- Thermal proteome profiling efficiently identifies ribosome destabilizing oxazolidinones
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Identifying the targets of bioactive small molecules is a challenging endeavor for which no general solution currently exists. Classical affinity purification experiments suffer from the need to functionalise a bioactive compound and link it to a solid support, which may interfere with target binding. A modern mass spectrometry-based proteomics technique that has partially circumvented this problem is thermal proteome profiling (TPP), which determines the effect of an unmodified small molecule on the thermal stability of the whole proteome simultaneously. Here, we use TPP to identify the mode-of-action of a newly-discovered autophagy inhibitor based on oxazolidinones often employed as chiral auxiliaries. Surprisingly, a significant portion of all ribosomal proteins were found to be destabilized by the inhibitor, highlighting the utility of this technology for determining a challenging mode-of-action.
- N?cker, Christina,Kaiser, Nadine,Foley, Daniel,Sievers, Sonja,Janning, Petra,Waldmann, Herbert,Laraia, Luca
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supporting information
(2021/04/22)
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- A CONJUGATE OF A TUBULYSIN ANALOG WITH BRANCHED LINKERS
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The present invention relates to the conjugation of a tubulysin analog compound to a cell-binding molecule with branched/side-chain linkers for having better delivery of the conjugate compound and targeted treatment of abnormal cells. It also relates to a branched-linkage method of conjugation of a tubulysin analog molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and autoimmune disease.
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Paragraph 000303; 000304
(2021/03/02)
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- CONJUGATION LINKERS CONTAINING 2,3-DIAMINOSUCCINYL GROUP
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Provided is a conjugate of a cytotoxic drug/molecule to a cell-binding molecule with a bis-linker (adual-linker) containing a 2, 3-diaminosuccinyl group. It also relates to preparation of the conjugate of a cytotoxic drug/molecule to a cell-binding molecule with the bis-linker, particularly when the drug having functional groups of amino, hydroxyl, diamino, amino-hydroxyl, dihydroxyl, carboxyl, hydrazine, aldehyde and thiol for conjugation with the bis-linker in a specific manner, as well as the therapeutic use of the conjugates.
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Page/Page column 250-251
(2020/05/19)
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- A CONJUGATE OF A TUBULYSIN ANALOG WITH BRANCHED LINKERS
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The present invention relates to the conjugation of a tubulysin analog compound to a cell-binding molecule with branched/side-chain linkers for having better delivery of the conjugate compound and targeted treatment of abnormal cells. It also relates to a branched-linkage method of conjugation of a tubulysin analog molecule to a cell-binding ligand, as well as methods of using the conjugate in targeted treatment of cancer, infection and autoimmune disease.
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Page/Page column 10; 169
(2019/07/17)
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- Synthesis of a diastereomer of the marine macrolide lytophilippine A
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The synthesis of a diastereomer of lytophilippine A required 22 longest linear steps using known building blocks. Cross-metathesis/asymmetric aldol addition and regioselective esterification/ring-closing metathesis served as efficient combi tools for scaffold construction. Detailed NMR investigations in different solvent (systems) provide evidence for a deep-seated configurational misassignment of the molecule named lytophilippine A.
- Klüppel, André,Gille, Annika,Karayel, Ceren Ester,Hiersemann, Martin
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supporting information
p. 2421 - 2425
(2019/03/29)
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- General and stereoselective aminoxylation of biradical titanium(iv) enolates with TEMPO: A detailed study on the effect of the chiral auxiliary
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A comprehensive analysis of the influence of the chiral auxiliary on the α-aminoxylation of titanium(iv) enolates with TEMPO indicated that (S) 4-tert-butyl-1-oxazolidine-2-thione is the most appropriate scaffold to provide a single diastereomer in high yields for a variety of substrates, which converts such a radical reaction into a highly chemo- and stereoselective oxidation.
- Kennington, Stuart C. D.,Gómez-Palomino, Alejandro,Salomó, Ernest,Romea, Pedro,Urpí, Fèlix,Font-Bardia, Mercè
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p. 4807 - 4815
(2018/07/13)
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- A method for synthesis of acylated oxazolidone
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The invention discloses a method for synthesis of acylated oxazolidone. Synthesis method of the invention, comprising the following steps: in the non-protic organic solvent, the compound III and under the action of an acid, the compound I with compound II carries out amidation reaction, to obtain compound IV. The method of the invention can be conducted under mild conditions, high yield, high purity, and is suitable for industrial production requirements.
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Paragraph 0031; 0032; 0033
(2019/01/08)
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- Structural Determination of (-)-SCH 64874 and Hirsutellomycin by Semisynthesis
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The structure of a C2-symmetric epidithiodiketopiperazine alkaloid, SCH 64874, was determined by semisynthesis. The relative stereochemistry of the β-hydroxy carboxylic acid chain having three chiral centers was determined by comparison of the NMR data of the four possible diastereomeric β-hydroxy carboxylic acid fragments with those of SCH 64874. Condensation of the (-)-deacetylaranotin core with two enantiomeric β-hydroxy carboxylic acids revealed the relative stereochemistry of SCH 64874. The relative stereochemistry of the β-keto carboxylic acid chain of the analogous alkaloid hirsutellomycin was determined in a stepwise manner. The C4′-C6′ syn relationships were predicted by comparing the NMR data of the corresponding ester fragments with that of hirsutellomycin. The relative stereochemistry of the whole molecule, including the epimerizable C2′ stereocenter, was determined by introduction of four possible side chains into the bisdethiodi(methylthio)deacetylaranotin core. We found that the stereochemistry of C2′ converged with that of the thermodynamically stable form influenced by the core structure.
- Tokuyama, Hidetoshi,Yamada, Kaori,Fujiwara, Hideto,Sakata, Juri,Okano, Kentaro,Sappan, Malipan,Isaka, Masahiko
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p. 353 - 371
(2017/04/26)
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- Stereocontrolled Syntheses of Seven-Membered Carbocycles by Tandem Allene Aziridination/[4+3] Reaction
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A tandem allene aziridination/[4+3]/reduction sequence converts simple homoallenic sulfamates into densely functionalized aminated cycloheptenes, where the relative stereochemistry at five contiguous asymmetric centers can be controlled through the choice
- Gerstner, Nels C.,Adams, Christopher S.,Tretbar, Maik,Schomaker, Jennifer M.
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supporting information
p. 13240 - 13243
(2016/10/30)
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- Absolute configuration of lactams and oxazolidinones using kinetic resolution catalysts
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A simple method for determining the absolute configuration of oxazolidinones, lactams, and their derivatives using kinetic resolution catalysts is described. The optically pure substrates were acylated using the (S)-HBTM and the (R)-HBTM catalyst, and the faster reaction was determined. An empirical mnemonic was developed for the assignment of the absolute configuration based on the fast-reacting catalyst.
- Perry, Matthew A.,Trinidad, Jonathan V.,Rychnovsky, Scott D.
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supporting information
p. 472 - 475
(2013/04/11)
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- Chemoselective N-acylation of indoles and oxazolidinones with carbonylazoles
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Unique reactivity: In the presence of more reactive amine and alcohol functional groups and of carboxylic acids, the chemoselective N-acylation of indoles (see scheme) and oxazolidinones is achieved by taking advantage of the unique reactivity of carbonylazole acylating agents with catalytic amounts of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Copyright
- Heller, Stephen T.,Schultz, Erica E.,Sarpong, Richmond
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supporting information; experimental part
p. 8304 - 8308
(2012/09/08)
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- Deglycobleomycin A6 analogues modified in the methylvalerate moiety
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Previous studies have indicated that the methylvalerate subunit of bleomycin (BLM) plays an important role in facilitating DNA cleavage by BLM and deglycoBLM. Eleven methylvalerate analogues have been synthesized and incorporated into deglycoBLM congeners by the use of solid-phase synthesis. The effect of the valerate moiety in the deglycoBLM analogues has been studied by comparison with the parent deglycoBLM A5 using supercoiled DNA relaxation and sequence-selective DNA cleavage assays. All of the deglycoBLM analogues were found to effect the relaxation of the plasmid DNA. Those analogues having aromatic C4-substituents exhibited cleavage efficiency comparable to that of deglycoBLM A5. Some, but not all, of the deglycoBLM analogues were also capable of mediating sequence-selective DNA cleavage.
- Cai, Xiaoqing,Zaleski, Paul A.,Cagir, Ali,Hecht, Sidney M.
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scheme or table
p. 3831 - 3844
(2011/08/02)
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- (-)-lytophilippine a: Synthesis of a C1-C18 building block
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The convergent enantioselective synthesis of a protected C1-C18 building block for the total synthesis of (-)-lytophilippine A was achieved. A catalytic asymmetric Gosteli-Claisen rearrangement and an Evans aldol reaction served as key C/C-connecting transformations during the assembling of the C1-C7 subunit (10 steps from 4, 29%). The synthesis of the C8-C18 segment was achieved utilizing d-galactose as inexpensive ex-chiral-pool starting material (15 steps, 15%). The merger of the subunits was accomplished by a remarkably efficient sequence consisting of esterification and ring-closing metathesis (five steps, 56%).
- Gille, Annika,Hiersemann, Martin
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supporting information; experimental part
p. 5258 - 5261
(2011/02/24)
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- PROCESS FOR STEREOSELECTIVE PREPARATION OF 4-BMA USING A CHIRAL AUXILIARY
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The present invention relates to a process for preparing (3R,4S)-3-[[[R]-V-t- butyldimethylsilyloxy] ethyl] -4- [(/?)- l"-carboxyethyl]-2-azetidinone [4-BMA: formula (6)], a key intermediate for the synthesis of carbapenem and penem antibiotics. Specifically, the present invention relates to a process comprising first, the preparation of a chiral auxiliary from cheap L-Valinol, and then the preparation of 4-BMA in high yield and high selectivity, under industrially mild conditions.
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Page/Page column 13-14
(2008/12/08)
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- On the influence of chiral auxiliaries in the stereoselective cross-coupling reactions of titanium enolates and acetals
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Titanium enolates from chiral N-propanoyl-1,3-thiazolidine-2-thiones containing bulky substituents at C4 turned out to be excellent platforms to get highly stereocontrolled cross-coupling reactions with acetals. Related oxazolidinethiones also afforded go
- Baiget, Jessica,Cosp, Annabel,Gálvez, Erik,Gómez-Pinal, Loreto,Romea, Pedro,Urpí, Fèlix
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p. 5637 - 5644
(2008/09/21)
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- Titanium mediated asymmetric aldol reaction with α-fluoropropionimide enolates
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Aldol reaction utilising Evans N-(α-fluoropropyl)-2-oxazolidinones with TiCl4 have been explored. Reactions of N-(α-fluoropropyl)-2-oxazolidinones with aliphatic aldehydes generated α-fluoro-β-hydroxy-aldol products with high diastereoselectivi
- Brunet, Vincent A.,O'Hagan, David,Slawin, Alexandra M.Z.
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p. 1271 - 1279
(2008/02/08)
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- Progress towards the total synthesis of callipeltin A. Asymmetric synthesis of (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid
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A silyl derivative of (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid, a moiety present in the cyclic depsipeptide callipeltin A, was successfully synthesized from L-valine in nine steps using the Heathcock variant of the Evans aldol reaction.
- Guerlavais, Vincent,Carroll, Patrick J.,Joullie, Madeleine M.
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p. 675 - 680
(2007/10/03)
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- Syntheses of isotopically labelled L-?±-amino acids with an asymmetric centre at C-3
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Approaches are described to the synthesis of a series of isotopically labelled L-a-amino acids each with an asymmetric centre at C-3, including isoleucine, allo-isoleucine, threonine and allo-threonine. The methods may be simply adapted for the selective incorporation of an isotopic label at each site of L-valine including the selective labelling of either diastereotopic methyl group with carbon-13 and/or deuterium and labelling of the amine with nitrogen-15. ? The Royal Society of Chemistry 2000.
- Harding, John R.,Hughes, Rachael A.,Kelly, Nicholas M.,Sutherland, Andrew,Willis, Christine L.
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p. 3406 - 3416
(2007/10/03)
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- Asymmetric alkylations using SuperQuat auxiliaries - An investigation into the synthesis and stability of enolates derived from 5,5-disubstituted oxazolidin-2-ones
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Studies on the alkylation of enolates derived from a range of N-acyl-5,5-dimethyloxazolidin-2-ones and N-acyl-5,5-diphenyloxazolidin-2-ones reveal that high yields and high diastereoselectivities are best obtained when homochiral 4-isopropyl-5,5-dimethyloxazolidin-2-one is employed as a chiral auxiliary.
- Bull, Steven D.,Davies, Stephen G.,Jones, Simon,Sanganee, Hitesh J.
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p. 387 - 398
(2007/10/03)
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- Total synthesis of oxazole-based virginiamycin antibiotics: 14,15- Anhydropristinamycin II(B)
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A total synthesis of 14,15-anhydropristinamycin II(B) (3), a member of the virginiamycin family of antibiotics (also known as streptogramins, pristinamycins or synergimycins) produced by STreptomyces is described. The synthesis is achieved from chiral, non-racemic starting materials and uses a convergent route involving synthesis of the substituted proline 7 and the 4- oxazole carboxylic acid 8, their coupling to the vinylstannane substituted vinyl bromide 6, and finally an intramolecular sp2-sp2 Stille coupling reaction, i.e. 6 → 22, to elaborate the macrocyclic core of the natural product.
- Entwistle, David A.,Jordan, Stuart I.,Montgomery, John,Pattenden, Gerald
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p. 603 - 612
(2007/10/03)
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- Interaction Modes of Titanium Tetrachloride with the Carbonyl Functionality
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Mesityl aldehyde binds TiCl4 leading to the first structurally characterized TiCl4-aldehyde adduct, cis- (Mes = 2,4,6-Me3C6H2) (1), which contains a pseudooctahedral titanium and two aldehyde carbonyl groups in a cis arrangement.However, in the case of a 1:1 TiCl4-acetone adduct 2(μ-Cl)2> (3) the solid-state structure of this acid-base complex is that of a chloro-bridged dimer.Both kinds of structures were suggested for the products 2(μ-Cl)2> (4) and (5) formed by the reaction of TiCl4 with acetophenone in 1:1 and 1:2 molar ratio.Thioesters behave like acetone in that they give adducts 8 and 9 with TiCl4, where 9, 2(μ-Cl)2>, exhibits a solid-state dimeric structure like 3.The bidentate bonding mode of the chiral propionyloxazolidone 12 with TiCl4 was revealed by an X-ray analysis of 13. - Keywords: Lewis acid-carbonyl complexes; Chiral oxazolidinone-TiCl4 adduct
- Cozzi, Pier Giorgio,Solari, Euro,Floriani, Carlo,Chiesi-Villa, Angiola,Rizzoli, Corrado
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p. 1361 - 1368
(2007/10/03)
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- Methods for the synthesis of L-leucine selectively labelled with carbon-13 or deuterium in either diastereotopic methyl group
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A versatile approach is described for the enantioselective synthesis of isotopically labelled L-leucine involving the preparation of 4-methylpentanoic acid labelled selectively with carbon-13 or deuterium in either the pro-R or pro-S methyl group followed by a reductive amination of the ketone catalysed by leucine dehydrogenase. This strategy is applied to the total synthesis of (2S,4R)-[5,5,5-D3]-leucine using CD3I as the source of deuterium.
- Kelly,Kelly, Nicholas M.,Reid,Gordon Reid,Willis,Willis, Christine L.,Winton,Winton, Peter L.
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p. 8315 - 8318
(2007/10/02)
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- One Pot Synthesis of N-Derivatized 2-Oxazolidinones from Amino Alcohol Carbamates
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A one pot protocol for the synthesis of N-derivatized 2-oxazolidinones from amino alcohol carbamates is described.The method is exceptionally useful if the parent amino acids are prepared in their enantiopure forms via enzymatic resolution of the racemic carbamate esters.
- Huwe, Christoph M.,Blechert, Siegfried
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p. 9533 - 9536
(2007/10/02)
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- Asymmetric Aldol Reactions. Use of the Titanium Enolate of a Chiral N-Acyloxazolidinone To Reverse Diastereofacial Selectivities
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Aldol reactions of the titanium enolate of (S)-N-propionyl-4-isopropyl-2-oxazolidinone (readily derived from L-valine) with representative aldehydes give high diastereofacial selectivities for the syn aldol adducts expected from chelation control.This represents a remarkable reversal in selectivity compared with the corresponding boron enolate, thus permitting either enantiomeric form of β-hydroxy-α-methyl carboxylic acids to be made from a single, readily available oxazolidinone simply by changing the metal.A lithium interference effect is shown to be easily prevented by use of excess titanium.Use of diethyl ether as solvent rather than THF significantly enhances the stereoselectivity.Mechanistically, the observed stereochemical reversal constitutes very strong evidence that chelation is operative with titanium, presumably through a chelated chairlike transition structure.In this transition structure, the conformation would be rigidly locked by chelation and the titanium would be at least hexacoordinate, resulting in a "superaxial" ligand, thus nicely explaining the high stereocontrol.
- Nerz-Stormes, Maryellen,Thornton, Edward R.
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p. 2489 - 2498
(2007/10/02)
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- Enantioselective process for producing 1-betamethylcarbapenem antibiotic intermediates
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A process is described for the stereochemically controlled synthesis of intermediates useful in producing 1-betamethylcarbapenem antibiotics.
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