- Structural Basis for α-Helix Mimicry and Inhibition of Protein–Protein Interactions with Oligourea Foldamers
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Efficient optimization of a peptide lead into a drug candidate frequently needs further transformation to augment properties such as bioavailability. Among the different options, foldamers, which are sequence-based oligomers with precise folded conformation, have emerged as a promising technology. We introduce oligourea foldamers to reduce the peptide character of inhibitors of protein–protein interactions (PPI). However, the precise design of such mimics is currently limited by the lack of structural information on how these foldamers adapt to protein surfaces. We report a collection of X-ray structures of peptide–oligourea hybrids in complex with ubiquitin ligase MDM2 and vitamin D receptor and show how such hybrid oligomers can be designed to bind with high affinity to protein targets. This work should enable the generation of more effective foldamer-based disruptors of PPIs in the context of peptide lead optimization.
- Cussol, Léonie,Mauran-Ambrosino, Laura,Buratto, Jérémie,Belorusova, Anna Y,Neuville, Maxime,Osz, Judit,Fribourg, Sébastien,Fremaux, Juliette,Dolain, Christel,Goudreau, Sébastien R.,Rochel, Natacha,Guichard, Gilles
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Read Online
- Urea based foldamers
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N,N′-linked oligoureas are a class of enantiopure, sequence-defined peptidomimetic oligomers without amino acids that form well-defined and predictable helical structures akin to the peptide α-helix. Oligourea-based foldamers combine a number of features—such as synthetic accessibility, sequence modularity, and folding fidelity—that bode well for their use in a range of applications from medicinal chemistry to catalysis. Moreover, it was recently recognized that this synthetic helical backbone can be combined with regular peptides to generate helically folded peptide-oligourea hybrids that display additional features in terms of helix mimicry and protein-surface recognition properties. Here we provide detailed protocols for the preparation of requested monomers and for the synthesis and purification of homo-oligoureas and peptide-oligourea hybrids.
- Yoo, Sung Hyun,Li, Bo,Dolain, Christel,Pasco, Morgane,Guichard, Gilles
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- Design, synthesis, and structure-activity relationship studies of L-amino alcohol derivatives as broad-spectrum antifungal agents
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To discover broad spectrum antifungal agents, two strategies were applied, and a novel class of L-amino alcohol derivatives were designed and synthesized. 3-F substituted compounds 14i, 14n, 14s and 14v exhibited excellent antifungal activities with broad antifungal spectra against C. albicans and C. tropicalis, with MIC values in the range of 0.03–0.06 μg/mL, and against A. fumigatus and C. neoformans, with MIC values in the range of 1–2 μg/mL. Notably, Compounds 14i, 14n, 14s and 14v also displayed moderate activities against fluconazole-resistance strains 17# and CaR that were isolated from AIDS patients. Moreover, only compounds in the S-configuration showed antifungal activity. Preliminary mechanistic studies showed that the potent antifungal activity of compound 14v stemmed from inhibition of C. albicans CYP51. Compounds 14n and 14v were almost nontoxic to mammalian A549 cells, and their stability in human plasma was excellent.
- Zhao, Liyu,Tian, Linfeng,Sun, Nannan,Sun, Yin,Chen, Yixuan,Wang, Xinran,Zhao, Shizhen,Su, Xin,Zhao, Dongmei,Cheng, Maosheng
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p. 374 - 385
(2019/06/05)
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- Synthesis of Enantiomerically Pure 3-Substituted Piperazine-2-acetic Acid Esters as Intermediates for Library Production
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The piperazine heterocycle is broadly exploited in FDA-approved drugs and biologically active compounds, but its chemical diversity is usually limited to ring nitrogen substitutions, leaving the four carbon atoms underutilized. Using an efficient six-step synthesis, chiral amino acids were transformed into 3-substituted piperazine-2-acetic acid esters as diastereomeric mixtures whose cis and trans products (dr 0.56 a? 2.2:1, respectively) could be chromatographically separated. From five amino acids (both antipodes) was obtained a complete matrix of 20 monoprotected chiral 2,3-disubstituted piperazines, each as a single absolute stereoisomer, all but one in multigram quantities. In keeping with our overall purpose of constructing more Csp3-enriched compound libraries for drug discovery, these diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as scaffolds for parallel library synthesis and as intermediates for the production of novel piperazine compounds.
- Reddy Guduru, Shiva Krishna,Chamakuri, Srinivas,Raji, Idris O.,MacKenzie, Kevin R.,Santini, Conrad,Young, Damian W.
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p. 11777 - 11793
(2018/09/27)
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- Conformational properties of ascydiacyclamide analogues with cyclic α-amino acids instead of oxazoline residues
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Ascidiacyclamide [ASC, cyclo(-Ile-oxazoline-D-Val-thiazole-)2] is a cyclic octapeptide isolated from tunicates. We designed ASC analogues [cyclo(-Ile-Xxx-D-Val-thiazole-)2] in which Pro or a homologue was substituted for oxazoline: [Pro]ASC (Xxx: proline), [Aze]ASC (Xxx: (S)-Azetidine-2-carboxylic acid), [Pip]ASC (Xxx: (S)-Piperidine-2-carboxylic acid) and [ΔPro]ASC (Xxx: (S)-3-pyrroline-2-carboxylic acid) to explore their potential to serve as substitutes for the oxazoline ring. The conformations of these analogues were examined using X-ray diffraction, 1H NMR and CD spectroscopy. In both the crystal and solution states, the conformations of [Pro]ASC, [Aze]ASC and [ΔPro]ASC were novel square structures having two trans imide bonds and stabilized by two intramolecular hydrogen bonds. The crystal structure of [Pip]ASC was a folded conformation with cis and trans imide bonds. Three isomers (cc, ct and tt) were present in a solution of [Pip]ASC. From crystal structures, the degree of puckering in the side chains of Pro and its homologues was estimated to be in the order Pip > Pro > Aze > ΔPro. [Pro]ASC and [Pip]ASC showed strong cytotoxicity, but [Aze]ASC and [ΔPro]ASC showed no cytotoxicity. Among the four analogues, there is consistency between the prolyl ring puckering and cytotoxicity, but not between the peptide backbone structure and cytotoxicity.
- Asano, Akiko,Numata, Shohei,Yamada, Takeshi,Minoura, Katsuhiko,Doi, Mitsunobu
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supporting information
p. 6554 - 6562
(2017/11/09)
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- Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 2: α-Branched quaternary amines
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We report the synthesis and biological evaluation of a series of novel α-branched pyrazinoyl quaternary amines for their ability to block ion transport via the epithelial sodium channel (ENaC) in human bronchial epithelial cells (HBECs). Compound 12g has an IC50 of 30 nM and is highly efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED50 of 1 μg kg-1 at 1 h. In addition the SAR results demonstrate for the first time the chiral nature of the binding site of human ENaC. As such, pyrazinoyl quaternary amines represent a promising new class of ENaC blockers for the treatment of cystic fibrosis that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride.
- Hunt, Thomas,Atherton-Watson, Hazel C.,Collingwood, Stephen P.,Coote, Kevin J.,Czarnecki, Sarah,Danahay, Henry,Howsham, Catherine,Hunt, Peter,Paisley, Derek,Young, Alice
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scheme or table
p. 2877 - 2879
(2012/05/20)
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- Synthesis of imidacloprid derivatives with a chiral alkylated imidazolidine ring and evaluation of their insecticidal activity and affinity to the nicotinic acetylcholine receptor
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A series of imidacloprid (IMI) derivatives with an alkylated imidazolidine ring were asymmetrically synthesized to evaluate their insecticidal activity against adult female housefly, Musca domestica, and affinity to the nicotinic acetylcholine receptor of the flies. The bulkier the alkyl group, the lower was the receptor affinity, but the derivatives methylated and ethylated at the R-5-position of the imidazolidine ring were equipotent to the unsubstituted compound. Quantitative structure-activity relationship (QSAR) analysis of the receptor affinity demonstrated that the introduction of a substituent into the imidazolidine ring was fundamentally disadvantageous, but the introduction of a substituent at the R-5-position was permissible in the case of its small size. The binding model of the synthesized derivatives with the receptor supported the QSAR analysis, indicating the existence of space for a short alkyl group around the R-5-position in the ligand-binding site. In addition, positive correlation was observed between the insecticidal activity and receptor affinity, suggesting that the receptor affinity was the primary factor in influencing the insecticidal activity even if the imidazolidine ring was modified.
- Nishiwaki, Hisashi,Kuriyama, Mituhiro,Nagaoka, Hikaru,Kato, Akira,Yamauchi, Satoshi,Shuto, Yoshihiro,Akamatsu, Miki
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p. 6305 - 6312,8
(2012/12/11)
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- 2,2-difunctionalization of alkenes via Pd(II)-catalyzed aza-Wacker reactions
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N-Ts and N-Boc derivatives of 1,2-diamines and 1,2-amino alcohols are shown to undergo efficient Pd(II)-catalyzed aza-Wacker reactions with a large range of electron-deficient alkenes. The resulting enamine intermediate generally undergoes cyclization with the second heteroatom to form 1,3-heterocycles. The sequence facilitates the rapid synthesis of saturated oxazolidines, imidazolidines, and their derivatives. Use of N-l-valinol derivatives results in highly diastereoselective reactions, where the net stereochemical outcome diverges between N-Ts and N-Boc.
- Elliott, Luke D.,Wrigglesworth, Joe W.,Cox, Brian,Lloyd-Jones, Guy C.,Booker-Milburn, Kevin I.
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supporting information; experimental part
p. 728 - 731
(2011/04/25)
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- Functional analysis of an aspartate-based epoxidation catalyst with amide-to-alkene peptidomimetic catalyst analogues
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Subtle exchange: Replacement of an amide function with alkene or fluoroalkene groups provides a new class of epoxidation catalysts (see scheme). The structure-dependent catalytic behavior of these isosteric peptides provides mechanistic insights in their mode of action. (Chemical Equation Presented).
- Jakobsche, Charles E.,Peris, Gorka,Miller, Scott J.
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supporting information; experimental part
p. 6707 - 6711
(2009/03/12)
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- The proline-catalyzed direct asymmetric three-component Mannich reaction: Scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols
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We have developed proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines. Several of the studied reactions provide β-amino carbonyl compounds (Mannich products) in excellent enantio-, diastereo-, regio-, an
- List, Benjamin,Pojarliev, Peter,Biller, William T.,Martin, Harry J.
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p. 827 - 833
(2007/10/03)
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- Macrocyclic difluorostatone derivatives useful as antiviral agents
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The present invention provides novel macrocyclic difluorostatone derivatives which are useful as antiviral agents. More specifically, these novel compounds are useful as inhibitors of retroviral proteases required for replication, particularly the HIV-1 and HIV-2 viral proteases, in the prevention or treatment of infection by the human immunodeficiency virus (HIV), and in the treatment of consequent pathological conditions such as the acquired immunodeficiency syndrome (AIDS) in mammals capable of being infected with HIV virus.
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- Chiral β-amino sulfoxides. Synthesis, configurational assignment and conformational analysis based on X-ray, CD, 1H NMR and theoretical calculations
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Enantiomerically pure u and l β-amino sulfoxides have been easily obtained from the respective homochiral α-amino alcohols. The absolute configuration at the created stereogenic centre was assigned by CD spectra and by X-ray analysis. Conformational analysis of the title compounds was carried out using quantum chemical energy-geometry optimization. Thus established conformational behavior explained the strongly configuration dependent NMR spectral patterns observed for the u and l diastereomers.
- Lewanowicz,Lipinski,Siedlecka,Skarzewski,Baert
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p. 6571 - 6586
(2007/10/03)
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- Difluoro statone antiviral analogs
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The present invention relates to difluorostatone derivatives useful as antiviral agents.
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- Chiral electrophilic 'glycinal' equivalents. New synthons for optically active α-amino acids and 4-substituted 2-oxazolidinones
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The thermal reaction of 3-[(1S)-2-alkoxy-1-apocamphanecarbonyl]-2-oxazolones (21a-c) with dialkyl azodicarboxylates (9) results in exclusive formation of [4 + 2] type cycloadducts (22 and 23) with moderate levels of diastereofacial selection (up to 72% d.e.). The diastereomers thus obtained were readily purified and subsequent treatment with acidic methanol followed by removal of the auxiliary with LiBH4/MeOH (1:2) gave optically pure 4-methoxy-5-hydrazino-2-oxazolidinones (26 and 27), which serve as α-aminoaldehyde templates useful for the synthesis of a wide variety of optically active α-amino acids as well as 4-alkyl and 4-aryl-2-oxazolidinones.
- Matsunaga, Hirofumi,Ishizuka, Tadao,Kunieda, Takehisa
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p. 1275 - 1294
(2007/10/03)
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- Versatile routes to chiral 4-substituted 2-oxazolindinones and α-amino acids. Use of chiron, [4 + 2] cycloadducts of dialkyl azodi-carboxylates and 2-oxazolones
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The thermal reaction of 3-[(1S)-2-alkoxy-1-apocamphanecarbonyl]-2-oxazolones with dialkyl azodicarboxylates results in exclusive formation of [4 + 2] type cycloadducts with moderate levels of diastereofacial selection, which serve as versatile chiral synthons for a wide variety of 4-alkyl and 4-alkyl-2-oxazolidinones as well as α-amino acids.
- Matsunaga,Ishizuka,Marubayashi,Kunieda
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p. 1077 - 1079
(2007/10/02)
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- Syntheses and Properties of Optically Active 2-Substituted Taurines
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The synthesis of nine 2-substituted taurines (5a-i), including the marine natural product D-cysteinolic acid (5f), are described.These involve the successive conversion of N-t-butoxycarbonyl(Boc)-protected amino acid esters (1) into the N-Boc-2-aminoethanols (2), their O-mesylated derivatives (3), the deprotected 2-aminoethyl methanesulphonates (4), followed by the replacement of the mesyloxy group by a sulpho group to give the optically active taurines (5a-e,g-i).Hydrogenolysis of 2-benzyloxymethyltaurine (5e) gives D-cysteinolic acid (5f).The structure of another of the products, (5b), is also confirmed by an alternative synthesis from N-Boc-valine methyl ester (1b) via twoβ-bromoethylamine derivatives, (6b) and (7b).
- Higashiura, Kunihiko,Morino, Hiroe,Matsuura, Hirohide,Toyomaki, Yoshio,Ienaga, Kazuharu
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p. 1479 - 1481
(2007/10/02)
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- New Methods and Reagents in Organic Synthesis. 67. A General Synthesis of Derivatives of Optically Pure 2-(1-Aminoalkyl)thiazole-4-carboxylic Acids
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Preparations of 2-(1-aminoalkyl)thiazole-4-carboxylic acids (thiazole amino acids), important constituents of a series of cytotoxic cyclic peptides from marine organisms, have been conveniently and efficiently achieved as their N- and C-protected derivatives 6 from N-Boc or N-Z α-amino acids 1 in five steps.Esterification of 1 with methyl iodide followed by reduction with lithium chloride-sodium borohydride afforded N-protected amino alcohols 3.Selective reduction of the α-ester functions of the glutamic acid derivatives (Z-D- and Z-L-Glu(O-t-Bu)-OMe and O-t-Bu) was also achieved under the above reduction conditions.Dimethyl sulfoxide oxidation, followed by condensation with cysteine methyl ester afforded the thiazolidine derivatives 5, which were conveniently dehydrogenated with manganese dioxide, called chemical manganese dioxide (CMD) and produced for batteries, to give the desired thiazole amino acid derivetives 6.The glutamine derivatives (Z-D- and Z-L-(gln)Thz-OMe) were prepared from the corresponding glutamic acid derivatives (Z-D- and Z-L-6f).No appreciable racemization was observed in the above conversion, which was proven by HPLC of the 3,5-dinitrobenzoyl derivatives of thiazole amino acids 6 using a chiral column.
- Hamada, Yasumasa,Shibata, Makoto,Sugiura, Tsuneyuki,Kato, Shinji,Shioiri, Takayuki
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p. 1252 - 1255
(2007/10/02)
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