- Asymmetric Synthesis of (+)-Phosphinothricin and Related Compounds by the Michael Addition of Glycine Schiff Bases to Vinyl Compounds
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(S)-(+)-Phosphinothricin was prepared in good optical yield by th Michael addition of chiral glycine Schiff base derived from (S)-2-hydroxy-3-pinanone to vinyl phosphorus compound. (R)-(-)-Phosphinothricin, an enantiomeric isomer, can also be prepared from the same chiral glycine Schiff base by choosing suitable reaction temperature.
- Minowa, Nobuto,Hirayama, Masao,Fukatsu, Shunzo
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- New access to the synthetic building block L-aspartic acid β-semialdehyde via Grignard reaction
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A new, efficient, and inexpensive synthesis of protected L-aspartic acid β-semialdehyde has been developed starting from L-glutamic acid via a substituted L-allylglycine derivative as intermediate. The key step of the reaction sequence was a strongly solvent-dependent Grignard reaction of an L-glutamic acid semiester. The desired regioselective addition to the C-5 ester group was achieved in 1,2-dimethoxyethane while reactions in diethyl ether gave products resulting from additional attack at the carboxylic acid functionality.
- Luesch, Hendrik,Uzar, Horst C.
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- Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma
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Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.
- Hansen, Joshua D.,Correa, Matthew,Nagy, Mark A.,Alexander, Matt,Plantevin, Veronique,Grant, Virginia,Whitefield, Brandon,Huang, Dehua,Kercher, Timothy,Harris, Roy,Narla, Rama Krishna,Leisten, Jim,Tang, Yang,Moghaddam, Mehran,Ebinger, Katalin,Piccotti, Joseph,Havens, Courtney G.,Cathers, Brian,Carmichael, James,Daniel, Thomas,Vessey, Rupert,Hamann, Lawrence G.,Leftheris, Katerina,Mendy, Derek,Baculi, Frans,Lebrun, Laurie A.,Khambatta, Gody,Lopez-Girona, Antonia
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p. 6648 - 6676
(2020/09/11)
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- ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein is 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof, and methods for treating, preventing or managing multiple myeloma using such compounds. Also provided are pharmaceutical compositions comprising the compounds, and methods of use of the compositions.
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Paragraph 0309
(2019/01/25)
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- ANTIPROLIFERATIVE COMPOUNDS AND BISPECIFIC ANTIBODY AGAINST BCMA AND CD3 FOR COMBINED USE
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Provided herein is are methods of using 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-l-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof and a bispecific antibody specifically binding to human B cell maturation antigen (BCMA) and to human CD3e (CD3) provided herein, in treating, preventing or managing multiple myeloma.
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Paragraph 00275
(2019/12/15)
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- METHODS FOR TREATING MULTIPLE MYELOMA AND THE USE OF COMPANION BIOMARKERS FOR 4-(4-(4-(((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-4-YL)OXY)METHYL)BENZYL)PIPERAZIN-1-YL)-3-FLUOROBENZONITRILE
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A method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising administering the treatment compound to the subject having the cancer; obtaining a sample from the subject; determining the level of a biomarker in the sample from the subject; and diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample of the subject changes as compared to a reference level of the biomarker; wherein the treatment compound is Compound 1, Compound 2, or Compound 3.
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Paragraph 1061
(2019/12/06)
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- Tetrabutylammonium Fluoride as a Mild and Versatile Reagent for Cleaving Boroxazolidones to Their Corresponding Free α-Amino Acids
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Protection of α-amino acids with 9-borabicyclo[3.3.1]nonane (9-BBN) to give their corresponding boroxazolidones is highly attractive, as it concurrently masks both the amino and the carboxylic acid functionalities. However, the harsh methods required for deprotection of these boroxazolidones have limited their use. Herein, we report that tetrabutylammonium fluoride serves as a mild and versatile reagent that can be used to cleave boroxazolidones to their corresponding free α-amino acids. The reaction conditions were explored, including the use of various nucleophilic fluoride sources, solvents, and reaction temperatures. Nucleophilic fluoride sources comprising an ammonium cation proved superior to other countercations. The scope of the reaction was extended to the cleavage of B,B-diphenyl- and B,B-diethyl boroxazolidone complexes. Furthermore, a wide range of α-amino acid side-chain functionalities were shown to be compatible, including acids, esters, amides, thiols, thioethers, alkynes, phenols, basic heterocycles, and important biorelevant molecules such as glutathione, (S)-adenosyl-l-homocysteine, and l-biocytin.
- Poulie, Christian B. M.,Bunch, Lennart
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supporting information
p. 1475 - 1478
(2017/04/01)
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- LYSINE ISOTOPOLOGUES, COMPOSITIONS COMPRISING THE SAME AND METHODS OF SYNTHESIS
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This invention relates to lysine isotopologues of Formulas I and 1-A, as described herein, and processes for synthesizing the same and derivatives and intermediates involved therein. In one aspect, described herein is a chemical compound comprising an isotopically labeled analog, i.e., an isotopologue of a standard or naturally occurring lysine. The lysine isotopologue is synthetically formed to have stable isotopes of elements incorporated at selected positions. As such, the lysine isotopologue has a molecular mass different from the mass of a standard or naturally occurring lysine.
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Paragraph 0163
(2016/02/12)
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- METHOD FOR SYNTHESIZING OPTICALLY ACTIVE a-AMINO ACID USING CHIRAL METAL COMPLEX COMPRISING AXIALLY CHIRAL N-(2-ACYLARYL)-2-[5,7-DIHYDRO-6H-DIBENZO[c,e]AZEPIN-6-YL] ACETAMIDE COMPOUND AND AMINO ACID
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Objects of the present invention are to provide an industrially applicable method for producing an optically active α-amino acid in high yield and in a highly enantioselective manner, to provide a simple production method of an optically active α,α-disubstituted α-amino acid, and to provide an intermediate useful for the above production methods of an optically active α-amino acid and an optically active α,α-disubstituted α-amino acid. The present invention provides a production method of an optically active α-amino acid or a salt thereof, the production method comprising introducing a substituent into the α carbon in the α-amino acid moiety of a metal complex represented by the following Formula (1): by an alkylation reaction, an aldol reaction, the Michael reaction, or the Mannich reaction, and releasing an optically pure α-amino acid enantiomer or a salt thereof by acid decomposition of the metal complex.
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Paragraph 0396-0404
(2016/05/10)
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- METHOD FOR SYNTHESIZING OPTICALLY ACTIVE α-AMINO ACID USING CHIRAL METAL COMPLEX COMPRISING AXIALLY CHIRAL N-(2-ACYLARYL)-2-[5,7-DIHYDRO-6H-DIBENZO[c,e]AZEPIN-6-YL]ACETAMIDE COMPOUND AND AMINO ACID
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Objects of the present invention are to provide an industrially applicable method for producing an optically active ±-amino acid in high yield and in a highly enantioselective manner, to provide a simple production method of an optically active ±,±-disubstituted ±-amino acid, and to provide an intermediate useful for the above production methods of an optically active ±-amino acid and an optically active ±,±-disubstituted ±-amino acid. The present invention provides a production method of an optically active ±-amino acid or a salt thereof, the production method comprising introducing a substituent into the ± carbon in the ±-amino acid moiety of a metal complex represented by the following Formula (1): by an alkylation reaction, an aldol reaction, the Michael reaction, or the Mannich reaction, and releasing an optically pure ±-amino acid enantiomer or a salt thereof by acid decomposition of the metal complex.
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Paragraph 0673-0675
(2016/11/17)
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- In situ deprotection and incorporation of unnatural amino acids during cell-free protein synthesis
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The S30 extract from E. coli BL21 Star (DE3) used for cell-free protein synthesis removes a wide range of α-amino acid protecting groups by cleaving α-carboxyl hydrazides; methyl, benzyl, tert-butyl, and adamantyl esters; tert-butyl and adamantyl carboxamides; α-amino form-, acet-, trifluoroacet-, and benzamides and sidechain hydrazides and esters. The free amino acids are produced and incorporated into a protein under standard conditions. This approach allows the deprotection of amino acids to be carried out in situ to avoid separate processing steps. The advantages of this approach are demonstrated by the efficient incorporation of the chemically intractable (S)-4-fluoroleucine, (S)-4,5- dehydroleucine, and (2S,3R)-4-chlorovaline into a protein through the direct use of their respective precursors, namely, (S)-4-fluoroleucine hydrazide, (S)-4,5-dehydroleucine hydrazide, and (2S,3R)-4-chlorovaline methyl ester. These results also show that the fluoroand dehydroleucine and the chlorovaline are incorporated into a protein by the normal biosynthetic machinery as substitutes for leucine and isoleucine, respectively. Copyright
- Arthur, Isaac N.,Hennessy, James E.,Padmakshan, Dharshana,Stigers, Dannon J.,Lesturgez, Stéphanie,Fraser, Samuel A.,Liutkus, Mantas,Otting, Gottfried,Oakeshott, John G.,Easton, Christopher J.
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supporting information
p. 6824 - 6830
(2013/06/26)
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- Phototriggering of neuroactive amino acids from 5,6-benzocoumarinyl conjugates
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Uncaging of several neuroactive amino acids, namely β-alanine, tyrosine, 3,4-dihydroxyphenylalanine (DOPA) and glutamic acid from the corresponding 5,6-benzocoumarinyl conjugates was carried out by irradiation at different wavelengths and in different solvent systems. The release of the various amino acids was faster in ACN/HEPES buffer mixtures and for the tyrosine conjugate, an increase in the photolysis reaction rates and the quantitative uncaging of the amino acid was associated with increasing water content in the solvent mixture.
- Fernandes, Maria José G.,Costa, Susana P.G.,Gonalves, M. Sameiro T.
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p. 2422 - 2426
(2011/05/06)
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- Synthesis of biobased succinonitrile from glutamic acid and glutamine
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Succinonitrile is the precursor of 1,4-diaminobutane, which is used for the industrial production of polyamides. This paper describes the synthesis of biobased succinonitrile from glutamic acid and glutamine, amino acids that are abundantly present in many plant proteins. Synthesis of the intermediate 3-cyanopropanoic amide was achieved from glutamic acid 5-methyl ester in an 86 mol % yield and from glutamine in a 56 mol % yield. 3-Cyanopropanoic acid can be converted into succinonitrile, with a selectivity close to 100 % and a 62 % conversion, by making use of a palladium(II)-catalyzed equilibrium reaction with acetonitrile. Thus, a new route to produce biobased 1,4-diaminobutane has been discovered. Copyright
- Lammens, Tijs M.,N?tre, Jér?me Le,Franssen, Maurice C. R.,Scott, Elinor L.,Sanders, Johan P. M.
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scheme or table
p. 785 - 791
(2012/05/04)
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- Facile transformation of glutamic acid into proline residue inside a tripeptide backbone
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In this Letter we present a simple reaction pathway which allows the conversion of the glutamic acid residue of a tripeptide into a proline residue. The reaction was performed by using Boc-Val-Glu-Phe-NH2 as a starting material and is based on a NaH-induced intraresidue alkylation under reaction conditions analogous to that adopted during the Freidinger lactams formation.
- Mollica, Adriano,Stefanucci, Azzurra,Feliciani, Federica,Torino, Domenica,Cacciatore, Ivana,Pinnen, Francesco,Lucente, Gino
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scheme or table
p. 1333 - 1335
(2010/04/29)
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- Design, synthesis, and binding studies of bidentate Zn-chelating peptidic inhibitors of glyoxalase-I
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The known affinity of ethyl acetoacetate (ACC) toward divalent zinc prompted us to attempt its employment as a chelating moiety in the design of glyoxalase-I inhibitors. A practical synthetic route was developed to incorporate this pharmacophore into the side chain of glutamic acid, with flexibility to allow incorporation of additional functionality at the end-stage of the synthesis. Herein, the details of this synthetic approach as well as the evaluation of the resultant β-keto ester compounds are reported.
- More, Swati S.,Vince, Robert
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p. 3793 - 3797
(2008/02/13)
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- Copper(I) mediated cross-coupling of amino acid derived organozinc reagents with acid chlorides
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This paper describes the development of a straightforward experimental protocol for copper-mediated cross-coupling of amino acid derived β-amido-alkylzinc iodides 1 and 3 with a range of acid chlorides. The present method uses CuCN·2LiCl as the copper source and for organozinc reagent 1 the methodology appears to be limited to reaction with more stable acid chlorides, providing the desired products in moderate yields. When applied to organozinc reagent 3, however, the protocol is more general and provides the products in good yields in all but one of the cases tested. The Royal Society of Chemistry 2006.
- Hjelmgaard, Thomas,Tanner, David
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p. 1796 - 1805
(2008/02/05)
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- The Synthesis of the High-Potency Sweetener, NC-00637. Part 3: The Glutamyl Moiety and Coupling Reactions
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The synthesis of the high-potency sweetener, NC-00637 (1), required selective preparation of the γ-protected glutamic acid. Coupling of the three components could be performed in any order, but the final route involved N-acylation of the protected L-glutamic acid with the acid chloride derived from (S)-2-methylhexanoic acid. Activation of the α-carboxyl group allowed condensation with 5-amino-2-cyanopyridine (4). Saponification of the γ-ester 19 then provided the sweetener 1.
- Ager, David J.,Babler, Scott,Erickson, Robert A.,Froen, Diane E.,Kittleson, Jeannine,Pantaleone, David P.,Prakash, Indra,Zhi, Ben
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- ACE-INHIBITORS HAVING ANTIOXIDANT AND NO-DONOR ACTIVITY
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Multifonctional ACE inhibitor compounds are provided, that combine ACE-inhibiting activity with capability to scavenge superoxide and other reactive oxygen species, and that may further function as nitric oxide donors. The compounds are useful for preventing or treating various disorders, including cardiovascular, and diabetes associated disorders.
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Page/Page column 57; 58
(2010/02/07)
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- Utility of tetrathiomolybdate and tetraselenotungstate: Efficient synthesis of cystine, selenocystine, and their higher homologues
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Efficient synthesis of cystine, selenocystine, and their higher homologues like homo and bishomo amino acid derivatives from natural amino acid derivatives using tetrathiomolybdate and tetraselenotungstate reagents under mild and neutral conditions is reported. The generality of the reaction has been studied by capping various groups to amino and carboxyl components of canonical amino acids.
- Bhat, Ramakrishna G.,Porhiel, Emmanuel,Saravanan, Vadivelu,Chandrasekaran, Srinivasan
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p. 5251 - 5253
(2007/10/03)
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- Isolation and structures of nostopeptolides A1, A2 and A3 from the cyanobacterium Nostoc sp. GSV224
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The isolation and total structure determinations of nostopeptolides A1 (1), A2 (2) and A3 (3) are described. These cyclic depsipeptides, which are devoid of cytotoxic, antifungal and inhibition of protease activities, are characteristic constituents of the cryptophycin-producing cyanobacterium Nostoc sp. GSV224. Structure elucidation by NMR analysis was made more challenging by the existence of each nostopeptolide in three conformations. One-dimensional TOCSY experiments proved to be very useful in isolating and identifying the nine amino acid residues and the butyryl group in each compound. The absolute stereochemistries of 1-3 were determined by comparing the amino acids in the acid hydrolyzates directly with authentic standards. (C) 2000 Elsevier Science Ltd.
- Golakoti, Trimurtulu,Yoshida, Wesley Y.,Chaganty, Sreedhara,Moore, Richard E.
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p. 9093 - 9102
(2007/10/03)
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- Total syntheses of novel dideoxynucleoside analogues using chiral amino acids
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N-Tritylated L- and D-methionine and L-glutamic acid were used to obtain novel chiral iso-dideoxynucleoside analogues incorporating a tetrahydrofuranyl or a tetrahyropyranyl ring as the pseudosugar part, and at positions 2 and 3 of the ring an hydroxyethyl group and thymine or adenine, respectively. (C) 2000 Elsevier Science Ltd.
- Balayiannis,Karigiannis,Gatos,Papaioannou,De Clercq
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p. 6191 - 6194
(2007/10/03)
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- Process for the production of omega-amino-alpha-hydroxycarboxylic acid
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An optically active ω-amino-α-hydroxycarboxylic acid of the formula: wherein n is 1 or 2, which process comprises reacting an ω-ester of an α-amino acid with nitrous acid under an acidic condition to convert an amino group to an hydroxy group to obtain an ω-alkoxycarbonyl-α-hydroxycarboxylic acid, reacting the ω-alkoxycarbonyl-α-hydroxycarboxylic acid with ammonia to convert an alkoxycarbonyl group to an amide group to obtain an ω-aminocarbonyl-α-hydroxycarboxylic acid, and reacting the ω-aminocarbonyl-α-hydroxycarboxylic acid with an active halogen to convert the amido group to an amino group.
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- Stereospecific Amino Acid Synthesis; Preparation of the γ-Anion derived from Glutamic Acid
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Reaction of α-t-butyl γ-methyl N-trityl-L-glutamate (7) with lithium isopropylcyclohexylamide in hexane leads to the specific formation of the γ-ester enolate, a potential synthetic equivalent to the γ-anion synthon for stereospecific α-amino acid synthesis.
- Baldwin, Jack E.,North, Michael,Flinn, Anthony,Moloney, Mark G.
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p. 828 - 829
(2007/10/02)
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- A Simple and Convenient Synthesis of β-Aspartates and γ-Glutamates
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A simple and convenient, high yield synthesis of ω-esters of aspartic as well as glutamic acid has been developed, using tetrafluoroboric acid as catalyst. (13)C-NMR data of the products are given.
- Albert, Rainer,Danklmaier, Johann,Hoenig, Helmut,Kandolf, Harald
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p. 635 - 637
(2007/10/02)
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- Chirally Selective Hydrolysis of D,L-Amino Acid Esters by Alkaline Protease
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Alcalase selectively catalyses the hydrolysis of D,L-amino acid methyl and benzyl ester to provide L-amino acid and D-amino acid ester with high optical purity.
- Chen, Shui-Tein,Wang, Kung-Tsung,Wong, Chi-Huey
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p. 1514 - 1516
(2007/10/02)
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