- Enantioselective Synthesis of Cyclohexenol Derivatives from ?-Aryl-Substituted Enals via an Organocatalyzed Three-Component Reaction
-
A three-component reaction between ?-aryl-substituted α,β-unsaturated aldehydes and nitroalkenes was realized by using cinchona alkaloid-derived (thio)ureas and squaramides via the dienolate intermediates. This unprecedented 1,3- A nd 1,5-reactivity of dienolates of the ?-aryl-α,β-unsaturated aldehydes led to the formation of cyclohexenol derivatives with four contiguous stereogenic centers and a chiral substituent at C2 with good diastereoselectivities and high ee values. Such reactivities of the dienolates are totally different from those of the corresponding dienamine intermediates.
- Majee, Debashis,Jakkampudi, Satish,Arman, Hadi D.,Zhao, John C.-G.
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supporting information
p. 9166 - 9170
(2019/11/14)
-
- PROTEASOME INHIBITORS
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The disclosure provides proteasome inhibitors that can be used to halt cell division of rapidly dividing cells by preventing the degradation of cell cycle-regulating proteins, such as cyclins, cyclin-dependent kinase inhibitors, and p53. The proteasome in
- -
-
Paragraph 0207-0208; 0209
(2019/11/19)
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- Protecting-Group-Free Amidation of Amino Acids using Lewis Acid Catalysts
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Amidation of unprotected amino acids has been investigated using a variety of ‘classical“ coupling reagents, stoichiometric or catalytic group(IV) metal salts, and boron Lewis acids. The scope of the reaction was explored through the attempted synthesis of amides derived from twenty natural, and several unnatural, amino acids, as well as a wide selection of primary and secondary amines. The study also examines the synthesis of medicinally relevant compounds, and the scalability of this direct amidation approach. Finally, we provide insight into the chemoselectivity observed in these reactions.
- Sabatini, Marco T.,Karaluka, Valerija,Lanigan, Rachel M.,Boulton, Lee T.,Badland, Matthew,Sheppard, Tom D.
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supporting information
p. 7033 - 7043
(2018/05/04)
-
- Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors
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The peptidic β-lactone proteasome inhibitors (PIs) cystargolides A and B were used to conduct structure-activity relationship (SAR) studies in order to assess their anticancer potential. A total of 24 different analogs were designed, synthesized and evaluated for proteasome inhibition, for cytotoxicity towards several cancer cell lines, and for their ability to enter intact cells. X-ray crystallographic analysis and subunit selectivity was used to determine the specific subunit binding associated with the structural modification of the β-lactone (P1), peptidic core, (Px and Py), and end-cap (Pz) of our scaffold. The cystargolide derivative 5k, structurally unique at both Py and P1, exhibited the most promising inhibitory activity for the β5 subunit of human proteasomes (IC50 = 3.1 nM) and significant cytotoxicity towards MCF-7 (IC50 = 416 nM), MDA-MB-231 (IC50 = 74 nM) and RPMI 8226 (IC50 = 41 nM) cancer cell lines. Cellular infiltration assays revealed that minor structural modifications have significant effects on the ability of our PIs to inhibit intracellular proteasomes, and we identified 5k as a promising candidate for continued therapeutic studies. Our novel drug lead 5k is a more potent proteasome inhibitor than carfilzomib with mid-to-low nanomolar IC50 measurements and it is cytotoxic against multiple cancer cell lines at levels approaching those of carfilzomib.
- Niroula, Doleshwar,Hallada, Liam P.,Le Chapelain, Camille,Ganegamage, Susantha K.,Dotson, Devon,Rogelj, Snezna,Groll, Michael,Tello-Aburto, Rodolfo
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supporting information
p. 962 - 977
(2018/09/04)
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- [...] - Orn (ClCH2NH) - AA - benzylamine, its synthesis, activity and application (by machine translation)
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The invention discloses the following formula of 13 for β - Carboline -3 - formyl - Orn (ClCH2 NH) - AA - NHCH2 C6 H5 (In the formula AA is selected from L - Arg, L - Asn, L - Asp, L - Glu, L - Gly, L - Ile, L - Leu, L - Met, L - Phe, L - Pro, L - Thr, L - Trp, L - Val residue), discloses a process for their preparation, discloses their inhibition of tumor cell growth, therefore this invention discloses their use as anti-tumor medicament. (by machine translation)
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-
Paragraph 0043; 0162; 0163
(2017/08/27)
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- l-tert-Leucine-Derived AmidPhos-Silver(I) Chiral Complexes for the Asymmetric [3+2] Cycloaddition of Azomethine Ylides
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The l-tert-leucine-derived AmidPhos/silver(I) catalytic system has been developed for the asymmetric [3+2] cycloaddition of azomethine ylides with electronic-deficient alkenes with or without Et3N. Under optimal conditions, highly functionalized endo-4-pyrrolidines were obtained with modest to high yields (up to 99% yield) and enantioselectivities (up to 98% ee).
- Zhou, Zhipeng,Zheng, Xiaojun,Liu, Jialin,Li, Jinlei,Wen, Pushan,Wang, Haifei
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p. 999 - 1003
(2017/05/05)
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- Mechanistic implications of the enantioselective addition of alkylzinc reagents to aldehydes catalyzed by nickel complexes with α-amino amide ligands
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The enantioselective alkylation of aldehydes catalysed by nickel(ii)-complexes derived from α-amino amides was studied by means of density functional theory (DFT) and ONIOM (B3LYP:UFF) calculations. A mechanism was proposed in order to investigate the origin of enantioselectivity. The chirality-determining step for the alkylation was the formation of the intermediate complexes with the involvement of a 5/4/4-fused tricyclic transition state. The predominant products predicted theoretically were of (S)-configuration, in good agreement with experimental observations. The scope of the reaction was examined and high yields and enantioselectivities were observed for the enantioselective addition of Et2Zn and Me2Zn to aromatic and aliphatic aldehydes.
- Escorihuela, Jorge,Burguete, M. Isabel,Ujaque, Gregori,Lledós, Agustí,Luis, Santiago V.
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p. 11125 - 11136
(2016/12/07)
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- Direct amidation of unprotected amino acids using B(OCH2CF3)3
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A commercially available borate ester, B(OCH2CF3)3, can be used to achieve protecting-group free direct amidation of α-amino acids with a range of amines in cyclopentyl methyl ether. The method can be applied to the synthesis of medicinally relevant compounds, and can be scaled up to obtain gram quantities of products.
- Lanigan, Rachel M.,Karaluka, Valerija,Sabatini, Marco T.,Starkov, Pavel,Badland, Matthew,Boulton, Lee,Sheppard, Tom D.
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supporting information
p. 8846 - 8849
(2016/07/22)
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- Ag2CO3/CA-AA-amidphos multifunctional catalysis in the enantioselective 1,3-dipolar cycloaddition of azomethine ylides
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The new Ag2CO3/CA-AA-amidphos complexes have been demonstrated as highly efficient multifunctional catalysts in the asymmetric 1,3-dipolar cycloaddition of azomethine ylides. Under optimal conditions, highly functionalized endo-4 pyrrolidines were obtained with excellent yields (up to 99% yield) and enantioselectivities (up to 96% ee).
- Wang, Haifei,Deng, Qifu,Zhou, Zhipeng,Hu, Shunqin,Liu, Zhiguo,Zhou, Li-Yi
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p. 404 - 407
(2016/02/18)
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- Design, synthesis, and fungicidal activities of imino diacid analogs of valine amide fungicides
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The novel imino diacid analogs of valine amides were synthesized via several steps, including the protection, amidation, deprotection, and amino alkylation of valine, with the resulting structures confirmed by 1H and 13C NMR and HRMS. Bioassays showed that some of these compounds exhibited good fungicidal activity. Notably, isopropyl 2-((1-((1-(3-fluorophenyl)ethyl)amino)-3-methyl-1-oxobutan-2-yl)amino)propanoate 5i displayed significant levels of control, at 50%, against Erysiphe graminis at 3.9 μM as well as a level of potency very similar to the reference azoxystrobin, which gave 60% activity at this concentration. The present work demonstrates that imino diacid analogs of valine amides could be potentially useful key compounds for the development of novel fungicides against wheat powdery mildew.
- Sun, Man,Yang, Hui-Hui,Tian, Lei,Li, Jian-Qiang,Zhao, Wei-Guang
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p. 5729 - 5731
(2015/11/24)
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- Highly modular dipeptide-like organocatalysts for direct asymmetric aldol reactions in brine
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A novel series of dipeptide-like organocatalysts derived from proline, amino acids and primary amines have been prepared for direct asymmetric aldol reactions between various aromatic aldehydes and acetone to afford aldol products in good yields (up to 82%) and moderate enantioselectivities (up to 67% ee) with only 1 mol% of catalyst-loading in brine. Under the same conditions, the direct asymmetric aldol reactions of aromatic aldehydes and cyclohexanone give aldol products with high yields (up to 91%) and moderate to good enantioselectivities (up to 88% ee) and excellent diastereoselectivities (up to 99% dr). These organocatalysts are easily synthesized from commercially available materials in multi-gram scale with high modularity in their structural and stereogenic properties.
- Hu, Xiao-Mu,Zhang, Dong-Xu,Zhang, Sheng-Yong,Wang, Ping-An
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p. 39557 - 39564
(2015/05/20)
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- C2 symmetrical nickel complexes derived from α-amino amides as efficient catalysts for the enantioselective addition of dialkylzinc reagents to aldehydes
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A series of C2 symmetrical 1:2 Ni:L complexes derived from α-amino amides were studied for the enantioselective addition of dialkylzinc reagents to aldehydes. Different structural elements on the ligands seem to play an important role in determining the observed enantioselectivity. Through optimization of structure and reaction conditions, the best ligand provided secondary alcohols in excellent yields (up to 98%) and enantioselectivity of up to 99% ee for (R)-enantiomer. A transition state model has been proposed to explain the observed enantioselectivities based on computational calculations at the DFT level. Very interestingly, calculations suggest a coordination model of the aldehyde to the metal complex through association of a lone pair of the carbonyl oxygen to the hydrogen atom of an amino group.
- Escorihuela, Jorge,Altava, Belen,Burguete, M. Isabel,Luis, Santiago V.
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p. 551 - 558
(2013/07/27)
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- Organocatalysis of asymmetric aldol reaction in water: Comparison of catalytic properties of (S)-valine and (S)-proline amides
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(S)-Valine amides containing (S)- or (R)-α-phenylethyl substituents at N1 atom efficiently catalyze asymmetric aldol reactions between cyclic (heterocyclic) ketones and aromatic aldehydes in water, predominantly giving rise to the aldol anti-di
- Kucherenko,Siyutkin,Dashkin,Zlotin
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p. 1010 - 1015
(2014/03/21)
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- The dimethylsulfoxonium methylide as unique reagent for the simultaneous deprotection of amino and carboxyl function of N-Fmoc-α-amino acid and N-Fmoc-peptide esters
-
The dimethylsulfoxonium methylide is described as a unique and useful reagent for the simultaneous deprotection of amino and carboxyl function of N-Fmoc-α-amino acid and N-Fmoc-peptide esters. The new methodology was applied successfully both to solution- and solid-phase peptide synthesis. The adopted methodology was extended successfully also to peptides containing amino acids bearing acid-sensitive protecting group in side chains. Furthermore no measurable epimerization was observed in the deprotection reaction of N-Fmoc-dipeptide methyl esters with dimethylsulfoxonium methylide.
- Spinella, Mariagiovanna,De Marco, Rosaria,Belsito, Emilia L.,Leggio, Antonella,Liguori, Angelo
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p. 2010 - 2016
(2013/03/13)
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- Reversal of selectivity in acetate aldol reactions of N-acetyl-(S)-4- isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one
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Synergistic effects of the exo- and endocyclic chiral centers of an imidazolidinone-based auxiliary were investigated in the perspective of acetate aldol reactions. The reversal in diastereoselectivity was accomplished by lithium and titanium enolate reactions, which proceed through proposed open and closed transitions states, respectively. The aldol adducts were used in the stereoselective synthesis of fluoxetine.
- Khatik, Gopal L.,Kumar, Varun,Nair, Vipin A.
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p. 2442 - 2445
(2012/07/03)
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- Primary amino acid derivatives: Compounds with anticonvulsant and neuropathic pain protection activities
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Pharmacological management remains the primary method to treat epilepsy and neuropathic pain. We have advanced a novel class of anticonvulsants termed functionalized amino acids (FAAs). In this study, we examine FAA derivatives from which the terminal acetyl moiety was removed and termed these compounds primary amino acid derivatives (PAADs). Twenty-seven PAADs were prepared; the central C(2) R-substituent was varied, including C(2) stereochemistry, and the compounds were tested in rodent models of seizures and neuropathic pain. C(2)-Hydrocarbon N-benzylamide PAADs were potent anticonvulsants and excellent anticonvulsant activity (mice, ip; rat, po) was observed for C(2) R-substituted PAADs in which the R group was ethyl, isopropyl, or tert-butyl, and the C(2) stereochemistry conformed to the d-amino acid configuration ((R)-stereoisomer). These values surpassed the activities of several clinical antiepileptic drugs. The C(2) (R)-ethyl and C(2) (R)-isopropyl PAADs also displayed excellent activities in the mouse (ip) formalin neuropathic pain model. Significantly, unlike the FAA structure-activity relationship, PAAD anticonvulsant activity increased upon substitution of a methylene unit for a heteroatom in the R-substituent that was one atom removed from the C(2) site, suggesting that these PAADs function by a different pathway than FAAs.
- King, Amber M.,Salomé, Christophe,Dinsmore, Jason,Salomé-Grosjean, Elise,De Ryck, Marc,Kaminski, Rafal,Valade, Anne,Kohn, Harold
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p. 4815 - 4830
(2011/10/01)
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- Enantioselective Morita-Baylis-Hillman reaction promoted by l-threonine-derived phosphine-thiourea catalysts
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A series of bifunctional phosphine-thiourea organic catalysts based on natural amino acid scaffolds were designed and prepared. l-Threonine-derived bifunctional phosphine catalysts were found to be very efficient in promoting asymmetric Morita-Baylis-Hillman (MBH) reaction of acrylates with aromatic aldehydes, affording the desired MBH adducts with up to 90% ee. To gain mechanistic insights into the reaction, the effects of adding various additives on the MBH reaction were investigated. We propose that the hydrogen bonding interactions between the thiourea moiety of the catalyst and the enolate intermediate are crucial for the stereochemical outcome of the reaction. The method described in this report may provide a practical solution to the enantioselective MBH reaction of simple acrylates.
- Han, Xiaoyu,Wang, Youqing,Zhong, Fangrui,Lu, Yixin
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p. 6734 - 6740
(2011/11/05)
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- Liquid chromatographic resolution of tocainide and its analogues on a doubly tethered chiral stationary phase based on (+)-(18-Crown-6)-2,3,11,12- tetracarboxylic acid
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A doubly tethered chiral stationary phase (CSP) based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid were applied to the liquid chromatographic resolution of racemic tocainide, an antiarrhythmic agent, and its analogues. The chiral recognition efficiency of the doubly tethered CSP for tocainide and its analogues was generally greater than that of the corresponding singly tethered CSP especially in terms of the resolution (RS). The resolution of tocainide and its analogues on the doubly tethered CSP were dependent on the content and the type of the organic and acidic modifiers in aqueous mobile phase and the column temperature. Especially, the retention behaviors of analytes on the doubly tethered CSP with the variation of the content of organic modifier in aqueous mobile phase were opposite to those on the corresponding singly tethered CSP and these opposite retention behaviors were rationalized by the lipophilicity differences of the two CSPs.
- Kim, Hee Jin,Choi, Hee Jung,Hyun, Myung Ho
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experimental part
p. 678 - 682
(2010/08/07)
-
- Design and synthesis of potent and selective BACE-1 inhibitor
-
Highly potent BACE-1 protease inhibitors have been developed from an inhibitors containing a hydroxyethylene (HE) core displaying aryloxymethyl or benzyloxymethyl P1 side chain and a methoxy P1′ side chain. The target molecules were synthesized in good overall yields from chiral carbohydrate starting materials. The inhibitors show high BACE-1 potency and good, selectivity against cathepsin D, where the most potent inhibitor furnishes BACE-1 Ki ? 1 nM and displays > 1000-fold selectivity over cathepsin D.
- Bj?rklund, Catarina,Oscarson, Stefan,Benkestock, Kurt,Borkakoti, Neera,Jansson, Katarina,Lindberg, Jimmy,Vrang, Lotta,Hallberg, Anders,Rosenquist, Asa,Samuelsson, Bertil
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supporting information; experimental part
p. 1458 - 1464
(2010/08/03)
-
- Synthesis and evaluation of pseudopeptidic fluorescence pH probes for acidic cellular organelles: In vivo monitoring of bacterial phagocytosis by multiparametric flow cytometry
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A new family of fluorescent anthracenic pH probes has been synthesized, chemically characterized, and their photophysical properties have been investigated by steady-state and time-resolved fluorescence spectroscopy. The ability of these compounds to monitor pH has been investigated in solution and it was found that molecules 1-12 can act as fluorescent sensors for pH in a range between 4.6 and 6.5. This range corresponds to the pH of acidic organelles in the cell (pH 4.5-6.0) for which a limited number of probes are described. The acid-base behavior of each sensor varies slightly depending on the nature of substituents close to the amines present in the molecules. Thus, the pK a of this family of compounds can be finely tuned by the appropriate selection of the synthetic building blocks at the design stage. To test the potential diagnostic applications of this family of probes, macrocyclic pseudopeptide 2 was used to monitor the phagocytosis of a culture of GFP-labelled bacteria by human monocytic cells U937 using flow cytometry as the analytical tool. It was found that the occurrence of bacterial killing was concomitant with the production of reactive oxygen species and a drop in pH, the latter monitored indirectly by macrocyclic sensor 2, which suggests its potential use for diagnostic purposes. A new family of anthracenic macrocycles has been synthesized that can act as fluorescent probes for pH in the range 4.6-6.5. The pKa values of these compounds can be finely tuned. In flow cytometry experiments, it was found that bacterial killing by human monocytes (U937) occurred with a simultaneous drop in pH, which was monitored by one of the macrocyclic sensors.
- Burguete, M. Isabel,Galindo, Francisco,Izquierdo, M. Angeles,O'Connor, Jose-Enrique,Herrera, Guadalupe,Luis, Santiago V.,Vigara, Laura
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supporting information; experimental part
p. 5967 - 5979
(2011/02/26)
-
- Synthesis and evaluation of a new class of tertiary alcohol based BACE-1 inhibitors
-
BACE-1 has emerged as one of the best characterized targets for future Alzheimer therapy. In accordance with the successful identification of masked inhibitors of HIV-1 protease, we envisioned that tert-alcohol containing transition-state mimicking struct
- Russo, Francesco,W?ngsell, Fredrik,S?vmarker, Jonas,Jacobsson, Micael,Larhed, Mats
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experimental part
p. 10047 - 10059
(2010/02/28)
-
- NEW COMPOUNDS
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The invention provides compounds of the formula I wherein Q is aryl or heterocyclyl any of which is optionally substituted; Z is O, S, NRa or S(=O)p; Y is NH, NHNH, CH2NH, O, S or S(=O)p; n is 0, 1, 2 or 3; m is 0, 1 or 2; p is 1 or 2; Ra is H or C1-C4alkyl; R1 is hydrogen, C1-C6alkyl, C0-C3alkanediylC3-C7cycloalkyl, C0-C3alkanediylaryl or C0- C3alkanediylheterocyclyl; R2 is hydrogen or C1-C6alkyl; X' is hydrogen, fluoro, hydroxy, amino or C1-C6alkoxy; X" is hydrogen, or when X' is fluoro, then X" may also be fluoro; R3is C1-C6alkyl; R4' is C1-C6alkyl; R4" is H or C1-C6alkyl; or R4' and R4" together with the carbon atom to which they are attached define a C3-C6cycloalkyl; W is C1-C6alkyl, C3-C7cycloalkyl, aryl or heterocyclyl any of which is optionally substituted; or a pharmaceutically acceptable salt, hydrate or N-oxide thereof. The compounds of the invention are inhibitors of aspartyl proteases such as renin and are among other things useful for the treatment of conditions associated with activities of the RAS, such as hypertension, heart failure and renal insufficiency.
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- Macrocyclic peptidomimetic inhibitors of β-secretase (BACE): First X-ray structure of a macrocyclic peptidomimetic-BACE complex
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The synthesis of novel macrocyclic peptidomimetic inhibitors of the enzyme BACE1 is described. These macrocycles are derived from a hydroxyethylene core structure. Compound 7 was co-crystallized with BACE1 and the X-ray structure of the complex elucidated at 1.6 A resolution. This molecule inhibits the production of the Aβ peptide in HEK293 cells overexpressing APP751sw.
- Rojo, Isabel,Martin, Jose Alfredo,Broughton, Howard,Timm, David,Erickson, Jon,Yang, Hsiu-Chiung,McCarthy, James R.
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p. 191 - 195
(2007/10/03)
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- Design of an organocatalyst for the enantioselective Diels-Alder reaction with α-acyloxyacroleins
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We have realized the first enantioselective organocatalytic Diels-Alder reaction between α-substituted acroleins, such as α-acyloxyacroleins, and not only cyclic but also acyclic dienes. α-Acyloxyacroleins are useful as synthetic equivalents of α-haloacro
- Ishihara, Kazuaki,Nakano, Kazuhiko
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p. 10504 - 10505
(2007/10/03)
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- A novel highly selective chiral auxiliary for the asymmetric synthesis of L- and D-α-amino acid derivatives via a multicomponent ugi reaction
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(Chemical Equation Presented) This paper describes the synthesis of a bicyclic β-amino acid scaffold in both pure enantiomeric forms and its application as chiral auxiliary in an intramolecular version of the Ugi multicomponent reaction (U-5C-4CR) to prepare α-amino acid derivatives of both D- and L-series in a straightforward and very stereoselective manner. The mild conditions required for the Ugi condensation and for the removal of the chiral auxiliary make this method very attractive to prepare a wide range of differently structured N-alkylated and unalkylated amino acid derivatives.
- Basso, Andrea,Banfi, Luca,Riva, Renata,Guanti, Giuseppe
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p. 575 - 579
(2007/10/03)
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- Synthesis of chiral α-amino-diazoketones on solid support: An access to β-homologated amino acid derivatives
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Diazoketone derivatives were obtained on solid support from their corresponding α-amino acids anchored by their N-terminus to the resin. A complete study was performed to optimize the two steps process of this synthesis on solid support: activation of the carboxylic acid function followed by reaction with diazomethane. The obtained diazoketones were then submitted to Wolff rearrangement in the presence of an amine to yield the corresponding homologated amides or in the presence of water to yield the corresponding β-homologated amino acids.
- Cantel, Sonia,Martinez, Jean,Fehrentz, Jean-Alain
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p. 2791 - 2793
(2007/10/03)
-
- Stereoselective syntheses of chiral (3S,9bS)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones
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Chiral (3S,9bS)-1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones 11a-11f, 14b,14c and 17a,b were prepared in 78-93% yields with high stereoselectivities (d.e. >99%) by the intermolecular condensations of 2-formylbenzoic acids 10 or 13 or 2-acetylbenzoic acid 15 with chiral diamines 9a-9f and 9h. Compounds 9a-9f and 9h were readily prepared in three steps from optically active N-Boc-α-amino acids 5a-5d.
- Katritzky, Alan R.,He, Hai-Ying,Verma, Akhilesh K.
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p. 933 - 938
(2007/10/03)
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- Structure-based design: Potent inhibitors of human brain memapsin 2 (β-secretase)
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Memapsin 2 (β-secretase) is one of two proteases that cleave the β-amyloid precursor protein (APP) to produce the 40-42 residue amyloid-β peptide (Aβ) in the human brain, a key event in the progression of Alzheimer's disease. On the basis of the X-ray crystal structure of our lead inhibitor (2, OM99-2 with eight residues) bound to memapsin, we have reduced the molecular weight and designed potent memapsin inhibitors. Structure-based design and preliminary structure-activity studies have been presented.
- Ghosh,Bilcer,Harwood,Kawahama,Shin,Hussain,Hong,Loy,Nguyen,Koelsch,Ermolieff,Tang
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p. 2865 - 2868
(2007/10/03)
-
- Inhibitors of tripeptidyl peptidase II. 2. Generation of the first novel lead inhibitor of cholecystokinin-8-inactivating peptidase: A strategy for the design of peptidase inhibitors
-
The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase which has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO3H)-Met-OH + Gly-Trp-Met-Asp-Phe-NH2. In seeking a reversible inhibitor of this peptidase, the enzymatic binding subsites were characterized using a fluorimetric assay based on the hydrolysis of the artificial substrate Ala-Ala-Phe-amidomethylcoumarin. A series of di- and tripeptides having various alkyl or aryl side chains was studied to determine the accessible volume for binding and to probe the potential for hydrophobic interactions. From this initial study the tripeptides Ile-Pro-Ile-OH (K(i) = 1 μM) and Ala-Pro-Ala-OH (K(i) = 3 μM) and dipeptide amide Val-Nvl-NHBu (K(i) = 3 μM) emerged as leads. Comparison of these structures led to the synthesis of Val-Pro-NHBu (K(i) = 0.57 μM) which served for later optimization in the design of butabindide, a potent reversible competitive and selective inhibitor of the CCK-8-inactivating peptidase. The strategy for this work is explicitly described since it illustrates a possible general approach for peptidase inhibitor design.
- Ganellin, C. Robin,Bishop, Paul B.,Bambal, Ramesh B.,Chan, Suzanne M. T.,Law, James K.,Marabout, Benoit,Luthra, Pratibha Mehta,Moore, Andrew N. J.,Peschard, Olivier,Bourgeat, Pierre,Rose, Christiane,Vargas, Froylan,Schwartz, Jean-Charles
-
p. 664 - 674
(2007/10/03)
-
- Peptide-titanium complex as catalyst for asymmetric addition of hydrogen cyanide to aldehyde
-
The complex of titanium ethoxide and an acyclic dipeptide ester whose terminal amino group is modified to a salicylal-type Schiff base catalyzes the asymmetric addition of hydrogen cyanide to aldehydes with high enantioselectivity. In the reaction of benzaldehyde and hydrogen cyanide, (R)-mandelonitrile is obtained with an enantiomeric excess of 90% when N-((2-hydroxy-1-naphthyl)methylene)-(S)-valyl-(S)-tryptophan methyl ester is employed. In place of the dipeptide, the amide derivatives of an amino acid modified by substituted salicylaldehyde, such as N-(3,5-dibromosalicylidene)-(S)-valine piperidide, exhibit an entirely opposite stereoselectivity to yield S-cyanohydrins with optical purities up to 97% ee. This novel peptide-titanium complex, therefore, enables us to afford optically active cyanohydrins of both absolute configurations by using natural S-amino acids as chiral auxiliaries.
- Nitta, Hideaki,Yu, Donghai,Kudo, Masanobu,Mori, Atsunori,Inoue, Shohei
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p. 7969 - 7975
(2007/10/02)
-
- Design and synthesis of HIV protease inhibitors. Variations of the carboxy terminus of the HIV protease inhibitor L-682,679
-
A series of tetrapeptide analogues of 1 (L-682,679), in which the carboxy terminus has been shortened and modified, was prepared and their inhibitory activity measured against the HIV protease in a peptide cleavage assay. Selected examples were tested as inhibitors of virus spread in cell culture. Compound 12 was a 10-fold more potent enzyme inhibitor than 1 in vitro and 30-fold more potent in inhibiting the viral spread in cells.
- DeSolms,Giuliani,Guare,Vacca,Sanders,Graham,Wiggins,Darke,Sigal,Zugay,Emini,Schleif,Quintero,Anderson,Huff
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p. 2852 - 2857
(2007/10/02)
-