- Isolation and synthesis of a host-selective toxin produced by Alternaria alternata
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Two phytotoxins are isolated from culture filtrates of an Alternaria alternata pathogenic to sunflower. One was identified by chemical and physicochemical techniques as the tetrapeptide Ser-Val-Gly-Glu. This peptide, for which we suggested the name AS-I toxin, was further characterised by synthesis and by its phytotoxic effect on sunflower and other plants.
- Liakopoulou-Kyriakides,Lagopodi,Thanassoulopoulos,Stavropoulos,Magafa
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Read Online
- Synthesis of 4-N-α-coumaryl amino acids and investigation of their antioxidant, antimicrobial activities and fluorescence spectra
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An efficient metal-free approach for the synthesis of N-coumaryl amino acids and the first one-step synthesis of 4-hydrazinocoumarin from 4-hydroxycoumarin was developed. The nucleophilic addition of amino acid methyl esters to 4-tosylcoumarins produced a series of 4-N-α-coumaryl amino acids in good to excellent yields without racemization. The antioxidant activities of the synthesized compounds were investigated using DPPH and FRAP methods. 4-Hydrazinocoumarin and N-coumaryl tyrosine had the best antioxidant activity. The antimicrobial activities of the compounds against Gram-positive was stronger than Gram-negative. 4-Hydrazinocoumarin showed the best antibacterial effect.
- Ghalehshahi, Hajar Golshadi,Balalaie, Saeed,Aliahmadi, Atousa,Moghimi, Roya
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Read Online
- Post-synthetic functionalization of tryptophan protected peptide sequences through indole (C-2) photocatalytic alkylation
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We report a selective, mild, and efficient C-H functionalization of tryptophan and tryptophan-containing peptides with activated α-bromo-carbonyl compounds under visible-light irradiation. The protocol efficiency is outlined by the wide substrate scope and excellent tolerance of sensitive functional groups present in the amino acid side chains. The method can be successfully extended to access pharmaco-peptide conjugate scaffolds.
- Ackermann, Lutz,Berlinck, Roberto G. S.,Bernardi, Darlon I.,Delgado, José A. C.,Kaplaneris, Nikolaos,Lima, Rafaely N.,Paix?o, Márcio W.
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supporting information
p. 5758 - 5761
(2021/06/16)
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- Ribose conversion with amino acids into pyrraline platform chemicals-expeditious synthesis of diverse pyrrole-fused alkaloid compounds
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One-pot conversion of sustainable d-ribose with l-amino acid, methyl esters produced pyrrole-2-carbaldehydes 5 in reasonable yields (32-63%) under pressurized conditions of 2.5 atm at 80 °C. The value-added pyrraline compounds 5 as platform chemicals were utilized for quick installation of poly-heterocyclic cores for the development of pyrrole-motif natural and artificial therapeutic agents. A pyrrole-fused piperazin-2-one scaffold 6 was prepared by reductive amination of pyrralines 5 with benzylamine. While further cyclization of pyrralines 5 with ethane-1,2-diamine produced pyrrolo-piperazin-2-ones 7 with an extra imidazolidine ring, the reaction with 2-amino alcohols derived from natural l-amino acids, alanine, valine, and phenylalanine, respectively provided pyrrolo-piperazin-2-ones 8, 9, and 10 with oxazolidine as the third structural core. Cell viability and an anti-inflammatory effect of the synthesized compounds were briefly tested by the MTT method and the Griess assay, among which 8h and 10g exhibited significant anti-inflammatory effects with negligible cell toxicity.
- Cho, Soohyeon,Gu, Lina,In, Ik Joon,Kim, Hakwon,Koo, Sangho,Lee, Taehoon,Wu, Bo
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p. 31511 - 31525
(2021/11/30)
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- Photochemical Deracemization at sp3-Hybridized Carbon Centers via a Reversible Hydrogen Atom Transfer
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A photochemical deracemization of 5-substituted 3-phenylimidazolidine-2,4-diones (hydantoins) is reported (27 examples, 69%-quant., 80–99% ee). The reaction is catalyzed by a chiral diarylketone which displays a two-point hydrogen bonding site. Mechanistic evidence (DFT calculations, radical clock experiments, H/D labeling) suggests the reaction to occur by selective hydrogen atom transfer (HAT). Upon hydrogen binding, one substrate enantiomer displays the hydrogen atom at the stereogenic center to the photoexcited catalyst allowing for a HAT from the substrate and eventually for its conversion into the product enantiomer. The product enantiomer is not processed by the catalyst and is thus enriched in the photostationary state.
- Bach, Thorsten,Breitenlechner, Stefan,Gro?kopf, Johannes,Plaza, Manuel,Seitz, Antonia,Storch, Golo
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supporting information
p. 21241 - 21245
(2021/12/27)
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- Synthesis and Penicillin-binding Protein Inhibitory Assessment of Dipeptidic 4-Phenyl-β-lactams from α-Amino Acid-derived Imines
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Monocyclic β-lactams revive the research field on antibiotics, which are threatened by the emergence of resistant bacteria. A six-step synthetic route was developed, providing easy access to new 3-amino-1-carboxymethyl-4-phenyl-β-lactams, of which the penicillin-binding protein (PBP) inhibitory potency was demonstrated biochemically.
- Decuyper, Lena,Juki?, Marko,Sosi?, Izidor,Amoroso, Ana Maria,Verlaine, Olivier,Joris, Bernard,Gobec, Stanislav,D'hooghe, Matthias
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supporting information
p. 51 - 55
(2019/11/28)
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- L-glutamic acid derivative and synthesis method and application thereof
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The invention belongs to the technical field of synthesis of medical and traditional Chinese medicine intermediates, and discloses an L-glutamic acid derivative and a synthesis method and applicationthereof. All the steps in the synthesis method are simple and in order , the obtained L-dimethyl glutamate hydrochloride oily matter is directly put into the next step of reaction through a one-pot method, L-dimethyl glutamate hydrochloride solids do not need to be obtained, the use of all the raw materials can be effectively reduced, and the cost is reduced; ethyl acetate is selected as a reaction solvent and can be effectively recycled, the utilization rate of the ethyl acetate is remarkably increased, and pollution to the environment is reduced; a final product is obtained in a crystallization manner so that the convenience and the storage convenience during transportation are improved, and the quality and the yield of the product can be further improved. The technical scheme of the synthesis method is complete and simple, the produced product is high in crystallization yield and better in quality, the overall yield of the product is conveniently, rapidly, scientifically and effectively increased to 85% or above, and raw materials are provided for research and development of new drugs.
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Paragraph 0044-0047; 0056-0059; 0066-0069; 0076-0079; 0086
(2020/11/01)
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- Amino acid conjugates of 2-mercaptobenzimidazole provide better anti-inflammatory pharmacology and improved toxicity profile
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Benzimidazole is an important pharmacophore for clinically active drugs against inflammation and treatment of pain, however, it is associated with gastrointestinal side effects. Here we synthesized benzimidazole based agents with significant analgesic/anti-inflammatory potential but with less gastrointestinal adverse effects. In this study, we synthesized novel, orally bioavailable 2-mercaptobenzimidazole amino acid conjugates (4a–4o) and screened them for analgesic, anti-inflammatory and gastro-protective effects. The synthesized 2-mercaptbenzimidazole derivatives were characterized for their structure using FTIR, 1H NMR and 13C NMR spectroscopic techniques. The 2-mercaptobenzimidazole amino acid conjugates have found to possess potent analgesic, anti-inflammatory and gastroprotective activities, particularly with compound 4j and 4k. Most of the compounds exhibited remarkable anti-ulcer and antisecretory effects. Molecular docking studies were carried out to study the binding affinities and interactions of the synthesized compounds with target proteins COX-2 (PDB ID: 3LN1) and H+/K+-ATPase (PDB ID: 5Y0B). Our results support the clinical promise of these newly synthesized 2-mercaptobezimidazol conjugates as a component of therapeutic strategies for inflammation and analgesia, for which the gastric side effects are always a major limitation.
- Khan, Muhammad T.,Nadeem, Humaira,Khan, Arif-ullah,Abbas, Muzaffar,Arif, Muazzam,Malik, Nadia Shamshad,Malik, Zulkifal,Javed, Ibrahim
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p. 1057 - 1072
(2020/08/13)
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- Synthesis, CYP 450 evaluation, and docking simulation of novel 4-aminopyridine and coumarin derivatives
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Four series of novel compounds based on 4-aminopyridine, glatiramer acetate, pyrone, and coumarin backbones were sufficiently synthesized and identified by spectroscopic methods. CYP enzyme inhibition assays of five predominate human P450 isozymes indicate that all compounds, except for 4-hydrazide pyridine 1c, seem to be less toxic than 4-aminopyridine. Further investigation of the compounds using molecular docking experiments revealed different, the same, or stronger binding modes for most of the synthesized compounds, with both polar and hydrophobic interactions with the 1WDA and 1J95 receptors compared to benzoyl l-arginine amide and 4-aminopyridine, respectively. These results introduce the synthesized compounds as K+ channel blockers that could be considered for in vivo CNS disease studies.
- Ghalehshahi, Hajar G.,Balalaie, Saeed,Sohbati, Hamid R.,Azizian, Homa,Alavijeh, Mohammad S.
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- PRODRUGS ACTIVATED BY REACTIVE OXYGEN SPECIES FOR USE IN THE TREATMENT OF INFLAMMATORY DISEASES AND CANCER
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Prodrugs activated predominantly or exclusively in inflammatory tissue, more particularly prodrugs of methotrexate and derivatives thereof, which are selectively activated by Reactive Oxygen Species (ROS) in inflammatory tissues associated with cancer and inflammatory diseases, as well as method for preparing said prodrugs.
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Page/Page column 27; 32
(2018/09/25)
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- Green preparation method of N-substituted-L-pyroglutamate
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The invention provides a green preparation method of N-substituted-L-pyroglutamate. The method comprises the steps as follows: L-glutamic acid diester hydrochloride (III) is prepared from L-glutamic acid (II) as a starting material in the presence of an acidic reagent by an esterification reaction; then, L-glutamic acid diester hydrochloride (III) is subjected to N-substituted protective reactionwith an N-substituent protective reagent with a one-pot method in the presence of a base and a solvent, an N-substituted protective group is introduced, heating is performed for dealcoholization cyclization in molecules, and N-substituted-L-pyroglutamate as shown in the formula (I) is obtained. The method has the advantages of cheap and easily available raw materials, classic reaction types, shortprocess route, simple and convenient operation, small waste water amount, green and environment-friendly production process, high reaction yield and low product cost. 5R-benzyloxyaminopiperidine-2S-carboxylate, 5R-benzyloxyaminopiperidine-2S-formate ethanedioate and avibactam can be prepared from N-substituted-L-pyroglutamate as shown in the formula (I).
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Paragraph 0053; 0054
(2018/03/28)
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- Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis
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A series of novel hydrogen peroxide sensitive prodrugs of methotrexate (MTX) and aminopterin (AMT) were synthesized and evaluated for therapeutic efficacy in mice with collagen induced arthritis (CIA) as a model of chronic rheumatoid arthritis (RA). The prodrug strategy selected is based on ROS-labile 4-methylphenylboronic acid promoieties linked to the drugs via a carbamate linkage or a direct C-N bond. Activation under pathophysiological concentrations of H2O2 proved to be effective, and prodrug candidates were selected in agreement with relevant in vitro physicochemical and pharmacokinetic assays. Selected candidates showed moderate to good solubility, high chemical and enzymatic stability, and therapeutic efficacy comparable to the parent drugs in the CIA model. Importantly, the prodrugs displayed the expected safer toxicity profile and increased therapeutic window compared to MTX and AMT while maintaining a comparable therapeutic efficacy, which is highly encouraging for future use in RA patients.
- Peiró Cadahía, Jorge,Bondebjerg, Jon,Hansen, Christian A.,Previtali, Viola,Hansen, Anders E.,Andresen, Thomas L.,Clausen, Mads H.
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p. 3503 - 3515
(2018/05/01)
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- Design and optimization of aspartate N-acetyltransferase inhibitors for the potential treatment of Canavan disease
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Canavan disease is a fatal neurological disorder caused by defects in the metabolism of N-acetyl-L-aspartate (NAA). Recent work has shown that the devastating symptoms of this disorder are correlated with the elevated levels of NAA observed in these patients, caused as a consequence of the inability of mutated forms of aspartoacylase to adequately catalyze its breakdown. The membrane-associated enzyme responsible for the synthesis of NAA, aspartate N-acetyltransferase (ANAT), has recently been purified and examined (Wang et al., Prot Expr Purif. 2016;119:11). With the availability, for the first time, of a stable and soluble form of ANAT we can now report the identification of initial inhibitors against this biosynthetic enzyme, obtained from the screening of several focused compound libraries. Two core structures of these moderate binding compounds have subsequently been optimized, with the most potent inhibitors in these series possessing sub-micromolar inhibition constants (Kivalues) against ANAT. Slowing the production of NAA via the inhibition of ANAT will lower the elevated levels of this metabolite and can potentially serve as a treatment option to moderate the symptoms of Canavan disease.
- Thangavelu, Bharani,Mutthamsetty, Vinay,Wang, Qinzhe,Viola, Ronald E.
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p. 870 - 885
(2017/02/05)
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- Synthesis of ortho-carboranyl derivatives of (S)-asparagine and (S)-glutamine
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(S)-Asparagine and (S)-glutamine ortho-carboranyl derivatives with free amino and carboxy groups in the α-position were synthesized. By an example of Nγ-(1,2-dicarba-closo-dodecarboran-3-yl)-(S)-glutamine it was demonstrated that the developed synthetic approach carboranyl derivatives of amino acids allowed the preparation of optically pure isomers.
- Gruzdev,Levit,Olshevskaya,Krasnov
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p. 769 - 776
(2017/07/07)
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- NOVEL STABLE SALTS OF PEMETREXED
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The present invention relates to novel crystalline salts of anticancer drug Pemetrexed and its process thereof. More particularly, the present invention relates to stable and highly soluble crystalline Pemetrexed dilithium heptahydrate and process for preparation thereof.
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Page/Page column 8; 13
(2017/11/03)
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- Rigidity versus Flexibility: Is This an Issue in σ1 Receptor Ligand Affinity and Activity?
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Stereoisomeric 2,5-diazabicyclo[2.2.2]octanes 14 and 15 were prepared in a chiral-pool synthesis starting from (S)- or (R)-aspartate. The key step in the synthesis was a Dieckmann-analogous cyclization of (dioxopiperazinyl)acetates 8, which involved trapping of the intermediate hemiketal anion with Me3SiCl. The σ1 affinity was tested using membrane preparations from animal (Guinea pig) and human origin. The binding of bicyclic compounds was analyzed by molecular dynamics simulations based on a 3D homology model of the σ1 receptor. The good correlation between Ki values observed in the σ1 assays and calculated free binding energy, coupled with the identification of four crucial ligand/receptor interactions, allowed the formulation of structure-affinity relationships. In an in vitro antitumor assay with seven human tumor cell lines, the bicyclic compounds inhibited selectively the growth of the cell line A427, which is due to induction of apoptosis. In this assay, the compounds behave like the known σ1 receptor antagonist haloperidol.
- Weber, Frauke,Brune, Stefanie,B?rgel, Frederik,Lange, Carsten,Korpis, Katharina,Bednarski, Patrick J.,Laurini, Erik,Fermeglia, Maurizio,Pricl, Sabrina,Schepmann, Dirk,Wünsch, Bernhard
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p. 5505 - 5519
(2016/07/06)
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- Synthesis of modified peptidoglycan precursor analogues for the inhibition of glycosyltransferase
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The peptidoglycan glycosyltransferases (GTs) are essential enzymes that catalyze the polymerization of glycan chains of the bacterial cell wall from lipid II and thus constitute a validated antibacterial target. Their enzymatic cavity is composed of a donor site for the growing glycan chain (where the inhibitor moenomycin binds) and an acceptor site for lipid II substrate. In order to find lead inhibitors able to fill this large active site, we have synthesized a series of substrate analogues of lipid I and lipid II with variations in the lipid, the pyrophosphate, and the peptide moieties and evaluated their biological effect on the GT activity of E. coli PBP1b and their antibacterial potential. We found several compounds able to inhibit the GT activity in vitro and cause growth defect in Bacillus subtilis. The more active was C16-phosphoglycerate-MurNAc-(l-Ala-d-Glu)-GlcNAc, which also showed antibacterial activity. These molecules are promising leads for the design of new antibacterial GT inhibitors.
- Dumbre, Shrinivas,Derouaux, Adeline,Lescrinier, Eveline,Piette, Andre,Joris, Bernard,Terrak, Mohammed,Herdewijn, Piet
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supporting information; experimental part
p. 9343 - 9351
(2012/07/14)
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- Asymmetric michael additions of α-nitrocyclohexanone to aryl nitroalkenes catalyzed by natural amino acid-derived bifunctional thioureas
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A series of new thiourea catalysts prepared from natural amino acids have been applied in organocatalytic asymmetric Michael additions of α-nitrocyclohexanone to nitroalkenes. The resulting addition products are formed with excellent enantioselectivities (up to an er of 98:2) in good yields (up to 90%).
- J?rres, Manuel,Schiffers, Ingo,Atodiresei, Iuliana,Bolm, Carsten
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supporting information
p. 4518 - 4521
(2012/10/29)
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- Total synthesis of argyrins A and e
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The total synthesis of argyrins A and E were accomplished using a convergent strategy by condensation of one tripeptide and two dipeptide fragments. The synthesis strategy, which was developed for the protection of peptide fragments and identification of the optimum macrocylization site, can be applied to further synthetic studies involving other members of the argyrin family.
- Wu, Wenbin,Li, Zheng,Zhou, Guangbiao,Jiang, Sheng
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supporting information; experimental part
p. 2488 - 2491
(2011/05/09)
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- OPTICALLY ACTIVE -AMINO ACID INTO WHICH BSH IS INTRODUCED AND METHOD FOR SYNTHESIZING THE SAME
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Disclosed is the method for producing an optically active BSH amino acid, which comprises a step of reacting an optically active α-amino acid derivative having a halogen in a side chain with a cyanoethyl BSH compound represented by formula (1). An optically active BSH amino acid obtained by the method is also disclosed.
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Page/Page column 8
(2011/05/14)
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- STEREOSELECTIVE SYNTHESIS OF PIPERIDINE DERIVATIVES
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This invention relates to dialdehyde or dinitrile compounds, which are useful for stereoselective synthesis of piperidine, pyrrolidine, and azepane derivatives.
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Page/Page column 9
(2010/06/22)
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- Relationships between the structure of 6-allyl-6,8-diazabicyclo[3.2.2]nonane derivatives and their σ receptor affinity and cytotoxic activity
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A series of bridged piperazine derivatives was prepared and the affinity toward σ1 and σ2 receptors by means of radioligand binding assays as well as the inhibition of the growth of six human tumor cell lines was investigated. All possible stereoisomers of the 2-hydroxy, 2-methoxy, 2,2-dimethoxy, 2-oxo, and 2-unsubstituted 6,8-diazabicyclo[3.2.2]nonanes were prepared in a chiral pool synthesis starting with (S)- and (R)-glutamate. A Dieckmann analogous cyclization was the key step in the synthesis of the bicyclic framework. The configuration in position 2 was established by a diastereoselective LiBH4 reduction and subsequent Mitsunobu inversion. Structure-affinity relationships demonstrate that substituents in position 2 decrease σ1 receptor affinity which might be due to unfavorable interactions with the σ1 receptor protein. Without a substituent in position 2 high σ1 affinity was obtained (23a ((+)-(1S,5S)-6-allyl-8-(4-methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane): Ki = 11 nM). Experiments with six human tumor cell lines showed a weak but selective growth inhibition of the human small cell lung cancer cell line A-427 by the methyl ethers ent-16b (IC50 = 18.9 μM), 21a (IC50 = 16.4 μM), ent-21a (IC50 = 20.4 μM), and 21b (IC50 = 27.1 μM) and the unsubstituted compounds 23a and 23b (42% inhibition at 20 μM).
- Holl, Ralph,Schepmann, Dirk,Gruenert, Renate,Bednarski, Patrick J.,Wuensch, Bernhard
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body text
p. 777 - 793
(2009/08/07)
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- Scale-up of trisodium [(3Β,5Β,12α)-3-[[4(S)-4-[bis[2- [bis[(carboxy-kO)methyl]aminokN] ethyl]amino-kN]-4-(carboxy-kO)-1-oxobutyl] amino]-12-hydroxycholan-24- oato(6-)]gadolinate(3-)], a Gd(III) complex under development as a contrast agent for MRI coronary angiography
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Process chemistry involved in the discovery and development routes to trisodium [(3Β,5Β,12α)-3-[[4(S)-4-[bis[2-[bis[(carboxykO) methyl]amino-kN]ethyl]amino-kN]-4-(carboxy-kO)-1-oxobutyl]- amino]-12- hydroxycholan-24-oato(6-)]gadolinate(3-)] (B22956/1) starting from L-glutamic acid and (3α,5Β,12α)-3,12-dihydroxycholan-24-oic acid is described. The best process is based on seven chemical steps and overcomes difficult purification protocols. Such process has been successfully implemented to prepare multikilogram batches of the target compound in 20% overall yield from (3α,5Β,12α)-3,12-dihydroxycholan-24-oic acid.
- Anelli, Pier Lucio,Brocchetta, Marino,Lattuada, Luciano,Manfredi, Giuseppe,Morosini, Pierfrancesco,Murru, Marcella,Palano, Daniela,Sipioni, Marco,Visigalli, Massimo
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experimental part
p. 739 - 746
(2010/04/22)
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- Synthesis and pharmacological evaluation of bicyclic SNC80 analogues with separated benzhydryl moiety
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Directed by molecular modeling studies the pharmacophoric benzhydryl moiety of the δ opioid receptor agonist SNC80 was separated and the two phenyl residues were attached to different positions of the conformationally constrained 6,8-diazabicyclo[3.2.2]nonane framework in order to find novel δ agonists. The crucial reaction step in the chiral pool synthesis was the establishment of the three carbon bridge by a Dieckmann analogous cyclization of the allyl and propyl derivatives 6 and 7 to yield the mixed methyl silyl acetals 8 and 9, respectively. Stereoselective Grignard reaction, dehydration, and introduction of the pharmacophoric (N,N-diethylcarbamoylbenzyl) residue led to the designed δ receptor agonists 3, ent-3, and 20 with a double bond in the bicyclic framework. Hydrogenation of the allyl derivative 14 was performed with ammonium formate and Pd/C to yield the saturated ligands 24a and 24b. Removal of the allyl substituent with RhCl3, hydrogenation of the ring system, and re-attachment of the allyl moiety provided the allyl derivatives 4a and 4b. In receptor binding studies with the radioligand [3H]-deltorphine II only ent-3 showed considerable δ receptor affinity (Ki = 740 nM). Since ent-3 also interacts with μ receptors (Ki = 250 nM) it belongs to the very interesting compound class of mixed δ/μ ligands.
- Jung, Bettina,Englberger, Werner,Froehlich, Roland,Schepmann, Dirk,Lehmkuhl, Kirstin,Wuensch, Bernhard
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p. 2870 - 2885
(2008/09/19)
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- Novel glycine like amino acids from glyco-α-aminonitriles as building blocks for peptide synthesis
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Our interest in the glycoaminocyanation reaction led us to apply this methodology to introduce amino acids on a monosaccharide using the N-terminal position. The GAAs described in this paper are characterized by having the amino and carboxylic acid functionalities on a disubstituted position of the saccharide backbone leading to α,α-disubstituted glycines. These new sugar amino acids showed a restricted conformation involving a spontaneous intramolecular cyclization between the C- and N-terminal positions during hydrolysis or hydrogenolysis to give the corresponding oxopiperazine. Tripeptide mimics were obtained by the introduction of an additional amino acid using one-pot conditions starting from these cyclic by-products under basic media. We demonstrated that these pseudo tripeptides are good candidates for extension of the peptidic scaffold and cyclization.
- Ducatel, Helene,Van Nhien, Albert Nguyen,Postel, Denis
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- Novel Dipeptides incorporating selenoamino acids with enhanced bioavailability- Synthesis, pharmaceutical and cosmeceutical applications thereof
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Disclosed is a novel synthetic method for isomeric peptides through an appropriate linkage of L-selenomethionine or Se-Methyl-L-selenocysteine with L-glutamic acid. The novel synthetic method produces isomeric peptides of L-selenomethionine or Se-Methyl-L-selenocysteine that exhibit (i) enhanced water solubility; (ii) enhanced rate of dissolution in water; (iii) enhanced bioavailability; (iv) excellent vascular endothelial growth factor promoting activity; (v) excellent anti-5-alpha-reductase activity; (vi) capabilities to prevent/reduce “hair fall” and promote “hair growth”, thereby maintaining a perfect homeostasis for “hair care”. Cosmeceutical and pharmaceutical compositions comprising the isomeric peptides obtained through an appropriate linkage of L-selenomethionine or Se-Methyl-L-selenocysteine with L-glutamic acid are also disclosed. Other dipeptides with several other amino acids and uses thereof are also disclosed.
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(2010/11/29)
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- Synthesis of bicyclic σ receptor ligands with cytotoxic activity
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All possible stereoisomeric alcohols (6-benzyl-8-(4-methoxybenzyl)-6,8- diazabicyclo[3.2.2]nonan-2-ol) and methyl ethers (6-benzyl-2-methoxy-8-(4- methoxybenzyl)-6,8-diazabicyclo[3.2.2]nonane) are prepared from (R)- and (S)-glutamate. A Dieckmann analogous cyclization, which makes use of trapping the primary cyclization product with Me3SiCl, generates the bicyclic framework. Stereoselective LiBH4 reduction and Mitsunobu inversion establish the configuration in position 2. Enantiomeric alcohols 15 (1S,2S,5R) and ent-15 (1R,2R,5S) as well as diastereomeric methyl ethers ent-17 (1R,2R,5S) and ent-22 (1R,2S,5S) display high σ1 receptor affinity. Cell growth inhibition of the stereoisomeric alcohols and methyl ethers against five human tumor cell lines is investigated. In particular, at a concentration of 20 μthe four methyl ethers stop completely the cell growth of the small cell lung cancer cell line A-427, indicating a specific target in this cell line. The IC50-values of methyl ethers ent-17 and ent-22 are in the range of the antitumor drugs cisplatin and oxaliplatin. Binding assays show that the investigated tumor cell lines express considerable amounts of σ1 and σ2 receptors.
- Geiger, Christian,Zelenka, Christel,Weigl, Manuela,Fr?hlich, Roland,Wibbeling, Birgit,Lehmkuhl, Kirstin,Schepmann, Dirk,Grünert, Renate,Bednarski, Patrick J.,Wünsch, Bernhard
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p. 6144 - 6153
(2008/09/16)
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- Toward the development of chemoprevention agents. Part II: Chemo-enzymatic synthesis and anti-inflammatory activities of a new class of 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes
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A new series of optically pure 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes were designed and synthesized via a chemo-enzymatic combined method to develop new chemoprevention agents. Twenty-four of newly synthesized compounds significantly inhibited xylene-induced rat ear edema and exhibited comparable or better anti-inflammatory activities than the reference drug aspirin. Treatment of these anti-inflammatory agents did not prolong the tail bleeding time in rat. In addition, 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes exhibited good membrane permeability based on in vitro Caco-2 cell monolayer permeability assay. Furthermore, some preliminary structure-activity relationships were further analyzed among these compounds. Taken together, 5-amino-2-substitutedphenyl-1,3-dioxacycloalkanes may represent a new class of anti-inflammatory drugs with safer pharmacological profile.
- Gu, Keli,Bi, Lanrong,Zhao, Ming,Wang, Chao,Ju, Jingfang,Peng, Shiqi
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p. 6273 - 6290
(2008/04/05)
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- The synthesis of novel methotrexate-like compounds
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Methotrexate (MTX) is a folate antagonist used in treatment of several chronic inflammatory and neoplastic conditions. In this study, new MTX-like compounds that may-be potential anticancer agents were synthesized and their structures were determined by IR, UV, GC-MS, 1H NMR, and 13C NMR spectra. Also, in this study, a series structurally related to MTX or folate analogous compounds were evaluated whether they have inhibitory properties on the dihydrofolate reductase activity (DHFR).
- Colak, Naki,Yildirir, Yilmaz,Kavutcu, Mustafa,Nurlu, Nilhan
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p. 1283 - 1287
(2008/03/27)
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- Regio- and stereospecific synthesis of β-sulfonamidodisulfides and β-sulfonamidosulfides from aziridines using tetrathiomolybdate as a sulfur transfer reagent
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A comprehensive study of a general and effective one-step procedure for the synthesis of β-sulfonamidodisulfides directly from N-tosyl aziridines in a regio- and stereospecific manner under neutral conditions without the use of any Lewis acid or base has been reported. This methodology is extended to the synthesis of an optically pure cyclic seven-membered disulfide 29. Synthesis of a variety of β-sulfonamidosulfides involving tandem, multistep reactions in one pot is also reported.
- Sureshkumar, Devarajulu,Gunasundari, Thanikachalam,Ganesh, Venkataraman,Chandrasekaran, Srinivasan
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p. 2106 - 2117
(2007/10/03)
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- Molecular modeling directed synthesis of a bicyclic analogue of the δ opioid receptor agonist SNC 80
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In order to find novel δ opioid receptor agonists, the pharmacophoric benzhydryl moiety of the lead compound SNC 80 (1) was dissected and the phenyl residues were attached to different positions of the 6,8-diazabicyclo[3.2.2] nonane core system (4). The position of the carboxamido group, the stereochemistry, the C3/C4 bond order and the kind and length of the spacer X were considered. The resulting compounds were compared with the four energetically most favourable conformations of SNC 80 by a multifit analysis. These calculations led to the structures 5-10, which fit best to SNC 80. Herein the synthesis of one of these compounds (9) is described. Starting from (S)-glutamate two alternative routes are detailed to obtain the key intermediate 14. A variation of the Dieckmann cyclization, which uses trapping of the first cyclization product with ClSiMe3 provided the mixed acetal 20, which was carefully hydrolyzed to yield the bicyclic ketone 17. Stereoselective addition of phenylmagnesium bromide, dehydration, LiAlH4 reduction and exchange of the N-6 residue afforded the designed compound 9. The affinities of 9 towards δ, μ, κ and ORL1 receptors were determined in receptor binding studies with radioligands. Only moderate receptor affinity was found.
- Jung, Bettina,Englberger, Werner,Wuensch, Bernhard
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p. 281 - 290
(2007/10/03)
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- ANTIMICROBIAL QUINOLONES, THEIR COMPOSITIONS AND USES
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Compounds of the following formula (I) are effective antimicrobial agents.
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Page 103; 105
(2010/02/06)
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- Engineering of Highly Luminescent Lanthanide Tags Suitable for Protein Labeling aad Time-Resolved Luminescence Imaging
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The synthesis of a new ligand LH4 based on a glutamic acid skeleton bis-functionalized on its nitrogen atom by 6-methylene-6′ -carboxy-2,2′-bipyridine chromophoric units is described. UV-vis spectrophotometric titrations revealed the formation of 1:1 M:L complexes with lanthanide(III) cations, and complexation of LH4 with equimolar amounts of hydrated LnCl3 salts (Ln = Eu, Gd, and Tb) gave water-soluble and stable complexes of the general formula [LnL(H 2O)]Na, which were characterized by elemental analysis, IR, UV-vis absorption spectroscopy, 1H NMR (Ln = Eu), and mass spectrometry. The conditional stability constant for formation of the [EuL(H2O)]Na complex was determined by competitive complexation experiments to be log K= 16. 5 ± 0.6 in 0.01 M TRIS/HCl buffer (pH = 7.0). In water solution, the [EuL(H2O)]Na and [TbL(H2O)]Na complexes were highly luminescent with quantum yields of 8% and 31%, respectively, despite the presence of ca. one water molecule in the first coordination sphere of the metal ions. Activation of the appended carboxylate function of the glutamate moiety in the form of an N-hydroxysuccinimidyl ester allows for the covalent linking of the complexes to primary amino groups of biological compounds. Bovine serum albumin (BSA) was labeled with both Eu or Tb complexes, and the Ln-BSA conjugates were characterized by UV-vis absorption and emission spectroscopy and MALDI-TOF mass spectrometry. Labeling ratios (number of complex molecules per BSA) of ca. 8:1 and 7:1 were established for Eu-BSA and Tb-BSA, respectively. The suitability of the tagged compound for use in bioanalytical time-resolved luminescence microscopy was established by comparison with fluorescein-labeled probes.
- Weibel, Nicolas,Charbonniere, Loic J.,Guardigli, Massimo,Roda, Aldo,Ziessel, Raymond
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p. 4888 - 4896
(2007/10/03)
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- A process for the preparation of 3-Glutamido bile ester derivatives using N-tBoc methyl pyroglutamate
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The present invention relates to a novel process for the preparation of bile esters derivatives of general formula (I), in which R1 is H or OH; R2 is H, α-OH or β-OH and R3 is a straight or branched C1-C4 alkyl group or a benzyl group.The process uses either L-glutamic acid hydrochloride (II) or L-glutamic acid as starting material, according to the following Scheme 1.
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- Synthesis of chiral non-racemic 3-(dioxopiperazin-2-yl)propionic acid derivatives
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Starting with the proteinogenic amino acid (S)-glutamate (3) a facile, high yielding synthesis of the chiral non-racemic 3-(dioxopiperazin-2-yl)propionates 6, 11, and 14 is presented. Key intermediates in the synthesis of N1-benzyl substituted (dioxopiperazin-2yl)propionates 11 and 14 are the N-monobenzylglutamate 8 and the chloroacetamide 12, which allow introduction of various substituents in position 4 of the piperazine ting. In receptor binding studies with radioligands the 3-(piperazin-2-yl)propanol 15 was found to have promising affinity for σ1-receptors (Ki=66.1 nM).
- Weigl, Manuela,Wünsch, Bernhard
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p. 1173 - 1183
(2007/10/03)
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- New 2-(2'-phenyl-9'-benzyl-8'-azapurin-6'-ylamino)-carboxylic acid methylesters as ligands for A1 adenosine receptors.
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Synthesis of a series of new 2-phenyl-9-benzyl-8-azaadenines bearing on N6 an alkyl or aralkyl chain having a carbonyloxymethyl group on the carbon bound to N6 were reported. The ester group could assure to the molecule a better water-solubility than the 8-azaadenines 2, 6 and 9 substituted with lipophilic groups synthesised in the past. Compounds synthesised demonstrated only little capability of binding A1 adenosine receptors.
- Biagi,Giorgi,Pacchini,Livi,Scartoni
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p. 929 - 931
(2007/10/03)
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- The synthesis of folic acid, multiply labelled with stable isotopes, for bio-availability studies in human nutrition
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Two different methods for the synthesis of folic acid, which are suitable for the incorporation of compounds multiply labelled with stable isotopes, are described. The first method is based on the use of a novel reductive amination to link 2-acetyIamino-4-hydroxy-6-formylpteridine withp-aminobenzoyl-L-glutamic acid. The second method is based on the penultimate formation of an amide bond between Ar-2-acetyl-Ar-10-trifluoroacetyIpteroic acid and dimethyl L-glutamate. Both methods have been used to transform [13C6]aniline into folic acid, labelled with [13C6] in the p-aminobenzoate moiety, and [3,3,4,4-2H4]-L-glutamic acid into folic acid, labelled with [2H4] in the glutamate moiety. Doubly labelled [13C6,2H 4]-p-aminobenzoyl-L-glutamate has also been prepared by the former method.
- Maunder, Peter,Finglas, Paul M.,Mallet, Anthony I.,Mellon, Fred A.,Aaqib Razzaque,Ridge, Brian,Vahteristo, Liisa,Witthoeft, Cornelia
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p. 1311 - 1323
(2007/10/03)
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- Antiviral and tumor cell antiproliferative SAR studies on tetracyclic eudistomins-II
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In a search for the minimum pharmacophore of the naturally occurring tetracyclic eudistomins, five structural analogues (4-8) were evaluated for their in vitro antiviral and tumor cell antiproliferative activities. For the synthesis of these derivatives both intra- and intermolecular Pictet-Spengler reactions have been used. Opening of the P-carboline annulated 7-membered D-ring in 6 and 7 resulted in a complete loss of activity. On the other hand, replacement of either the oxygen atom or the sulfur atom in the 7-membered ring by a methylene group in 5 and 8, respectively, is allowed. These results combined with previous SAR data underline the crucial importance of the D-ring in eudistomins as a scaffold for the correct positioning of both basic nitrogen atoms. Also bioisosteric replacement of the bicyclic indole system with a dimethoxyphenyl group, to give the isoquinoline skeleton, is allowed. The tricyclic isoquinoline derivative 4 is, so far, the most promising antiviral analogue; it combines a high potency (MIG at 100 ng/ mL (340 nM)) with high MCC/MIC ratios (ranging from 1000 to 5000 against HSV-1, HSV-2, vaccinia virus, and vesicular stomatitis virus).
- Van Maarseveen, Jan H.,Scheeren, Hans W.,De Clercq, Erik,Balzarini, Jan,Kruse, Chris G.
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p. 955 - 970
(2007/10/03)
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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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- Lascivol, the Bitter Component of Tricholoma lascivum (Agaricales)
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The structure of lascivol (1), the bitter principle of the toadstool Tricholoma lascivum, has been elucidated by chemical and spectroscopic studies including a single crystal X-ray structure analysis. 1 is degrated to dimethyl L-glutamate (6) and 5-methoxy-2,4-dimethylindole (5) by acid methanolysis.
- Eizenhoefer, Thomas,Fugmann, Burkhard,Sheldrick, William S.,Steffan, Bert,Steglich, Wolfgang
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p. 1115 - 1118
(2007/10/02)
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- SYNTHESIS OF NONPROTEINOGENIC AMINO ACIDS PART 2: PREPARATION OF A SYNTHETIC EQUIVALENT OF THE γ-ANION SYNTHON FOR ASYMMETRIC AMINO ACID SYNTHESIS
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The synthesis of α-t-butyl γ-methyl N-trityl-(S)-glutamate (12) from (S)-glutamic acid (6) is described.Diester (12), on treatment with lithium isopropylcyclohexylamide followed by the addition of carbonyl compounds, reacts to give the γ-substituted glutamic acid derivatives (13a-i) with retention of optical purity at the α centre.
- Baldwin, Jack E.,North, Michael,Flinn, Anthony,Moloney, Mark G.
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p. 1453 - 1464
(2007/10/02)
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- Synthesis and Stereochemical Studies of the Chiral Ruthenium Complexes X> .Crystal Structure of Cl>
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A simple procedure for the preparation of H> from is described.The hydride reacts stereospecifically with chloroform or carbon tetrachloride to give Cl> whose structure is reported.The crystals are monoclinic, space group P21 with a = 11.076(2), b = 10.908(2), c = 12.825(3) Angstroem, β = 92.26(2), and Z = 2.The structure was solved by the heavy-atom method and refined to R = 0.0322 using 2 306 diffractometer data with I > 3?(I).Synthesis of this chloro-complex from and (S)dpompyr proceeds with only modest diastereoselectivity whereas reduction of Cl> using LiAlH4 regenerates 88percent H>.Mechanisms are proposed to explain the observed diastereoselectivities.Circular dichroism and 1H, 13C, and 31P n.m.r. spectra of all new compounds are also reported.
- Cesarotti, Edoardo,Prati, Laura,Sironi, Angelo,Ciani, Gianfranco,White, Colin
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p. 1149 - 1156
(2007/10/02)
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