in bioassays, but good affinity (IC50 = 48.6 nM) and excellent selectivity (IC50 δ/IC50 μ = 412) for the rat brain μ opioid receptors. These conformationally constrained cyclic photoaffinity peptides may be useful tools to investigate the pharmacology of δ and μ opioid receptors.
- Landis,Lui,Shook,Yamamura,Burks,Hruby
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p. 638 - 643
(2007/10/02)
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- Photoinduced Electron Transfer on a Single α-Helical Polypeptide Chain
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Electron transfer on an α-helical polypeptide carrying the sequence L-p-(dimethylamino)phenylalanine (dmaPhe)-L-alanine-L-1-pyrenylalanine (pyrAla) at the midpoint of an α-helical poly(γ-benzyl L-glutamate) chain was studied.Conformational energy calculation for the side-chain orientations predicted that only one type of orientation is allowed for both the dmaPhe and the pyrAla units.The center-to-center (edge-to-edge) distance between the two chromophores was estimated to be 13.2 (9.4) Angstroem.The fluorescence spectrum showed no exciplex emission in thepolypeptide, in contrast to the strong exciplex observed for a model tripeptide having the same dmaPhe-Ala-pyrAla sequence.The rate of electron transfer was calculated from the decay times of pyrenyl fluorescence of the polypeptide in trimethyl phosphate and in tetrahydrofuran solutions.The ket was on the order of 1E5 (s-1).The activation enthalpy was 1.4 kcal mol-1 in trimethyl phosphate and smaller than 1 kcal mol-1 in less polar solvents near room temperature.It was even smaller at lower temperatures.The activation entropy was less than -25 eu, suggesting a nonadiabatic electron transfer.In contrast to the slow electron transfer in the polypeptide, the rate constant for the model tripeptide was on the order of 1E7-1E8 (s-1) around room temperature, and the activation enthalpy was higher than that in the polypeptide case.
- Sisido, Masahiko,Tanaka, Ryo,Inai, Yoshihito,Imanishi, Yukio
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p. 6790 - 6796
(2007/10/02)
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- Efficiency of Second Harmonic Generation from Amino Acids, Peptides, and Polypeptides Carrying Polarizable Aromatic Groups
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The SHG efficiencies of optically active amino acids, their monomeric derivatives, linear and cyclic dipeptides, tripeptides, and polypeptides carrying polarizable groups were tested.Among the 91 samples, L-valine-p-nitroanilide (Val-NA) showed the largest SHG 2ω(urea)>.Val-NA was found to be phase-matchable and transparent down to 420 nm.Monopeptide and dipeptide derivatives of p-nitrophenylalanine also showed large SHG and were transparent down to 420 nm.
- Tokutake, S.,Imanishi, Y.,Sisido, M.
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p. 245 - 258
(2007/10/02)
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- DERIVATIVES OF BETA-ADRENERGIC ANTAGONISTS
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Molecular structures of β-adrenergic antagonists are modified to produce biologically active compounds. The β-antagonists are modified to form molecules of the general structure: STR1 wherein R is most generally R"--OCH 2--, and in some instances is R"--, and R"=an aryl or substituted aryl moiety; R'=--H,--CH 3, or a short chain alkyl moiety; and Y=--OH, or more usually,--OAX or--NHAX, where A=an alkyl, aryl, or aralkyl moiety, and X=a terminal grouping, such as--CH 3,--CF 3 or--(CH 2) n COOH; or AX may be a carrier moiety consisting of a defined peptide or protein. "
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- Puromycin Analogues. Effect of Aryl-Substituted Puromycin Analogues on the Ribosomal Peptidyltransferase Reaction
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A series of ortho- and para-substituted L-phenylalanylpuromycin analogues were synthesized and evaluated as substrates for the peptidyltransferase reaction of Escherichia coli ribosomes.Kinetic results reveal that substitution of the p-methoxy group of the puromycin molecule alters the peptidyltransferase activity of the molecule with the following decreasing order of substrate efficiencies: p-NH2 > p-NHCOCH3 > p-NO2 = p-NHCO(CH2)2CH3 > p-NHCOCH2Br.However, the inability of the ribosome to tolerate a nitro group at the ortho position of the phenylalanine ring precluded the use of the photosensitive puromycin analogue, 2-nitro-4-azidophenylalanylpuromycin aminonucleoside (7a), as a photoaffinity label for the peptidyltransferase site.
- Lee, Heejoo,Fong, Kei-Lai,Vince, Robert
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p. 304 - 308
(2007/10/02)
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