- Synthesis of Chiral N-Protected α-Amino Aldehydes by Reduction of N-Protected N-Carboxyanhydrides (UNCAs)
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A facile one step synthesis of a wide variety of N-protected (Boc, Z, Fmoc) α-amino aldehydes under mild conditions is described.Pure N-protected (Boc, Z, Fmoc) α-amino aldehydes were obtained in high yields by reduction of N-protected (Z, Boc, Fmoc)-N-ca
- Fehrentz, Jean-Alain,Pothion, Catherine,Califano, Jean-Christophe,Loffet, Albert,Martinez, Jean
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- Discovery of a Potent and Selective ATAD2 Bromodomain Inhibitor with Antiproliferative Activity in Breast Cancer Models
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ATAD2 is an epigenetic bromodomain-containing target which is overexpressed in many cancers and has been suggested as a potential oncology target. While several small molecule inhibitors have been described in the literature, their cellular activity has proved to be underwhelming. In this work, we describe the identification of a novel series of ATAD2 inhibitors by high throughput screening, confirmation of the bromodomain region as the site of action, and the optimization campaign undertaken to improve the potency, selectivity, and permeability of the initial hit. The result is compound 5 (AZ13824374), a highly potent and selective ATAD2 inhibitor which shows cellular target engagement and antiproliferative activity in a range of breast cancer models.
- Winter-Holt, Jon J.,Bardelle, Catherine,Chiarparin, Elisabetta,Dale, Ian L.,Davey, Paul R. J.,Davies, Nichola L.,Denz, Christopher,Fillery, Shaun M.,Guérot, Carine M.,Han, Fujin,Hughes, Samantha J.,Kulkarni, Meghana,Liu, Zhaoqun,Milbradt, Alexander,Moss, Thomas A.,Niu, Huijun,Patel, Joe,Rabow, Alfred A.,Schimpl, Marianne,Shi, Junjie,Sun, Dongqing,Yang, Dejian,Guichard, Sylvie
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p. 3306 - 3331
(2022/02/23)
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- Phosphatase Binding Compounds and Methods of Using Same
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The present invention provides bifunctional compounds that efficiently dephosphorylate certain phospho-activated target proteins. Such target proteins can be any protein involved in the pathway of a disease or disorder, such as but not limited to cancer, neurodegeneration, metabolic disease, diabetes, insulin resistance, and so forth.
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Page/Page column 3; 232
(2020/07/25)
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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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p. 6554 - 6562
(2017/11/09)
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- Binding cooperativity between a ligand carbonyl group and a hydrophobic side chain can be enhanced by additional H-bonds in a distance dependent manner: A case study with thrombin inhibitors
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One of the underappreciated non-covalent binding factors, which can significantly affect ligand-protein binding affinity, is the cooperativity between ligand functional groups. Using four different series of thrombin inhibitors, we reveal a strong positiv
- Said, Ahmed M.,Hangauer, David G.
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supporting information
p. 405 - 424
(2015/05/05)
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- Cu(I)-catalyzed synthesis of dihydropyrimidin-4-ones toward the preparation of β- And β3-amino acid analogues
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A copper(I)-catalyzed synthesis of substituted dihydropyrimidin-4-ones from propargyl amides via the formation of ketenimine intermediate has been successfully developed; the synthesis afforded good isolated yields (80-95%). The mild reaction conditions at room temperature allow the reaction to proceed to completion in a few hours without altering the stereochemistry. Further, by involving a variety of reactive nucleophiles, the obtained substituted dihydropyrimidin-4-ones were elegantly transformed into the corresponding β- and β3-amino acid analogues.
- Rajagopal, Basker,Chen, Ying-Yu,Chen, Chun-Chi,Liu, Xuan-Yu,Wang, Huei-Ren,Lin, Po-Chiao
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supporting information
p. 1254 - 1264
(2014/03/21)
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- Metal-free, mild, nonepimerizing, chemo- and enantio- or diastereoselective N-alkylation of amines by alcohols via oxidation/imine-iminium formation/reductive amination: A pragmatic synthesis of octahydropyrazinopyridoindoles and higher ring analogues
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A mild step and atom-economical nonepimerizing chemo- and enantioselective N-alkylating procedure has been developed via oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Bronsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL-derived phosphoric acid (VAPOL-PA) as the Bronsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues.
- Khan, Imran A.,Saxena, Anil K.
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p. 11656 - 11669
(2014/01/06)
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- Synthesis of α, β-unsaturated γ-amino esters with unprecedented high (E)-stereoselectivity and their conformational analysis in peptides
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Mild, efficient and racemization-free synthesis of N-protected α, β-unsaturated γ-amino esters with unprecedented high E- stereoselectivity is described. This method is found to be compatible with Boc-, Fmoc- and other side chain protecting groups. The crystal conformations of the vinylogous γ-amino esters in monomers and in homo- and mixed dipeptides are studied. Further, the vinylogous homo-dipeptide showed a β-sheet conformation, while mixed α- and α,β-unsaturated γ-hybrid dipeptide adapted an irregular structure in single crystals.
- Mali, Sachitanand M.,Bandyopadhyay, Anupam,Jadhav, Sandip V.,Kumar, Mothukuri Ganesh,Gopi, Hosahudya N.
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supporting information; experimental part
p. 6566 - 6574
(2011/11/05)
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- Preparation of α-hydroxy-β-Fmoc amino acids from N-Boc amino acids
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A general method for the conversion of N-Boc amino acids into their homologated α-hydroxy-β-Fmoc amino acids is described. The protocol involved preparation of the amino aldehyde by reduction of the corresponding Weinreb amides, hydrocyanation, and hydrol
- Johnson, Erik P.,Hubieki, M. Patricia,Combs, Andrew P.,Teleha, Christopher A.
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experimental part
p. 4023 - 4026
(2012/01/12)
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- Catalytic activity dependency on catalyst components in aerobic copper-TEMPO oxidation
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The influence of catalyst components in the copper-TEMPO (2,2,6,6-tetramethylpiperidine N-oxide) catalysed aerobic oxidation of alcohols was investigated. The type and amount of base greatly influences reactivity. The bipyridyl ligand concentration had no major influence on catalysis, but ex-cessive amounts led to a decrease in activity for longer reaction times. The kinetic dependency for TEMPO was found to be 1.15, and for copper 2.25, which is an indication of a binuclear catalytic system. Optimised conditions with various allylic and aliphatic alcohols give good to excellent rapid oxidations.
- Kumpulainen, Esa T. T.,Koskinen, Ari M. P.
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experimental part
p. 10901 - 10911
(2010/04/05)
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- β-isocupreidine-catalyzed Baylis-Hillman reaction of chiral N-Boc-α-amino aldehydes
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β-Isocupreidine (β-ICD)-catalyzed Baylis-Hillman reaction of chiral N-Boc-α-amino aldehydes and 1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA) takes place without racemization and exhibits the match-mismatch relationship between the substrate and the catalyst. In the case of acyclic amino aldehydes, α,-substrates show excellent syn selectivity and high reactivity in contrast to L-substrates. On the other hand, in the case of cyclic amino aldehydes, D-substrates rather than L-substrates show excellent anti selectivity and high reactivity.
- Nakano, Ayako,Takahashi, Keisuke,Ishihara, Jun,Hatakeyama, Susumi
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p. 5357 - 5360
(2007/10/03)
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- Synthesis and dipeptidyl peptidase inhibition of N-(4-substituted-2,4-diaminobutanoyl)piperidines
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In this paper, we report the synthesis of diastereomerically pure N-(4-substituted-2,4-diaminobutanoyl)piperidines. These compounds were prepared to investigate the influence of the 4-substitution on the dipeptidyl peptidase II (DPP II) activity and selectivity of the parent N-(2,4-diaminobutanoyl)piperidine. The (4S)-methyl compound showed subnanomolar inhibition, comparable with the parent compound. The (4R)-methyl group or bigger substituents decreased the activity.
- Soroka, Anna,der Veken, Pieter Van,Meester, Ingrid De,Lambeir, Anne-Marie,Maes, Marie-Berthe,Scharpe, Simon,Haemers, Achiel,Augustyns, Koen
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p. 4777 - 4779
(2007/10/03)
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- A direct and efficient stereoconservative procedure for the selective oxidation of N-protected β-amino alcohols
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An efficient, very simple and eco-friendly procedure has been developed for the synthesis of highly enantioenriched α-amino aldehydes by IBX-mediated oxidation of the corresponding β-amino alcohols. The procedure has been applied to a wide range of substr
- Ocejo, Marta,Vicario, Jose L.,Badía, Dolores,Carrillo, Luisa,Reyes, Efraim
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p. 2110 - 2112
(2007/10/03)
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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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