- Structural and Activity Relationships of 6-Sulfonyl-8-Nitrobenzothiazinones as Antitubercular Agents
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The benzothiazinone (BTZ) scaffold compound PBTZ169 kills Mycobacterium tuberculosis by inhibiting the essential flavoenzyme DprE1, consequently blocking the synthesis of the cell wall component arabinans. While extraordinarily potent against M. tuberculosis with a minimum inhibitory concentration (MIC) less than 0.2 ng/mL, its low aqueous solubility and bioavailability issues need to be addressed. Here, we designed and synthesized a series of 6-methanesulfonyl substituted BTZ analogues; further exploration introduced five-member aromatic heterocycles as linkers to attach an aryl group as the side chain. Our work led to the discovery of a number of BTZ derived compounds with potent antitubercular activity. The optimized compounds 6 and 38 exhibited MIC 47 and 30 nM, respectively. Compared to PBTZ169, both compounds displayed increased aqueous solubility and higher stability in human liver microsomes. This study suggested that an alternative side-chain modification strategy could be implemented to improve the druglike properties of the BTZ-based compounds.
- Chiarelli, Laurent R.,Fan, Dongguang,Han, Quanquan,Lu, Yu,Qiao, Chunhua,Shi, Rui,Stelitano, Giovanni,Wang, Bin,Huszár, Stanislav,Miku?ová, Katarína,Savková, Karin
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supporting information
p. 14526 - 14539
(2021/10/26)
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- Synthesis and Structure-Activity Relationship of Xenocoumacin 1 and Analogues as Inhibitors of Ribosomal Protein Synthesis
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Ribosomal protein synthesis is an important target in antibacterial drug discovery. Numerous natural products have served as starting points for the development of antibiotics. We report here the total synthesis of xenocoumacin 1, a natural product that binds to 16S ribosomal RNA at a highly conserved region, as well as analogues thereof. Preliminary structure–activity relationship studies were aimed at understanding and modulating the selectivity between eukaryotic and prokaryotic ribosomes. Modifications were mainly tolerated in the aromatic region. Whole-cell activity against Gram-negative bacteria is limited by efflux and penetration, as demonstrated in genetically modified strains of E. coli. Analogues with high selectivity for eukaryotic ribosomes were identified, but it was not possible to obtain inhibitors selective for bacterial protein synthesis. Achieving high selectivity (albeit not the desired one) was thus possible despite the high homology between eukaryotic and prokaryotic ribosomes in the binding region.
- Zumbrunn, Cornelia,Krüsi, Daniela,Stamm, Christina,Caspers, Patrick,Ritz, Daniel,Rueedi, Georg
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supporting information
p. 891 - 897
(2020/12/15)
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- Synthesis of chiral branched allylamines through dual photoredox/nickel catalysis
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Allylamines are versatile building blocks in the synthesis of various naturally occurring products and pharmaceuticals. In contrast to terminal allylamines, the methods of synthesis of their branched congeners with internal, stereodefined double bonds are less explored. This work describes a new approach for the preparation of allylaminesviacross-coupling of alkyl bromides with simple 3-bromoallylamines by merging the photoredox approach and Ni catalysis. The reaction proceeds under mild conditions, under blue light irradiation, and in the presence of an organic dye, 4CzIPN, as a photocatalyst. The scope of suitable reaction partners is broad, including alkyl bromides bearing reactive functionalities (e.g., esters, nitriles, aldehydes, ketones, epoxides) andN-protected allylamines, as well asN-allylated secondary and tertiary amines and heterocycles. The employment of non-racemic starting materials allows for rapid and easy construction of complex multifunctional allylamine derivatives without the loss of enantiomeric purity.
- Garbacz, Mateusz,Stecko, Sebastian
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supporting information
p. 8578 - 8585
(2021/10/20)
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- Triazolo-peptidomimetics: novel radiolabeled minigastrin analogs for improved tumor targeting
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MG11 is a truncated analog of minigastrin, a peptide with high affinity and specificity toward the cholecystokinin-2 receptor (CCK2R), which is overexpressed by different tumors. Thus, radiolabeled MG11 derivatives have great potential for use in cancer d
- Grob, Nathalie M.,H?ussinger, Daniel,Deupi, Xavier,Schibli, Roger,Behe, Martin,Mindt, Thomas L.
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supporting information
p. 4484 - 4495
(2020/06/08)
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- Chiral 1,5-disubstituted 1,2,3-triazoles-versatile tools for foldamers and peptidomimetic applications
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1,4- A nd 1,5-Disubstituted triazole amino acid monomers have gained increasing interest among peptidic foldamers, as they are easily prepared via Cu- A nd Ru-catalyzed click reactions, with the potential for side chain variation. While the latter is key to their applicability, the synthesis and structural properties of the chiral mono-or disubstituted triazole amino acids have only been partially addressed. We here present the synthesis of all eight possible chiral derivatives of a triazole monomer prepared via a ruthenium-catalyzed azide alkyne cycloaddition (RuAAC). To evaluate the conformational properties of the individual building units, a systematic quantum chemical study was performed on all monomers, indicating their capacity to form several low energy conformers. This feature may be used to effect structural diversity when the monomers are inserted into various peptide sequences. We envisage that these results will facilitate new applications for these artificial oligomeric compounds in diverse areas, ranging from pharmaceutics to biotechnology.
- Beke-Somfai, Tamás,Johansson, Johan R.,Kann, Nina,Paterson, Andrew J.,Said St?lsmeden, Anna,Szigyártó, Imola Cs.,Thunberg, Linda
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p. 1957 - 1967
(2020/03/23)
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- Functionalized Helical β-Peptoids
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Peptidomimetic foldamers adopting well-defined three-dimensional structures while being stable toward proteolysis are of interest in biomedical research, chemical biology, and biomimetic materials science. Despite their backbone flexibility, β-peptoids containing N-(S)-1-(1-naphthyl)ethyl (Ns1npe) side chains can fold into unique triangular prism-shaped helices. We report herein the successful introduction of amino groups onto robustly folded β-peptoid helices by construction and incorporation of novel chiral building blocks. This is the first example of an X-ray crystal structure of a linear β-peptoid containing more than one type of side chain. We thus present a unique foldamer design comprising a robustly folded core with functionalized side chains protruding perpendicular to the helical axis to provide a highly predictable display of functional groups. This work paves the way for development of β-peptoid foldamers with a desired function, such as catalytic properties or as scaffolds enabling polyvalent display.
- Wellh?fer, Isabelle,Frydenvang, Karla,Kotesova, Simona,Christiansen, Andreas M.,Laursen, Jonas S.,Olsen, Christian A.
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p. 3762 - 3779
(2019/05/01)
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- 1,5-Disubstituted 1,2,3-Triazole-Containing Peptidotriazolamers: Design Principles for a Class of Versatile Peptidomimetics
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Peptidotriazolamers are hybrid foldamers combining features of peptides and triazolamers—repetitive peptidomimetic structures with triazoles replacing peptide bonds. We report on the synthesis of a new class of peptidomimetics, containing 1,5-disubstituted 1,2,3-triazoles in an alternating fashion with amide bonds and the analysis of their conformation in solid state and solution. Homo- or heterochiral peptidotriazolamers were obtained from enantiomerically pure propargylamines with stereogenic centers in the propargylic position and α-azido esters by ruthenium-catalyzed azide–alkyne cycloaddition (RuAAC) under microwave conditions in high yields. With such building blocks the peptidotriazolamers are readily available by solution phase synthesis. While the conformation of the homochiral peptidotriazolamer Boc-Ala[5Tz]Phe-Val[5Tz]Ala-Leu[5Tz]Val-OBzl resembles that of a β VIa1 turn, the heterochiral peptidotriazolamer Boc-d-Ala[5Tz]Phe-d-Val[5Tz]Ala-d-Leu[5Tz]Val-OBzl adopts a polyproline-like repetitive structure.
- Kracker, Oliver,Góra, Jerzy,Krzciuk-Gula, Joanna,Marion, Antoine,Neumann, Beate,Stammler, Hans-Georg,Nie?, Anke,Antes, Iris,Latajka, Rafa?,Sewald, Norbert
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supporting information
p. 953 - 961
(2017/12/26)
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- Structure–Activity Relationships of Antiplasmodial Pantothenamide Analogues Reveal a New Way by Which Triazoles Mimic Amide Bonds
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Pantothenamides are potent growth inhibitors of the malaria parasite Plasmodium falciparum. Their clinical use is, however, hindered due to the ubiquitous presence of pantetheinases in human serum, which rapidly degrade pantothenamides into pantothenate and the corresponding amine. We previously reported that replacement of the labile amide bond with a triazole ring not only imparts stability toward pantetheinases, but also improves activity against P. falciparum. A small library of new triazole derivatives was synthesized, and their use in establishing structure–activity relationships relevant to antiplasmodial activity of this family of compounds is discussed herein. Overall it was observed that 1,4-substitution on the triazole ring and use of an unbranched, one-carbon linker between the pantoyl group and the triazole are optimal for inhibition of intraerythrocytic P. falciparum growth. Our results imply that the triazole ring may mimic the amide bond with an orientation different from what was previously suggested for this amide bioisostere.
- Guan, Jinming,Tjhin, Erick T.,Howieson, Vanessa M.,Kittikool, Tanakorn,Spry, Christina,Saliba, Kevin J.,Auclair, Karine
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supporting information
p. 2677 - 2683
(2018/12/11)
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- Synthesis of Acylborons by Ozonolysis of Alkenylboronates: Preparation of an Enantioenriched Amino Acid Acylboronate
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A concise synthesis of acylborons was achieved by ozonolysis of alkenyl MIDA (N-methyliminodiacetic acid) boronates. This reaction exhibits excellent functional-group tolerance and is applicable to various acyl MIDA boronates and potassium acyltriflurobor
- Taguchi, Jumpei,Ikeda, Toshiki,Takahashi, Rina,Sasaki, Ikuo,Ogasawara, Yasushi,Dairi, Tohru,Kato, Naoya,Yamamoto, Yasunori,Bode, Jeffrey W.,Ito, Hajime
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supporting information
p. 13847 - 13851
(2017/10/12)
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- Enzymatic Macrocyclization of 1,2,3-Triazole Peptide Mimetics
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The macrocyclization of linear peptides is very often accompanied by significant improvements in their stability and biological activity. Many strategies are available for their chemical macrocyclization, however, enzyme-mediated methods remain of great interest in terms of synthetic utility. To date, known macrocyclization enzymes have been shown to be active on both peptide and protein substrates. Here we show that the macrocyclization enzyme of the cyanobactin family, PatGmac, is capable of macrocyclizing substrates with one, two, or three 1,4-substituted 1,2,3-triazole moieties. The introduction of non-peptidic scaffolds into macrocycles is highly desirable in tuning the activity and physical properties of peptidic macrocycles. We have isolated and fully characterized nine non-natural triazole-containing cyclic peptides, a further ten molecules are also synthesized. PatGmac has now been shown to be an effective and versatile tool for the ring closure by peptide bond formation.
- Oueis, Emilia,Jaspars, Marcel,Westwood, Nicholas J.,Naismith, James H.
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supporting information
p. 5842 - 5845
(2016/05/09)
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- Design and synthesis of triazole-based peptidomimetics of a PSD-95 PDZ domain inhibitor
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PSD-95 PDZ domains are biologically important and promising drug targets. Here, we discover a triazole-based peptidomimetic, 10, by 'click chemistry'. Compound 10 inhibits the PDZ2/GluN2B interaction with affinity similar to tripeptide SAV and better than current small-molecules. Thus, 10 represents a new class of PSD-95 PDZ inhibitors.
- Bach, Anders,Pedersen, Thomas B.,Str?mgaard, Kristian
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supporting information
p. 531 - 536
(2016/04/01)
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- Methodology for Synthesis of Enantiopure 3,5-Disubstituted Pyrrol-2-ones
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A new synthetic route towards chiral 3,5-disubstituted pyrrol-2-ones by starting from amino acids has been developed. The sequence features the conversion of amino acids into their corresponding alkynoic acid derivative followed by a Pd-catalyzed hydrosta
- Krenk, Ondej,Kratochvl, Ji,pulk, Marcel,Buchta, Vladimr,Kune, Ji,Novkov, Lucie,Ghavre, Mukund,Pour, Milan
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p. 5414 - 5423
(2015/08/24)
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- Radiolabeled antagonistic bombesin peptidomimetics for tumor targeting
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The replacement of amide bonds in the backbone of peptides by proteolytically stable 1,2,3-triazole isosteres can provide novel peptidomimetics with promising properties for the development of tumor-targeting radiopeptides. On the basis of our previous work with radiolabeled agonistic bombesin (BBN) derivatives of the sequence [Nle14]BBN(7-14), we substituted selected amide bonds of the structurally closely related antagonistic peptide analog JMV594. With the exception of the C-terminal modification, amide-to-triazole substitutions tolerated by [Nle 14]BBN(7-14) without loss of biological function led to abolished receptor affinity in the case of JMV594. These findings provide an additional piece of evidence for the currently disputed differences in the modes of action of agonistic and antagonistic gastrin-releasing peptide receptor (GRPR)-targeting radiopeptides.
- Valverde, Ibai E.,Huxol, Elena,Mindt, Thomas L.
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p. 275 - 278
(2014/05/06)
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- 3-PYRIMIDIN-4-YL-OXAZOLIDIN-2-ONES AS INHIBITORS OF MUTANT IDH
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The invention is directed to a formula (I): or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b and R3-R7 are described herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant I DH proteins including, but not limited to, cell-proliferation disorders, such as cancer.
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Page/Page column 44
(2014/09/29)
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- 3-PYRIMIDIN-4-YL-OXAZOLIDIN-2-ONES AS INHIBITORS OF MUTANT IDH
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The invention is directed to a formula (I), or a pharmamceutically acceptable salt thereof, wherein R1, R2a, R2b and R3-R7 are herein. The invention is also directed to compositions containing a compound of formula (I) and to the use of such compounds in the inhibition of mutant IDH proteins having a neomorphic activity. The invention is further directed to the use of a compound of formula (I) in the treatment of diseases or disorders associated with such mutant IDH proteins including, but not limited to, cell-proliferation disorders, such as cancer.
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Page/Page column 109
(2014/09/29)
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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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- 1,2,3-Triazoles as amide bond mimics: Triazole scan yields protease-resistant peptidomimetics for tumor targeting
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The triazole makes the difference: Replacement of amide bonds in the backbone of peptides by 1,4-disubstituted 1,2,3-triazole isosteres affords peptidomimetics with retained receptor affinity and cell-internalization properties, enhanced proteolytic stability, and improved tumor-targeting capabilities. Copyright
- Valverde, Ibai E.,Bauman, Andreas,Kluba, Christiane A.,Vomstein, Sandra,Walter, Martin A.,Mindt, Thomas L.
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supporting information
p. 8957 - 8960
(2013/09/02)
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- Heterocyclic Compounds Useful as RAF Kinase Inhibitors
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The present invention provides compounds useful as inhibitors of Raf protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.
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Page/Page column 42
(2009/01/24)
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- COMPOUNDS USEFUL AS RAF KINASE INHIBITORS
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The present invention provides compounds useful as inhibitors of Raf protein kinase. The present invention also provides compositions thereof, and methods of treating Raf-mediated diseases.
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Page/Page column 87
(2009/03/07)
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- MACROCYCLIC GHRELIN RECEPTOR MODULATORS AND METHODS OF USING THE SAME
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The present invention provides novel conformationally-defined macrocyclic compounds that can function as selective modulators of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, isoforms and variants thereof). Methods of synthesizing the novel compounds are also described herein. These compounds are useful as agonists of the ghrelin receptor and as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, obesity and obesity-associated disorders, central nervous system disorders, bone disorders, genetic disorders, hyperproliferative disorders and inflammatory disorders.
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Page/Page column 40-41
(2008/12/07)
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- Protein prosthesis: 1,5-Disubstituted[1,2,3]triazoles as cis-peptide bond surrogates
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Proline is unique among the natural amino acids in the similar propensity of its peptide bond to be in the cis or trans conformation. This attribute affects many processes, including the rate at which proteins fold, their structures, and their activities. Other aliphatic amino acids can serve as mimics for proline residues with trans-peptide bonds. In contrast, chemical synthesis is needed to create surrogates for cis-prolyl peptide bonds. Here, 1,5-disubstituted[1,2,3]triazoles were assessed as cis-peptide bond surrogates. Huisgen's 1,3-dipolar cycloaddition reaction of amino alkynes and azido acids and a Ru(II) catalyst was used to synthesize a variety of Xaa-1,5-triazole-Ala modules in moderate-to-high yields. Two of these modules, along with their 1,4-triazole regioisomers, were installed in a turn region of bovine pancreatic ribonuclease by using expressed protein ligation. The resulting semisynthetic enzymes displayed full enzymatic activity, indicating the maintenance of native structure. The 1,5-triazole surrogates instilled conformational stability that was comparable to that of Xaa-cis-Pro segments, whereas the 1,4-triazoles conferred markedly less stability. The stability conferred by both surrogates was independent of the Xaa residue, eliminating an uncertainty in protein design. We conclude that Xaa-1,5-triazole-Ala modules can serve as viable mimics of Xaa-cis-Pro segments. The possibility of synthesizing this surrogate by the ligation of fragments in situ and the emergence of biocompatible catalysts for that process portends its widespread use. Copyright
- Tam, Annie,Arnold, Ulrich,Soellner, Matthew B.,Raines, Ronald T.
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p. 12670 - 12671
(2008/03/14)
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- FACTOR XA INHIBITORS
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The present invention is directed to compounds represented by Formula I and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof which are inhibitors of Factor Xa. The present invention is also directed to and intermediates used in making such compounds, pharmaceutical compositions containing such compounds, methods to prevent or treat a number of conditions characterized by undesired thrombosis and methods of inhibiting the coagulation of a blood sample.
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Page/Page column 95
(2008/06/13)
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- PYRIDO PYRIMIDINONES, DIHYDRO PYRIMIDO PYRIMIDINONES AND PTERIDINONES USEFUL AS RAF KINASE INHIBITORS
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The present invention provides compounds having the formula: (I) wherein A-B together represents one of the following structures; (II), (III), (IV) and n, R1, R2, R3, R4, L1, L2, Y and Z are as defined in classes and subclasses herein, and pharmaceutical compositions thereof, as described generally and in subclasses herein, which compounds are useful as inhibitors of protein kinase (e.g., RAF), and thus are useful, for example, for the treatment of RAF mediated diseases.
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Page/Page column 97
(2010/11/08)
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- A convenient scalable one-pot conversion of esters and Weinreb amides to terminal alkynes
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Esters and amides undergo reduction to the corresponding aldehydes using DIBAL-H followed by same pot conversion to terminal alkynes utilizing the Bestmann-Ohira reagent in good to excellent yields. Additionally chiral nonracemic substrates undergo this transformation with complete preservation of stereochemical integrity.
- Dickson, Hamilton D.,Smith, Stephon C.,Hinkle, Kevin W.
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p. 5597 - 5599
(2007/10/03)
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- A new stereoselective synthesis of chiral γ-functionalized (E)-allylic amines
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Chiral t-Boc protected propargylic amines have been obtained starting from aminoaldehydes derived from natural aminoacids. Stannylcupration of these substrates affords an easy regio- and stereocontrolled route to the corresponding γ-stannylated (E)-allylamines which are useful intermediates for the synthesis of the corresponding γ-functionalized allylic systems.
- Reginato, Gianna,Mordini, Alessandro,Messina, Flavia,Degl'Innocenti, Alessandro,Poli, Giovanni
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p. 10985 - 10996
(2007/10/03)
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- Preparation and Reactions of Chiral Propargylic Amines
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Exposure of chiral amino aldehydes (1) to dimethyl diazophosphonate (4) affords propargylic amines (2) of high optical purity.Chain extension of these intermediates is readily accomplished via hydrozirconation of the acetylene moiety and subsequent Ni(II) catalyzed Michael addition to a variety of Michael acceptors.
- Hauske, James R.,Dorff, Peter,Julin, Susan,Martinelli, Gary,Bussolari, Jacqueline
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p. 3715 - 3716
(2007/10/02)
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