- 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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- 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 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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- 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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- 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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- 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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- 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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- 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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- 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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- 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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- 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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