- PNA Hybrid Sequences as Recognition Units in SNARE-Protein-Mimicking Peptides
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Membrane fusion is an essential process in nature and is often accomplished by the specific interaction of SNARE proteins. SNARE model systems, in which SNARE domains are replaced by small artificial units, represent valuable tools to study membrane fusio
- Hubrich, Barbara E.,Kumar, Pawan,Neitz, Hermann,Grunwald, Matthias,Grothe, Tobias,Walla, Peter Jomo,Jahn, Reinhard,Diederichsen, Ulf
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- Synthesis of the stereoisomers of a novel antibacterial agent and interpretation of their relative activities in terms of a theoretical model of the penicillin receptor
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2,2-Dimethyl-3-(2'-hydroxypropyl)-5-carboxy-Δ3-1,4-thiazine (1) is a designed antibacterial agent. Based on an analysis of how penicillin complexes to and reacts with a model of a penicillin-binding protein, 1 contains a functional group (C=N) that can react with a serine hydroxyl group of the receptor according to the putative reaction Enz-OH + C=N → Enz-O-C-NH. Compound 1 also contains additional substituents that are designed to position the O-H and C=N groups relative to one another in the enzyme-substrate complex in a geometry that attempts to reproduce the optimum geometry of approach of two such reactants. A most important assumption is that this optimum geometry can be computed ab initio. In a first preparation of 1, (±)-5-methyl-4-hexene-2-ol (2) was converted to the lithium salt of (±)-2-mercapto-2-methyl-5-tert-butyldimethylsiloxy-3-hexanone (7), which was condensed with the N-tert-butoxycarbonyl-D- and L-serine-β-lactones (3). The synthesis was completed by deprotection with formic acid and cyclization in water. The R and S enantiomers of 2 have now been obtained, and the absolute configuration of the alcohol established, by reaction of the R- and S-propylene oxides with an organometallic reagent prepared from β,β-dimethylvinyl bromide. The R alcohol has also been secured by lipase-catalyzed transesterification with trifluoroethyl butyrate, and chemical hydrolysis of the trifluoroethyl ester. The R and S enantiomers of 2 were converted to the R and S enantiomers of 7, and these were condensed with the R and S enantiomers of 3 to yield each of the stereoisomers of the chemically unstable 1 in ca. 95% optically pure form. Antibacterial activity resides in the 5S,8R and 5S,8R isomers. These findings are shown to be consistent with the theoretical model. It is hoped that the stability of the lead structure 1 can be improved, to allow binding experiments with penicillin recognizing enzymes to proceed. 2,2-Dimethyl-3-(2′-hydroxypropyl)-5-carboxy- Δ3-1,4-thiazine (1) is a designed antibacterial agent. Based on an analysis of how penicillin complexes to and reacts with a model of a penicillin-binding protein, 1 contains a functional group (C = N) that can react with a serine hydroxyl group of the receptor according to the putative reaction Enz-OH + C = N → Enz-O-C-NH. Compound 1 also contains additional substituents that are designed to position the O-H and C = N groups relative to one another in the enzyme-substrate complex in a geometry that attempts to reproduce the optimum geometry of approach of two such reactants. A most important assumption is that this optimum geometry can be computed ab initio. In a first preparation of 1, (±)-5-methyl-4-hexene-2-ol (2) was converted to the lithium salt of (±)-2-mercapto-2-methyl-5-tert-butyldimethylsiloxy-3-hex anone (7), which was condensed with the N-tert-butoxycarbonyl-D- and L-serine-β-lactones (3). The synthesis was completed by deprotection with formic acid and cyclization in water. The R and S enantiomers of 2 have now been obtained, and the absolute configuration of the alcohol established, by reaction of the R- and S-propylene oxides with an organometallic reagent prepared from β,β-dimethylvinyl bromide. The R alcohol has also been secured by lipase-catalyzed transesterification with trifluoroethyl butyrate, and chemical hydrolysis of the trifluoroethyl ester. The R and S enantiomers of 2 were converted to the R and S enantiomers of 7, and these were condensed with the R and S enantiomers of 3 to yield each of the stereoisomers of the chemically unstable 1 in ca. 95% optically pure form. Antibacterial activity resides in the 5S,8R and 5S,8S isomers. These findings are shown to be consistent with the theoretical model. It is hoped that the stability of the lead structure 1 can be improved, to allow binding experiments with penicillin recognizing enzymes to proceed.
- Wolfe,Zhang,Johnston,Kim
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- Gatorbulin-1, a distinct cyclodepsipeptide chemotype, targets a seventh tubulin pharmacological site
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Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquid malignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/β-tubulin either promoting microtubule stabilization or depolymerization. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/β-tubulin?GB1 complex.
- Matthew, Susan,Chen, Qi-Yin,Ratnayake, Ranjala,Fermaintt, Charles S.,Lucena-Agell, Daniel,Bonato, Francesca,Prota, Andrea E.,Lim, Seok Ting,Wang, Xiaomeng,Díaz, J. Fernando,Risinger, April L.,Paul, Valerie J.,Oliva, Maria ángela,Luesch, Hendrik
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- Exploring the dNTP -binding site of HIV-1 reverse transcriptase for inhibitor design
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HIV-1 reverse transcriptase (RT) plays a central role in the viral life cycle, and roughly half of the FDA-approved anti-HIV drugs are targeting RT. Nucleoside analogs (NRTIs) require cellular phosphorylation for binding to RT, and to bypass this rate-limiting path, we designed a new series of acyclic nucleoside phosphonate analogs as nucleoside triphosphate mimics, aiming at the chelation of the catalytic Mg2+ ions via a phosphonate and/or a carboxylic acid group. Novel synthetic procedures were developed to access these nucleoside phosphonate analogs. X-ray structures in complex with HIV-1 RT/dsDNA demonstrated that their binding modes are distinct from that of our previously reported compound series. The impact of chain length, chirality and linker atom have been discussed. The detailed structural understanding of these new compounds provides opportunities for designing new class of HIV-1 RT inhibitors.
- Gu, Weijie,Martinez, Sergio,Singh, Abhimanyu K.,Nguyen, Hoai,Rozenski, Jef,Schols, Dominique,Herdewijn, Piet,Das, Kalyan,De Jonghe, Steven
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- Novel Easily Recyclable Bifunctional Phosphonic Acid Carrying Tripeptides for the Stereoselective Michael Addition of Aldehydes with Nitroalkenes
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A novel bifunctional organocatalyst library combining both aminocatalysis and phosphonic acid activation was used for the first time as an efficient tool for the stereoselective Michael addition of aldehydes with several aromatic nitroalkenes with good selectivities up to 95:5 dr and 93:7 er. Due to their high water solubility, the catalysts were easily recyclable and could be reused over several cycles without any significant loss of selectivity.
- Cortes-Clerget, Margery,Gager, Olivier,Monteil, Maelle,Pirat, Jean-Luc,Migianu-Griffoni, Evelyne,Deschamp, Julia,Lecouvey, Marc
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supporting information
p. 34 - 40
(2016/01/25)
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- N -(2-Oxo-3-oxetanyl)carbamic acid esters as N-acylethanolamine acid amidase inhibitors: Synthesis and structure-activity and structure-property relationships
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The β-lactone ring of N-(2-oxo-3-oxetanyl)amides, a class of N-acylethanolamine acid amidase (NAAA) inhibitors endowed with anti-inflammatory properties, is responsible for both NAAA inhibition and low compound stability. Here, we investigate the structure-activity and structure-property relationships for a set of known and new β-lactone derivatives, focusing on the new class of N-(2-oxo-3-oxetanyl)carbamates. Replacement of the amide group with a carbamate one led to different stereoselectivity for NAAA inhibition and higher intrinsic stability, because of the reduced level of intramolecular attack at the lactone ring. The introduction of a syn methyl at the β-position of the lactone further improved chemical stability. A tert-butyl substituent in the side chain reduced the reactivity with bovine serum albumin. (2S,3R)-2-Methyl-4-oxo-3-oxetanylcarbamic acid 5-phenylpentyl ester (27, URB913/ARN077) inhibited NAAA with good in vitro potency (IC50 = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications.
- Duranti, Andrea,Tontini, Andrea,Antonietti, Francesca,Vacondio, Federica,Fioni, Alessandro,Silva, Claudia,Lodola, Alessio,Rivara, Silvia,Solorzano, Carlos,Piomelli, Daniele,Tarzia, Giorgio,Mor, Marco
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scheme or table
p. 4824 - 4836
(2012/07/03)
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- Synthesis and structure - Activity relationships of N -(2-Oxo-3-oxetanyl) amides as N -acylethanolamine-hydrolyzing acid amidase inhibitors
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The fatty acid ethanolamides (FAEs) are a family of bioactive lipid mediators that include the endogenous agonist of peroxisome proliferator- activated receptor-α, palmitoylethanolamide (PEA). FAEs are hydrolyzed intracellularly by either fatty acid amide hydrolase or N-acylethanolamine- hydrolyzing acid amidase (NAAA). Selective inhibition of NAAA by (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide [(S)-OOPP, 7a] prevents PEA degradation in mouse leukocytes and attenuates responses to proinflammatory stimuli. Starting from the structure of 7a, a series of β-lactones was prepared and tested on recombinant rat NAAA to explore structure-activity relationships (SARs) for this class of inhibitors and improve their in vitro potency. Following the hypothesis that these compounds inhibit NAAA by acylation of the catalytic cysteine, we identified several requirements for recognition at the active site and obtained new potent inhibitors. In particular, (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide (7h) was more potent than 7a at inhibiting recombinant rat NAAA activity (7a, IC50 = 420 nM; 7h, IC50 = 115 nM) in vitro and at reducing carrageenan-induced leukocyte infiltration in vivo.
- Solorzano, Carlos,Antonietti, Francesca,Duranti, Andrea,Tontini, Andrea,Rivara, Silvia,Lodola, Alessio,Vacondio, Federica,Tarzia, Giorgio,Piomelli, Daniele,Mor, Marco
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scheme or table
p. 5770 - 5781
(2010/10/20)
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- Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV
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Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4- phenylbutyric acid) HIV protease inhibitors. The synthetic analogues exhibited potent inhibitory activity
- Nakatani, Shingo,Hidaka, Koushi,Ami, Ei'Ichi,Nakahara, Koichiro,Sato, Akihiko,Nguyen, Jeffrey-Tri,Hamada, Yoshio,Hori, Yasuko,Ohnishi, Nobuyuki,Nagai, Akinori,Kimura, Tooru,Hayashi, Yoshio,Kiso, Yoshiaki
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scheme or table
p. 2992 - 3004
(2009/04/05)
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- Side chain homologation of alanyl peptide nucleic acids: Pairing selectivity and stacking
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Alanyl peptide nucleic acids (alanyl-PNAs) are oligomers based on a regular peptide backbone with alternating configuration of the amino acids. All side chains are modified by covalently linked nucleobases. Alanyl-PNAs form very rigid, well defined, and l
- Diederichsen, Ulf,Weicherding, Daniel,Diezemann, Nicola
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p. 1058 - 1066
(2007/10/03)
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- Total synthesis of the cyclic heptapeptide Argyrin B: A new potent inhibitor of T-cell independent antibody formation
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(equation presented) Argyrin B (1) The total synthesis of Argyrin B (1) is presented using a synthetic plan that is convergent and flexible and conserves the stereogenic centers. The unusual amino acid 4-methoxy tryptophan (6) was obtained via an enzymati
- Ley, Steven V.,Prieur, Alain,Heusser, Christoph
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p. 711 - 714
(2007/10/03)
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- The design, synthesis, and biological evaluation of analogues of the serine-threonine protein phosphatase 1 and 2A selective inhibitor microcystin LA: Rational modifications imparting PP1 selectivity
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Based on the results from previously reported molecular modeling analyses of the interactions between the inhibitor microcystin and the serine-threonine protein phosphatases 1 and 2A, we have designed analogues of microcystin LA with structural modifications intended to impart PP1 selectivity. The synthesis of several first generation analogues followed by inhibition assays revealed that all three are PP1-selective, as predicted. Although the observed selectivities are modest, one of the designed analogues is more selective for PP1 than any known small molecule inhibitor. Copyright (C) 1999 Elsevier Science Ltd.
- Aggen, James B.,Humphrey, John M.,Gauss, Carla-Maria,Huang, Hsien-Bin,Nairn, Angus C.,Chamberlin, A. Richard
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p. 543 - 564
(2007/10/03)
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- Synthesis of chiral 1-(2'-amino-2'-carboxyethyl)-1,4-dihydro-6,7- quinoxaline-2,3-diones: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor agonists and antagonists
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Recently discovered 6,7-disubstituted quinoxaline-2,3-diones, 1, have been found to antagonize specific binding and functional responses to both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainic acid. Although a variety of studies have an
- Sun, Guoping,Uretsky, Norman J.,Wallace, Lane J.,Shams, Gamal,Weinstein, David M.,Miller, Duane D.
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p. 4430 - 4438
(2007/10/03)
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- Farnesyl Diphosphate-Based Inhibitors of Ras Farnesyl Protein Transferase
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The rational design, synthesis, and biological activity of farnesyl diphosphate (FPP)-based inhibitors of the enzyme Ras farnesyl protein transferase (FPT) is described.Compound 3, wherein a β-carboxylic phosphonic acid type pyrophosphate (PP) surrogate is connected to the hydrophobic farnesyl group by an amide linker, was found to be a potent (I50(FPT) = 75 nM) and selective inhibitor of FPT, as evidenced by its inferior activity against squalene synthetase (I50(SS) = 516 μM) and mevalonate kinase (I50(MK) = >200 μM).A systematic structure-activity relationship study involving modifications of the farnesyl group, the amide linker, and the PP surrogate of 3 was undertaken.Both the carboxylic and phosphonic acid groups of the β-carboxylic phosphonic acid PP surrogate are essential for activity, since deletion of either group results in 50-2600-fold loss in activity (6-9, I50 = 4.6-220 μM).The farnesyl group also displays very stringent requirements and does not tolerate one carbon homologation (12, I50 = 17.7 μM), substitution by a dodecyl fragment (14, I50 = 9 μM), or introduction of an extra methyl group at the allylic position (18, I50 = 55 μM).Modifications around the amide linker group of 3 were more forgiving, as evidenced by the activity of N-methyl analog (21, I50 = 0.53 μM), the one carbon atom shorter farnesoic acid-derived retroamide analog (32, I50 = 250 nM), and the exact retroamide analog (49, I50 = 50 nM).FPP analogs such as 3, 32, and 49 are novel, potent, selective, small-sized, nonpeptidic inhibitors of FPT that may find utility as antitumor agents.
- Patel, Dinesh V.,Schmidt, Robert J.,Biller, Scott A.,Gordon, Eric M.,Robinson, Simon S.,Manne, Veeraswamy
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p. 2906 - 2921
(2007/10/02)
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- Syntheses of optically pure α-amino acids from 3-amino-2-oxetanone salts
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A process for the preparation of optically pure α-amino acids comprising the nucleophilic ring-opening of 3-amino-2-oxetanone salts. N-Protected serine β-lactones are deprotected to form heretofore unknown 3-amino-2-oxetanone and its corresponding salts. In turn these previously unknown 3-amino-2-oxetanone salts may be used in the synthesis of other novel or rare stereochemically-pure free amino acids.
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