- Benchtop-Stabssle Hypervalent Bromine(III) Compounds: Versatile Strategy and Platform for Air- And Moisture-Stable λ3-Bromanes
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We present the first synthesis of air/moisture-stable λ3-bromanes (9and10) by using a cyclic 1,2-benzbromoxol-3-one (BBX) strategy. X-ray crystallography and NMR and IR spectroscopy ofN-triflylimino-λ3-bromane (12) revealed that the bromine(III) center is effectively stabilized by intramolecular R-Br-O hypervalent bonding. This strategy enables the synthesis of a variety of air-, moisture-, and benchtop-stable Br-hydroxy, -acetoxy, -alkynyl, -aryl, and bis[(trifluoromethyl)sulfonyl]methylide λ3-bromane derivatives.
- Miyamoto, Kazunori,Saito, Motomichi,Tsuji, Shunsuke,Takagi, Taisei,Shiro, Motoo,Uchiyama, Masanobu,Ochiai, Masahito
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supporting information
p. 9327 - 9331
(2021/07/01)
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- 2,3-EPOXY SUCCINYL DERIVATIVE, PREPARATION METHOD THEREFOR, AND USES THEREOF
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The present invention relates to a 2,3-epoxy succinyl derivative, a preparation method and a use thereof, in particular, the present invention relates to a compound represented by Formula (1), a racemate or an optical isomer thereof, a solvate thereof, or
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-
Paragraph 0220; 0221; 0222
(2019/01/17)
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- Approaching an experimental electron density model of the biologically active trans-epoxysuccinyl amide group—Substituent effects vs. crystal packing
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The trans-epoxysuccinyl amide group as a biologically active moiety in cysteine protease inhibitors such as loxistatin acid E64c has been used as a benchmark system for theoretical studies of environmental effects on the electron density of small active i
- Shi, Ming W.,Stewart, Scott G.,Sobolev, Alexandre N.,Dittrich, Birger,Schirmeister, Tanja,Luger, Peter,Hesse, Malte,Chen, Yu-Sheng,Spackman, Peter R.,Spackman, Mark A.,Grabowsky, Simon
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supporting information
(2017/10/17)
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- Design, synthesis, and structure–activity relationship study of epoxysuccinyl–peptide derivatives as cathepsin B inhibitors
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Cathepsin B is a lysosomal cysteine protease involved in many diseases. The present research demonstrates that derivatives of epoxysuccinyl–peptide are effective and selective cathepsin B inhibitors. We synthesized a series of epoxysuccinyl–peptide deriva
- Zhang, Xiaoye,Yang, Xiaohong,Wang, Hongqiang,Li, Song,Guo, Kun,Jiang, Dan,Xiao, Junhai,Liang, Di
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p. 1240 - 1246
(2017/08/09)
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- Cysteine protease inhibitors and uses thereof
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The invention provides for novel cysteine protease inhibitors and compositions comprising novel cysteine protease derivatives. The invention further provides for methods for treatment of neurodegenerative diseases comprising administration novel cysteine
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Page/Page column 39
(2016/08/29)
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- 2, 3-Butanediamide Epoxide Compound and Preparation Method and Use Thereof
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Provided are a compound of formula I which can be used as a drug against small RNA virus infections, and optical isomers, pharmaceutically acceptable salts, solvates or hydrates thereof. Also provided are the preparation method of the compound, the method for using the compound for treating bacterial infections and the use of the compound in the preparation of a drug for preventing and/or treating viral diseases caused by small RNA viruses.
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Paragraph 0161
(2016/05/19)
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- Design, synthesis, and optimization of novel epoxide incorporating peptidomimetics as selective calpain inhibitors
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Hyperactivation of the calcium-dependent cysteine protease calpain 1 (Cal1) is implicated as a primary or secondary pathological event in a wide range of illnesses and in neurodegenerative states, including Alzheimer's disease (AD). E-64 is an epoxide-containing natural product identified as a potent nonselective, calpain inhibitor, with demonstrated efficacy in animal models of AD. By use of E-64 as a lead, three successive generations of calpain inhibitors were developed using computationally assisted design to increase selectivity for Cal1. First generation analogues were potent inhibitors, effecting covalent modification of recombinant Cal1 catalytic domain (Cal1cat), demonstrated using LC-MS/MS. Refinement yielded second generation inhibitors with improved selectivity. Further library expansion and ligand refinement gave three Cal1 inhibitors, one of which was designed as an activity-based protein profiling probe. These were determined to be irreversible and selective inhibitors by kinetics studies comparing full length Cal1 with the general cysteine protease papain.
- Schiefer, Isaac T.,Tapadar, Subhasish,Litosh, Vladislav,Siklos, Marton,Scism, Rob,Wijewickrama, Gihani T.,Chandrasena, Esala P.,Sinha, Vaishali,Tavassoli, Ehsan,Brunsteiner, Michael,Fa', Mauro,Arancio, Ottavio,Petukhov, Pavel,Thatcher, Gregory R. J.
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supporting information
p. 6054 - 6068
(2013/09/02)
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- Design, synthesis, and screen of cathepsin K inhibitors
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We synthesized a series of epoxysuccinic acid derivatives and evaluated their in vitro cathepsin K inhibitory activity The screening results show that the potency of compounds 9e, 9d, 9p, 9j and 9k (IC50 ≤ 0.005 μmol/L) were equal to or greater than that of the lead compound 9a. Less hydrophobic compounds showed weaker potency, which can be explained by the hydrophobic nature of the cathepsin K binding pockets.
- Yu, Ying-Ying,Sun, Wei,Dong, Lei,Liu, Hai-Dong,Jiang, Dan,Xiao, Jun-Hai,Yang, Xiao-Hong,Li, Song
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p. 715 - 718
(2013/07/26)
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- 3-Fluoroaspartate and pyruvoyl-dependant aspartate decarboxylase: Exploiting the unique characteristics of fluorine to probe reactivity and binding
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Fluorine-containing amino acids have been used with great success as mechanism-based inhibitors of pyridoxal phosphate (PLP)-dependent enzymes, and the influence of fluorine on the conformation of molecules has also been extensively studied and practically exploited. In this study, we sought to use these unique characteristics to probe the reactivity and binding of aspartate decarboxylase (ADC) enzymes, which are members of the small class of pyruvoyl-dependant decarboxylases. Since ADC activity has been shown to be essential to the virulence of Mycobacterium tuberculosis, information gained in this manner could be used for the development of inhibitors that selectively target pyruvoyl-dependent enzymes such as ADC, without affecting PLP-dependent enzymes in the host. For this purpose, we synthesized the L-erythro and L-threo isomers of 3-fluoroaspartate and tested their ability to act as substrates and/or inhibitors of the M. tuberculosis and Escherichia coli ADC enzymes. Trapping and MS-based binding analysis was additionally used to confirm that both isomers enter the enzymes' active sites. Our studies show that both isomers undergo single turnover decarboxylation and fluorine elimination reactions to give enamine products that can be trapped within the active site. Interestingly, the enamine/ADC complex that forms from the lerythro (but not the L-threo) isomer is sufficiently stable that it can be observed even without any trapping. This finding suggests that the two 3-fluoroaspartates maintain different conformations within the ADC active site, which leads to the enamine products with configurations of different stabilities. Taken together, our results provide new insights for the development of cofactor-specific inhibitors, and confirm the utility of fluorine as a unique tool for probing reactivity and binding profiles within enzymes.
- De Villiers, Jandre,Koekemoer, Lizbe,Strauss, Erick
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experimental part
p. 10030 - 10041
(2011/01/13)
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- Two-step labeling of endogenous enzymatic activities by Diels-Alder ligation
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A ligation strategy based on the Diels-Alder [4+2] cycloaddition for the two-step activity-based labeling of endogenously expressed enzymes in complex biological samples has been developed. A panel of four diene-derivatized proteasome probes was synthesized, along with a dienophile-functionalized BODIPY(TMR) tag. These probes were applied in a Diels-Alder labeling procedure that enabled us to label active proteasome β-subunits selectively in cellular extracts and in living cells. We were also able to label the activity of cysteine proteases in cell extracts by utilizing a diene-derivatized cathepsin probe. Importantly, the Diels-Alder strategy described here is fully orthogonal with respect to the Staudinger-Bertozzi ligation, as demonstrated by the independent labeling of different proteolytic activities by the two methods in a single experiment.
- Willems, Lianne I.,Verdoes, Martijn,Florea, Bogdan I.,Van Der Marel, Gijsbert A.,Overkleeft, Herman S.
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experimental part
p. 1769 - 1781
(2011/04/18)
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- NOVEL DRUGS FOR DEMENTIA
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The invention is directed to compounds that are prodrugs containing a chemical delivery system (CDS) moiety and a cysteine protease inhibitor moiety. The CDS moiety targets the prodrug to the brain or central nervous system. The cysteine protease inhibitor inhibits cysteine proteases upon release from the prodrug. Cysteine protease inhibitors are effective for treating dementia, Alzheimer's disease and vascular dementia. Targeting the brain or central nervous system offers significant advantages in treating these conditions and diseases. A preferred CDS prodrug is a dihydrotrigoneline CDS moiety coupled to an epoxysuccinyl peptide cysteine protease inhibitor moiety.
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- First asymmetric total synthesis of synerazol, an antifungal antibiotic, and determination of its absolute stereochemistry
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By synthesizing two possible diastereomers, the first asymmetric total synthesis of synerazol, an antifungal antibiotic, has been accomplished, allowing determination of its absolute stereochemistry. A more practical second generation route was also estab
- Hayashi, Yujiro,Shoji, Mitsuru,Mukaiyama, Takasuke,Gotoh, Hiroaki,Yamaguchi, Shinpei,Nakata, Munetaka,Kakeya, Hideaki,Osada, Hiroyuki
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p. 5643 - 5654
(2007/10/03)
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- An improved preparation of the activity-based probe JPM-OEt and in situ applications
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A short, stereoselective synthesis of the general, cell permeable cathepsin probe JPM-OEt, is presented. The synthetic route is improved and described in more detail than previous reports for related compounds. This serves as a facile method for the synth
- Chehade, Kareem A. H.,Baruch, Amos,Verhelst, Steven H. L.,Bogyo, Matthew
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p. 240 - 244
(2007/10/03)
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- Design, Synthesis, and Evaluation of Aza-Peptide Epoxides as Selective and Potent Inhibitors of Caspases-1, -3, -6, and -8
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Aza-peptide epoxides, a novel class of irreversible protease inhibitors, are specific for the clan CD cysteine proteases. Aza-peptide epoxides with an aza-Asp residue at P1 are excellent irreversible inhibitors of caspases-1, -3, -6, and -8 with second-order inhibition rates up to 1 910 000 M-1 s-1. In general, the order of reactivity of aza-peptide epoxides is S,S > R,R > trans > cis. Interestingly, some of the R,R epoxides while being less potent are actually more selective than the S,S epoxides. Our aza-peptide epoxides designed for caspases are stable, potent, and specific inhibitors, as they show little to no inhibition of other proteases such as the aspartyl proteases porcine pepsin, human cathepsin D, plasmepsin 2 from P. falciparum, HIV-1 protease, and the secreted aspartic proteinase 2 (SAP-2) from Candida albicans; the serine proteases granzyme B and α-chymotrypsin; and the cysteine proteases cathepsin B and papain (clan CA), and legumain (clan CD).
- James, Karen Ellis,Asgian, Juliana L.,Li, Zhao Zhao,Ekici, ?zlem Do?an,Rubin, John R.,Mikolajczyk, Jowita,Salvesen, Guy S.,Powers, James C.
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p. 1553 - 1574
(2007/10/03)
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- Configuration and enantioselective synthesis of the fungal metabolite WF14861
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A short enantioselective synthesis of the cathepsine inhibitor WF14861 (1) from the funghi Colletotrichum sp. as well as of its diasteroisomer 21 is presented. Comparison of the NMR data of the final products and, in particular, of the [α]D values of the intermediates allowed the confirmation of the formerly proposed structure 1. In addition, the so far unknown absolute configuration of all three stereogenic centres of WF14861 could be established by this synthesis.
- Detterbeck, Richard,Hesse, Manfred
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p. 222 - 232
(2007/10/03)
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- Base promoted isomerization of aziridinyl ethers: a new access to alpha- and beta-amino acids.
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Aziridinyl ethers are selectively and easily converted to either amino vinyl ethers or alkoxy allylamines by treatment with mixed metal bases (superbases).
- Mordini, Alessandro,Sbaragli, Laura,Valacchi, Michela,Russo, Francesco,Reginato, Gianna
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p. 778 - 779
(2007/10/03)
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- Aza-peptide epoxides: A new class of inhibitors selective for clan CD cysteine proteases
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Aza-peptide epoxides, a new class of irreversible protease inhibitors, are specific for the clan CD cysteine proteases. The inhibitors have second-order rate constants up to 105 M-1 s-1, with the most potent epoxides having the S,S stereochemistry. The aza-Asn derivatives are effective legumain inhibitors, while the aza-Asp epoxides were specific for caspases. The inhibitors have little or no inhibition with other proteases such as chymotrypsin, papain, or cathepsin B.
- Asgian, Juliana L.,James, Karen Ellis,Li, Zhao Zhao,Carter, Wendy,Barrett, Alan J.,Mikolajczyk, Jowita,Salvesen, Guy S.,Powers, James C.
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p. 4958 - 4960
(2007/10/03)
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- Mechanistic studies on the inactivation of papain by epoxysuccinyl inhibitors
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Analogs of the epoxysuccinyl peptide cysteine proteinase inhibitor, EP- 475 (2a), in which the free carboxylate has been replaced by hydroxamic acid, amide, methyl ketone, hydroxyl, and ethyl ester functionalities, have been synthesized. Individual rate c
- Meara, Joseph P.,Rich, Daniel H.
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p. 3357 - 3366
(2007/10/03)
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- Kinetic Mechanism and Reaction Pathway of Thermus thermophilus Isopropylmalate Dehydrogenase
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Mechanistic studies of isopropylmalate dehydrogenase (IMDH, EC 1.1.1.85), the penultimate enzyme in leucine biosynthesis in bacteria and yeast, have been conducted.It performs two chemical operations, oxidation and decarboxylation, on isopropylmalate to p
- Pirrung, Michael C.,Han, Hyunsoo,Nunn, David S.
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p. 2423 - 2429
(2007/10/02)
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- A convenient synthesis of optically pure (2R, 3R)-2, 3-epoxysuccinyl - Dipeptides
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(2R,3R)-trans-Epoxysuccinyl-dipeptides (7a-7d) were synthesized by acylation of dipeptides with the N-hydroxysuccinimide or pentafluorophenyl ester of monoethyl (2R,3R)-trans-epoxysuccinate (6a-6b). A nucleophilic oxirane ring opening by N-hydroxysuccinimide and pentafluorophenol during the preparation of the active esters could not be observed. Subsequent saponification of the monoethyl ester 7a-7d with KOH in ethanolic solution allowed to produce the dipeptide derivatives as potassium salts (8a-8d) which were found to be stable on storage in the cold. The attempts to convert (2R,3R)-trans-epoxysuccinyl-glycyl-proline (7a) into the corresponding (2S,3S)-trans-epithiosuccinyl derivative via an oxygen sulfur exchange reaction with 3-methylbenzothiazole-2-thione failed completely as among the various products of unknown nature formed only the desulfurated fumaryl derivative could be isolated and characterized.
- Korn,Rudolph-Bohner,Moroder
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p. 8381 - 8392
(2007/10/02)
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- Applications of Biotransformations in Organic Synthesis: Preparation of Enantiomerically Pure Esters of cis- and trans-Epoxysuccinic Acid
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Chemical and enzymatic procedures have been investigated for the resolution of esters of trans-epoxysuccinic acid (trans-oxirane-2,3-dicarboxylic acid).A successful resolution was achieved by transesterification of the diethyl ester against heptanol catalysed by the lipase from Rhizopus javanicus.Asymmetrization of cis-epoxysuccinic acid was achieved by enantioselective and regiospecific hydrolysis of the racemic diethyl ester of 2-(toluene-p-sulfonyloxy)tartaric acid , followed by esterification with 2-methylpropanol and oxirane formation.
- Crout, David H. G.,Gaudet, S. B.,Hallinan, Keith O.
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p. 805 - 812
(2007/10/02)
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- Olefin Epoxidation Using Elemental Fluorine
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F2 reacts with water and CH3CN, apparently to produce the relatively stable complex HOF*CH3CN.This is probably the best known oxygen-transfer reagent and can epoxidize olefins quickly and efficiently.Various types of alkenes including aliphatic, benzylic, enones, dienones, maleates, and fumarates have been examined, and all react with the reagent to produce the corresponding mono- or diepoxides in good to excellent yields.This epoxidation is fully stereospecific, and the configuration of the starting olefin is fully retained in the resulting oxirane.In cases where exceptionally stable oxocarbocations can be formed as in 1,1-diphenylethene, the reaction produces vicinal glycols in good yields.Since the origin of the epoxides' oxygen is in the water, this method is very suitable for introducing the isotopes 17O and 18O in various molecules.
- Rozen, Shlomo,Kol, Moshe
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p. 5155 - 5159
(2007/10/02)
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- A Novel Synthesis of the Monobactam Antibiotic Carumonam
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A novel synthesis of the monobactam 4, a precursor of the antibiotic carumonam (3), has been achieved via the epoxide methyl (2R,3S)-4-acetoxy-2,3-epoxybutyrate (10).The latter was prepared from calcium L-threonate in three steps and 85percent overall yield.In a related study, ethyl (2R,3S)-4-hydroxy-2,3-epoxybutyrate (17) was prepared from L-(+)-tartaric acid in 45percent overall yield.Treatment of the sodium salt derived from 10 or 17 with ammonia led to a stereo- and regiospecific opening of the oxirane ring to give 20, after esterification, amide formation, and protection of the amino group.Conversion of 20 into 4 was accomplished by selective protection of the primary hydroxy group with chloroacetyl chloride, mesylation, sulfonation with 2-picoline-SO3, and ring closure with potassium bicarbonate.
- Manchand, Percy S.,Luk, Kin-Chun,Belica, Peter S.,Choudhry, Satish C.,Wei, Chung Chen,Soukup, Milan
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p. 5507 - 5512
(2007/10/02)
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- 17. Herstellung von erythro-2-Hydroxybernsteinsaure-Derivaten aus Apfelsaureester
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As a contribution to the much discussed diastereoselective synthesis of enantiomers of open chain compounds, >90percent erythro-selective branching of malic esters by alkylation of the doubly deprotonated derivative 2 (alkoxy-enolate) with methyl, allyl, and benzyl halides in THF at -78 deg (- 3aa, 3ba, 3bb, 3bc, Table 1) is described.A second alkylation (- 4) and addition of 2 to acetone (- 5) are also possible.Cyclization of 2 to the enantiomerically pure trans-epoxides 6 is achieved by treatment with iodine.Cuprate opening of 6b furnishes the same product 3ba obtained from the methylation of 2b, establishing the configurational assignment.
- Seebach, Dieter,Wasmuth, Daniel
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p. 197 - 200
(2007/10/02)
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- Stereoselective synthesis of optically active forms of δ-multistriatin, the attractant for european populations of the smaller european elm bark beet
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A stereoselective synthesis of highly optically pure enantiomers of δ-multistriatin [(1S,2S,4S,5R)-2,4-dimethyl-5-ethyl-6, 8-dioxabicyclo[3.2.1)octane and its antipode] was accomplished starting from tartaric acid enantiomers.
- Mori, Kenji,Iwasawa, Hiroko
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-