- A one-pot procedure for the preparation of N-9-fluorenylmethyloxycarbonyl- α-amino diazoketones from α-amino acids
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The study describes a new "one-pot" route to the synthesis of N-9-fluorenylmethyloxycarbonyl (Fmoc) α-amino diazoketones. The procedure was tested on a series of commercially available free or side-chain protected α-amino acids employed as precursors. The conversion into the title compounds was achieved by masking and activating the α-amino acids with a single reagent, namely, 9-fluorenylmethyl chloroformate (Fmoc-Cl). The resulting N-protected mixed anhydrides were reacted with diazomethane to lead to the α-amino diazoketones, which were isolated by flash column chromatography in very good to excellent overall yields. The versatility of the procedure was verified on lipophilic α-amino acids and further demonstrated by the preparation of N-Fmoc-α-amino diazoketones also from α-amino acids containing side-chain masking groups, which are orthogonal to the Fmoc one. The results confirmed that tert-butyloxycarbonyl (Boc), tert-butyl (tBu), and 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), three acid-labile protecting groups mostly adopted in the solution and solid-phase peptide synthesis, are compatible to the adopted reaction conditions. In all cases, the formation of the corresponding C-methyl ester of the starting amino acid was not observed. Moreover, the proposed method respects the chirality of the starting α-amino acids. No racemization occurred when the procedure was applied to the synthesis of the respective N-Fmoc-protected α-amino diazoketones from l-isoleucine and l-threonine and to the preparation of a diastereomeric pair of N-Fmoc-protected dipeptidyl diazoketones.
- Siciliano, Carlo,De Marco, Rosaria,Guidi, Ludovica Evelin,Spinella, Mariagiovanna,Liguori, Angelo
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- Synthesis and biological evaluation of novel FK228 analogues as potential isoform selective HDAC inhibitors
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Novel C4- and C7-modified FK228 analogues were efficiently synthesized in a highly convergent and unified manner. This synthesis features the amide condensation of glycine-d-cysteine-containing segments with d-valine-containing segments for the direct assembly of the corresponding seco-acids, which are key precursors of macrolactones. The HDAC inhibition assay and cell-growth inhibition analysis of the synthesized analogues revealed novel aspects of their structure-activity relationship. This study demonstrated that simple modification at the C4 and C7 side chains in FK228 is effective for improving both HDAC inhibitory activity and isoform selectivity; moreover, potent and highly isoform-selective class I HDAC1 inhibitors were identified.
- Narita, Koichi,Matsuhara, Keisuke,Itoh, Jun,Akiyama, Yui,Dan, Singo,Yamori, Takao,Ito, Akihiro,Yoshida, Minoru,Katoh, Tadashi
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- Structure-guided engineering of: Meso -diaminopimelate dehydrogenase for enantioselective reductive amination of sterically bulky 2-keto acids
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meso-Diaminopimelate dehydrogenase (DAPDH) and mutant enzymes are an excellent choice of biocatalysts for the conversion of 2-keto acids to the corresponding d-amino acids. However, their application in the enantioselective reductive amination of bulky 2-keto acids, such as phenylglyoxylic acid, 2-oxo-4-phenylbutyric acid, and indole-3-pyruvic acid, is still challenging. In this study, the structure-guided site-saturation mutagenesis of a Symbiobacterium thermophilum DAPDH (StDAPDH) gave rise to a double-site mutant W121L/H227I, which showed dramatically improved enzyme activities towards various 2-keto acids including these sterically bulky substrates. Several d-amino acids were prepared in optically pure form. The molecular docking of substrates into the active sites of wild-type and mutant W121L/H227I enzymes revealed that the substrate binding cavity of the mutant enzyme was reshaped to accommodate these bulky substrates, thus leading to higher enzyme activity. These results lay a foundation for further shaping the substrate binding pocket and manipulating the interactions between the substrate and binding sites to access highly active d-amino acid dehydrogenases for the preparation of synthetically challenging d-amino acids.
- Cheng, Xinkuan,Chen, Xi,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming
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- Kras inhibitory cyclic peptide compound
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The following were discovered: a cyclic peptide compound that interacts with Ras; and an unnatural amino acid that is useful in the production of said cyclic peptide compound. The cyclic peptide compound was also discovered to inhibit bonding between Ras and SOS. The following were additionally discovered: a specific unnatural amino acid included in said cyclic peptide compound; and a manufacturing method therefor.
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Paragraph 0682; 0821; 0824
(2021/06/03)
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- Novel chiral stationary phases based on 3,5-dimethyl phenylcarbamoylated β-cyclodextrin combining cinchona alkaloid moiety
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Novel chiral selectors based on 3,5-dimethyl phenylcarbamoylated β-cyclodextrin connecting quinine (QN) or quinidine (QD) moiety were synthesized and immobilized on silica gel. Their chromatographic performances were investigated by comparing to the 3,5-dimethyl phenylcarbamoylated β-cyclodextrin (β-CD) chiral stationary phase (CSP) and 9-O-(tert-butylcarbamoyl)-QN-based CSP (QN-AX). Fmoc-protected amino acids, chiral drug cloprostenol (which has been successfully employed in veterinary medicine), and neutral chiral analytes were evaluated on CSPs, and the results showed that the novel CSPs characterized as both enantioseparation capabilities of CD-based CSP and QN/QD-based CSPs have broader application range than β-CD-based CSP or QN/QD-based CSPs. It was found that QN/QD moieties play a dominant role in the overall enantioseparation process of Fmoc-amino acids accompanied by the synergistic effect of β-CD moiety, which lead to the different enantioseparation of β-CD-QN-based CSP and β-CD-QD-based CSP. Furthermore, new CSPs retain extraordinary enantioseparation of cyclodextrin-based CSP for some neutral analytes on normal phase and even exhibit better enantioseparation than the corresponding β-CD-based CSP for certain samples.
- Zhu, Lunan,Zhu, Junchen,Sun, Xiaotong,Wu, Yaling,Wang, Huiying,Cheng, Lingping,Shen, Jiawei,Ke, Yanxiong
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p. 1080 - 1090
(2020/05/25)
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- Determination of Chemical and Enantiomeric Purity of α-Amino Acids and their Methyl Esters as N-Fluorenylmethoxycarbonyl Derivatives Using Amylose-derived Chiral Stationary Phases
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Liquid chromatographic enantiomer separation and simultaneous determination of chemical and enantiomeric purity of α-amino acids and their methyl esters as N-fluorenylmethoxycarbonyl (FMOC) derivatives was performed on three covalently bonded type chiral stationary phases (CSPs) derived from amylose derivatives. The enantiomer separation of α-amino acid esters as N-FMOC derivatives was better than that of the corresponding acids, especially for CSP 1 and 2. Chemical impurities as the corresponding racemic acids present in several commercially available racemic amino acid methyl esters were observed to be 0.49–17.50%. Enantiomeric impurities of several commercially available L-amino acid methyl esters were found to be 0.03–0.58%, whereas chemical impurities as the corresponding racemic acids present in the same analytes were found to be 0.13–13.62%. This developed analytical method will be useful for the determination of chemical and enantiomeric purity of α-amino acids and/or esters as N-FMOC derivatives using amylose-derived CSPs.
- Islam, Md. Fokhrul,Adhikari, Suraj,Paik, Man-Jeong,Lee, Wonjae
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p. 332 - 338
(2019/04/13)
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- Synthesis of A83586C analogs with potent anticancer and β-catenin/TCF4/osteopontin inhibitory effects and insights into how A83586C modulates E2Fs and pRb
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(Chemical Equation Presented) The synthesis of three potent new antitumor agents is described: the A83586C -citropeptin hybrid (1), the A83586C-GE3 hybrid (2), and L-Pro-A83586C (3). Significantly, compounds 1 and 2 function as highly potent inhibitors of β-catenin/TCF4 signaling within cancer cells, while simultaneously downregulating osteopontin (Opn) expression. A83586C antitumor cyclodepsipeptides also inhibit E2F-mediated transcription by downregulating E2F1 expression and inducing dephosphorylation of the oncogenic hyperphosphorylated retinoblastoma protein (pRb).
- Hale, Karl J.,Manaviazar, Soraya,Lazarides, Linos,George, Jonathan,Walters, Marcus A.,Cai, Jiaqiang,Delisser, Vern M.,Bhatia, Gurpreet S.,Peak, S. Andrew,Dalby, Stephen M.,Lefranc, Amandine,Chen, Ying-Nan P.,Wood, Alexander W.,Crowe, Paul,Erwin, Pauline,El-Tanani, Mohamed
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supporting information; experimental part
p. 737 - 740
(2009/09/27)
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- CYCLIC DEPSIPEPTIDES AND DRUGS CONTAINING THE SAME AS THE ACTIVE INGREDIENT
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Cyclic depsipeptides represented by the formula (1) (wherein: R is a straight or branched alkyl group of 5-20 carbon atoms or a straight or branched alkoxymethyl group of 5-15 carbon atoms; A, B, D, E and F independently each other are alanine, valine, leucine, isoleucine, phenylalanine, etc.; W and Z independently each other are aspartic acid, asparagine, glutamic acid or glutamine; and m and n independently each other is 0 or 1) or pharmacologically acceptable salts thereof. The present compounds are prepared according to a method conventionally used in peptide synthesis. The present compounds are useful as an agent for promoting the production of apolipoprotein E, a therapeutic agent for neurologic damages, a therapeutic agent for dementia, an agent for inhibiting the production of apolipoprotein B, an agent for promoting the production of apolipoprotein A1 or a therapeutic agent for hyperlipemia.
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- Highly practical methodology for the synthesis of D- and L-α-amino acids, N-protected α-amino acids, and N-methyl-α-amino acids
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Full details are provided for an exceedingly practical method to synthesize D- and L-α-amino acids, N-protected α-amino acids, and N-methyl-α-amino acids, employing as a key step the asymmetric alkylation of pseudoephedrine glycinamide (1) or pseudoephedrine sarcosinamide (2). Practical procedures for the synthesis of 1 and 2 from pseudoephedrine and glycine methyl ester or sarcosine methyl ester, respectively, are presented. Optimum protocols for the enolization and subsequent alkylation of 1 and 2 are described. Alkylation reactions of 1 and 2 are found to be quite efficient with a wide range of alkyl halide substrates, and the products are formed with high diastereoselectivity. The products of these alkylation reactions are hydrolyzed efficiently and with little to no racemization simply by heating in water or water-dioxane mixtures. This protocol provides an exceedingly practical method for the preparation of salt-free α-amino acids of high enantiomeric purity. Alternatively, the alkylation products may be hydrolyzed in high yield and with little to no racemization by heating with aqueous sodium hydroxide. The alkaline hydrolyzate can then be treated with an acylating reagent to provide directly highly enantiomerically enriched N-protected derivatives such as N-Boc and N-Fmoc. Key features necessary for the successful execution of these experimental procedures are identified.
- Myers, Andrew G.,Gleason, James L.,Yoon, Taeyoung,Kung, Daniel W.
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p. 656 - 673
(2007/10/03)
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