- Electrochemical Dimethyl Sulfide-Mediated Esterification of Amino Acids
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Dimethyl sulfide-mediated electrochemical synthetic strategy for esterification of amino acids has been reported. A series of amino acids could react smoothly with alcohols, affording the desired esterification products with good efficiency. Importantly, the tolerance of peptides and gram-scale synthesis shed light on the utility of this protocol. Mechanistically, the dimethyl sulfide as a mediator plays an essential role in the transformation of amino acids.
- Li, Yongli,Wang, Huamin,Zhang, Heng,Lei, Aiwen
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supporting information
p. 3023 - 3028
(2021/08/30)
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- Structure-Based Design of Inhibitors Selective for Human Proteasome β2c or β2i Subunits
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Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the β1c, β1i, β5c, and β5i subunits exploit the differences in the substrate-binding channels identified by X-ray crystallography, compounds selectively targeting β2c or β2i could not yet be rationally designed because of the high structural similarity of these two subunits. Here, we report the development, chemical synthesis, and biological screening of a compound library that led to the identification of the β2c- and β2i-selective compounds LU-002c (4; IC50 β2c: 8 nM, IC50 β2i/β2c: 40-fold) and LU-002i (5; IC50 β2i: 220 nM, IC50 β2c/β2i: 45-fold), respectively. Co-crystal structures with β2 humanized yeast proteasomes visualize protein-ligand interactions crucial for subunit specificity. Altogether, organic syntheses, activity-based protein profiling, yeast mutagenesis, and structural biology allowed us to decipher significant differences of β2 substrate-binding channels and to complete the set of subunit-selective proteasome inhibitors.
- Xin, Bo-Tao,Huber, Eva M.,De Bruin, Gerjan,Heinemeyer, Wolfgang,Maurits, Elmer,Espinal, Christofer,Du, Yimeng,Janssens, Marissa,Weyburne, Emily S.,Kisselev, Alexei F.,Florea, Bogdan I.,Driessen, Christoph,Van Der Marel, Gijsbert A.,Groll, Michael,Overkleeft, Herman S.
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supporting information
p. 1626 - 1642
(2019/02/19)
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- COMBINATION OF A SELECTIVE HISTONE DEACETYLASE 3 (HDAC3) INHIBITOR AND AN IMMUNOTHERAPY AGENT FOR THE TREATMENT OF CANCER
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Aspects of the disclosure relate to compositions, kits, and methods for the treatment of cancer that utilize a selective histonc deacetylase 3 (HDAC3) inhibitor. In some aspects, the compositions, kits, and methods relate to use of a selective HDAC3 inhibitor in combination with an immunotherapy agent (e.g., an immune checkpoint inhibitor).
- -
-
Paragraph 0807; 0821; 0822
(2019/07/29)
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- Preparation and biological evaluation of soluble tetrapeptide epoxyketone proteasome inhibitors
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A series of novel tetrapeptidyl epoxyketone inhibitors of 20S proteasome was designed and synthesized. To fully understand the SAR, various groups at R1, R2, R3, R4 and R5 positions, including aromatic and aliphatic substituents were designed, synthesized and biologically assayed. Based on the enzymatic results, seven compounds were selected to evaluate their cellular activities and soluble compound 36 showed strong potency against human multiple myeloma (MM) cell lines. Microsomal stability results indicated that compound 36 was more stable in mice, rat and human microsomes than marketed carfilzomib. The in vivo activities of this compound were evaluated with the xenograft mice models of MM cell lines ARH77 and RPMI-8226 with luciferase expression and the T/C value of the two models were 49.5% and 37.6%, respectively. To evaluate the potential cardiovascular toxicity, inhibition of hERG ion channel in HEK293 cells by compound 36 and carfilzomib was carried out. The results indicated that 36 had no binding affinity for the hERG ion channel while carfilzomib could bind it with IC50 of 92.1 μM.
- Lei, Meng,Zhang, Haoyang,Miao, Hang,Du, Xiao,Zhou, Hui,Wang, Jia,Wang, Xueyuan,Feng, Huayun,Shi, Jingmiao,Liu, Zhaogang,Shen, Jian,Zhu, Yongqiang
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p. 4151 - 4162
(2019/08/07)
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- Novel l-prolyl-l-leucylglycinamide (PLG) tripeptidomimetics based on a 2-azanorbornane scaffold as positive allosteric modulators of the D2R
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An efficient and straightforward orthogonal methodology was successfully developed to achieve constrained l-prolyl-l-leucylglycinamide (PLG) analogues starting from two proline mimetics based on a 2-azanorbornane scaffold. A preliminary dopamine D2 receptor radiolabeled binding assay with [3H]-N-propylnorapomorphine shows that enantiopurity of PLG peptidomimetics based on 2-azanorbornane is a requirement to achieve statistically significant positive modulators of the D2 receptor. This is the first documented active peptidomimetic of PLG whose bioactivity is not correlated with the C-terminal carboxamide pharmacophore and which cannot adopt the hypothesized type II β-turn conformation.
- Sampaio-Dias, Ivo E.,Sousa, Carlos A. D.,García-Mera, Xerardo,Ferreira Da Costa, Joana,Caama?o, Olga,Rodríguez-Borges, José E.
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supporting information
p. 11065 - 11069
(2016/12/09)
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- Design and Synthesis of Simplified Largazole Analogues as Isoform-Selective Human Lysine Deacetylase Inhibitors
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Selective inhibition of KDAC isoforms while maintaining potency remains a challenge. Using the largazole macrocyclic depsipeptide structure as a starting point for developing new KDACIs with increased selectivity, a combination of four different simplified largazole analogue (SLA) scaffolds with diverse zinc-binding groups (for a total of 60 compounds) were designed, synthesized, and evaluated against class I KDACs 1, 3, and 8, and class II KDAC6. Experimental evidence as well as molecular docking poses converged to establish the cyclic tetrapeptides (CTPs) as the primary determinant of both potency and selectivity by influencing the correct alignment of the zinc-binding group in the KDAC active site, providing a further basis for developing new KDACIs of higher isoform selectivity and potency.
- Reddy, Damodara N.,Ballante, Flavio,Chuang, Timothy,Pirolli, Adele,Marrocco, Biagina,Marshall, Garland R.
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supporting information
p. 1613 - 1633
(2016/03/05)
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- ISOFORM-SELECTIVE LYSINE DEACETYLASE INHIBITORS
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Isoform-selective lysine deacetylase inhibitors are described. Inhibitors of the lysine deacetylase enzyme are useful as antitumor drugs and for treating addiction, asthma, cardio-vascular disease, immunosuppression, neurodegenerative diseases, sepsis, sickle-cell disease, uveal melanoma and termination of viral latency, particularly HIV-1 latency.
- -
-
Paragraph 0091; 0121-0123
(2016/11/21)
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- First Total Synthesis and Biological Potential of a Heptacyclopeptide of Plant Origin
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Synthesis of a natural glycine-rich heptacyclopeptide - mahafacyclin A (7) was accomplished by solution-phase technique of peptide synthesis via coupling of tetrapeptide unit Boc-L-Thr-L-Ile-L-Leu-Gly-OH with tripeptide unit L-Val-L-Phe-Gly-OMe followed b
- Dahiya, Rajiv,Singh, Sunil
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p. 1158 - 1164
(2016/11/25)
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- Inhibitors of histone deacetylase
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The present invention relates to compounds of formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein U, J, V, X, R2a, R2b, R2c, R5 and t are as described herein. The present invention relates generally to inhibitors of histone deacetylase and to methods of making and using them. These compounds are useful for promoting cognitive function and enhancing learning and memory formation. In addition, these compounds are useful for treating, alleviating, and/or preventing various conditions, including for example, neurological disorders, memory and cognitive function disorders/impairments, extinction learning disorders, fungal diseases and infections, inflammatory diseases, hematological diseases, and neoplastic diseases in humans and animals.
- -
-
Page/Page column 245; 246; 247
(2016/09/26)
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- AGRICULTURAL PLANT-PROTECTING AGENTS CONTAINING DIPEPTIDE DERIVATIVE AS ACTIVE INGREDIENT
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Provided is an agricultural plant-protecting agent including a dipeptide derivative or an agro-pharmaceutically acceptable salt thereof as an active ingredient, which has a plant disease-preventing effect, a plant growth-promoting effect, and a plant immunity-activating effect.
- -
-
Paragraph 0118; 0119
(2015/05/05)
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- Design, synthesis and preliminary evaluation of α-sulfonyl γ-(glycinyl-amino)proline peptidomimetics as matrix metalloproteinase inhibitors
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A series of novel α-sulfonyl γ-(glycinyl-amino)proline peptidomimetic derivatives were designed, synthesized and assayed for their activities against matrix metalloproteinase-2 (MMP-2), aminopeptidase N (APN)/CD13 and HDACs. The results indicated that all the compounds exhibited highly selective inhibition against MMP-2 as compared with APN and HDACs. The antiproliferative activities of some compounds against SKOV3, HL60 and A549 cells were also investigated. Comparing with the control LY52, compound 12u, with excellent activity both in the enzymatic inhibition assay and cell-based assay, could be used as lead compound for the further development of MMP inhibitors.
- Zhang, Jian,Li, Xiaoyang,Jiang, Yuqi,Feng, Jinhong,Li, Xiaoguang,Zhang, Yingjie,Xu, Wenfang
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p. 3055 - 3064
(2014/05/20)
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- INHIBITORS OF HISTONE DEACETYLASE
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The present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein X1, X2, X3, X4, X5, W1, W2, W3, and W4 are as described. The present invention relates generally to inhibitors of histone deacetylase and to methods of making and using them. In one aspect, the invention relates to selective HDAC3 inhibitors useful for protecting β-cells and improving insulin resistence. The selective HDAC3 inhibitors are also useful for promoting cognitive function and enhancing learning and memory formation. Compounds of the invention are useful for treating, alleviating, and/or preventing various conditions, including for example, a metabolic disorder such as type 1 or type 2 diabetes, dyslipidemias, lipodystrophies, liver disease associated with metabolic syndrome, polycystic ovarian syndrome, or obesity; inflammatory disease; neurological disorder; a memory or cognitive function disorder/impairment; an extinction learning disorder; fungal disease or infection; viral disease or infection such as HIV; hematological disease; liver disease; lysosomal storage disease; or neoplastic disease in humans or animals.
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-
Page/Page column 98-99
(2014/02/16)
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- Revisiting oxytocin through the medium of isonitriles
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The reaction of thioamino acids and N-terminal peptides, mediated by hindered isonitriles and hydroxybenzotriazole, gives rise to peptide bonds. In one pathway, oxytocin was synthesized by eight such reiterative amidations. In another stereospecific track, oxytocin was constructed by native chemical ligation, wherein the two building blocks were assembled by thioacid amine amidation. The NMR spectra of oxytocin and dihydrooxytocin suggest a high level of preorganization in the latter, perhaps favoring oxidative folding.
- Wang, Ting,Danishefsky, Samuel J.
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supporting information; experimental part
p. 13244 - 13247
(2012/09/25)
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- Design, synthesis and primary activity assay of bi- or tri-peptide analogues with the scaffold l-arginine as amino-peptidase N/CD13 inhibitors
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A series of bi- or tri-peptide analogues with the scaffold l-arginine were designed, synthesized and evaluated for their inhibitory activities against amino-peptidase N (APN) and metalloproteinase-2 (MMP-2). The primary activity assay showed that all the compounds exhibited higher inhibitory activities against APN than MMP-2. Within this series, compounds C6 and C7 (IC50 = 4.2 and 4.3 μM) showed comparable APN inhibitory activities with the positive control bestatin (IC50 = 3.8 μM).
- Mou, Jiajia,Fang, Hao,Liu, Yingzi,Shang, Luqing,Wang, Qiang,Zhang, Lei,Xu, Wenfang
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experimental part
p. 887 - 895
(2010/05/02)
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- Synthetic studies on novel benzimidazolopeptides with antimicrobial, cytotoxic and anthelmintic potential
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Four substituted benzimidazolyl-benzoic/salicylic acids 5-8 were synthesized by interaction of 5,6-dimethyl-/6-nitrobenzimidazoles with diazotized substituted/unsubstituted aminobenzoic acids in the presence of cupric chloride. The coupling of compounds 5-8 with different amino acid ester hydrochlorides/dipeptide/tripeptide/tetrapeptide methyl esters afforded novel benzimidazolopeptide derivatives 5a-f, 6a-h, 7a-g and 8a-g. The structures of all newly synthesized compounds were established on the basis of analytical, IR, 1H NMR, 13C NMR and mass spectral data. Selected peptide ester derivatives were further hydrolyzed by using lithium hydroxide (LiOH) to yield corresponding acid derivatives 5ba-da, 6ea-ga, 7ca-ea and 8ea-ga. All peptide derivatives were screened for their antimicrobial, anthelmintic and cytotoxic activities. Almost all newly synthesized benzimidazolopeptides have shown moderate to good anthelmintic activity against all three earthworm species and good antimicrobial activity against pathogenic fungal strains Candida albicans and Aspergillus niger, gram negative bacterial strains Pseudomonas aeruginosa and Escherichia coli. Compounds 8g and 8ga possessed significant cytotoxic activity against Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC) cell lines.
- Dahiya, Rajiv,Pathak, Devender
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p. 772 - 798
(2008/02/13)
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- Noncovalent inhibitors of human leukocyte elastase based on the 4-imidazolidinone scaffold
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A central problem associated with the design of enzyme inhibitors in general, and serine protease inhibitors in particular, is the identification of templates capable of binding to the active site of an enzyme in a predictable and substrate-like fashion, orienting appended recognition elements in a correct spatial relationship so that favorable binding interactions with multiple sites are achieved. Described herein for the first time is the design of noncovalent inhibitors of human leukocyte elastase that employs a functionalized 4-imidazolidinone scaffold.
- Wei, Liuqing,Gan, Xiangdong,Zhong, Jiaying,Alliston, Kevin R.,Groutas, William C.
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p. 5149 - 5153
(2007/10/03)
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- A convenient strategy of dimerization by microwave heating and using 2,5-diketopiperazine as scaffold
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A novel and convenient microwave-assisted dimerization of an active peptide compound using the DKPs as scaffold is described. The key reaction giving rise to the diketopiperazine scaffold is the intermolecular coupling. No epimerization was detected in the reactions used. Conventional and microwave heating of the reactions are compared. Synthesis by microwave irradiation gave the desired compounds in higher yields and in shorter reaction times than those obtained by conventional heating.
- Santagada, Vincenzo,Fiorino, Ferdinando,Perissutti, Elisa,Severino, Beatrice,Terracciano, Sara,Cirino, Giuseppe,Caliendo, Giuseppe
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p. 1145 - 1148
(2007/10/03)
-
- Synthesis and evaluation of anti-inflammatory activity of 2-(4- isobutylphenyl)propionyl derivatives of amino acids and peptides
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A series of new 2-(4-isobutylphenyl)propionyl amino acids and peptide methyl esters have been synthesized by coupling ibuprofen with amino acid methyl esters and di- and tetra-peptide methyl esters. The structures of these compounds have been confirmed by elemental and spectral analyses. The anti-inflammatory activity of these compounds is also studied.
- Belagali,Himaja
-
p. 505 - 507
(2007/10/03)
-
- Partially modified retro-inverso pseudopeptides as non-natural ligands for the human class I histocompatibility molecule HLA-A2
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Syntheses of a series of partially modified retro-inverso analogues of the antigenic peptide M58-66 derived from the influenza virus matrix protein are reported. The retro-inverso modification Ψ(NH-CO) was obtained by replacement of two successive amino acid residues with a 2-substituted malonate derivative and gem-diaminoalkyl residue. The resulting compounds 1- 8 were tested for their binding to the human histocompatibility class I molecule HLA-A2 in an assembly assay using lysates of peptide transporter- deficient cells T2. Specific peptide-dependent HLA-A2 assembly was revealed by an enzyme-linked immunosorbent assay. Significant HLA-A2 assembly was detected in the presence of analogues [gGly58-(S)mLeu59]-M58-66 (1a), [gGly61-(R,S)mPhe62]M58-66 (4), [gVal63-(R,S)mPhe64]M58-66 (6), and [gPhe64(R,S)mAla65]M58-66 (7). The introduction of the retro-inverso modification between P2-P3, P3-P4, P5-P6, and P8-P9 (compounds 2, 3, 5, and 8, respectively) however led to a dramatic reduction in peptide binding to HLA-A2. Interestingly, compound 1a which contains modification between P1-P2 was found to be the most potent analogue, being able to retain the original HLA-A2 binding profile of the parent peptide M58-66. Taken together, these results and recent binding data obtained in the context of murine MHC class I molecule H-2K(d) suggest that the incorporation of peptide bond surrogates in MHC class I-restricted epitopes is a useful approach to design molecules having both increased stability and high MHC-binding capacity. Depending on their agonist or antagonist effects at the T-cell receptor, such non-natural MHC ligands are likely to find many applications in the development of peptide-based vaccines or as potential therapeutic agents in the treatment of allergies and autoimmune diseases.
- Guichard, Gilles,Connan, Francine,Graff, Roland,Ostankovitch, Marina,Muller, Sylviane,Guillet, Jean-Gérard,Chopping, Jeannine,Briand, Jean-Paul
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p. 2030 - 2039
(2007/10/03)
-
- N-tert-Butylglyoxylicamide, the New Reagent for Peptide Segment Coupling by Four-Component Reaction
-
In contrast to the use of other aldehyd components, the Tetra Component Reactions (4CR) of carboxyl acids and primary amines with combinations of N-tert-butylglyoxylicamide and isocyanides produce carbonamides that yield the desired stereochemically unifo
- Koenig, Stephan,Kloesel, Roland,Karl, Rosi,Ugi, Ivar
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p. 1586 - 1596
(2007/10/02)
-
- N,N'-Bis-morpholinophosphinic chloride as a coupling reagent in peptide synthesis
-
N,N'-bis-morpholinophosphinic chloride (BMP-Cl) has been successfully used as a coupling reagent for first time in the peptide synthesis.Few peptides have been prepared using this coupling reagent and the results have been compared with those obtained by anhydride method.
- Panse, G. T.,Kamat, S. K.
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p. 793 - 795
(2007/10/02)
-
- Synthese a grande echelle de la somatocrinine humaine
-
We have developped a new large-scale synthesis of hGRF-NH2 a very promising peptide characterized by the following features: - Liquid phase stepwise synthesis of the subfragments , , , , , , , , 3
- Diaz, Joseph,Guegan, Remy,Muneaux, Yvette,Perreaut, Pierre,Vedel, Michel,et al.
-
p. 493 - 510
(2007/10/02)
-
- Reactivity of Aromatic o-Hydroxy Oximes. II. The Use of Esters of Aromatic o-Hydroxy Oximes in Peptide Synthesis
-
Esters of N-protected amino acids with o-hydroxybenzaldehyde oxime, o-hydroxyacetophenone oxime, o-hydroxybenzophenone oxime, and their 5-Cl and 5-NO2 derivatives were prepared by several methods.Various dipeptide derivatives with high purity were obtaine
- Hayashi, Ikuo,Shimizu, Kiyoshi
-
p. 3197 - 3198
(2007/10/02)
-
- 3-O--HYDROXY-2-PHENYLINDENONES, PREPARATION AND USE IN THE SYNTHESIS OF PEPTIDES
-
Several 3-O--hydroxy-2-phenylindenones were obtained and used in the synthesis of peptides.Synthesis of Leu-enkephalin was carried out.
- Mincev, Stoyan,Derdowska, Izabela,Kupryszewski, Gotfryd
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p. 443 - 452
(2007/10/02)
-
- Amino Acids and Peptides. XXX. Phosphorus in Organic Synthesis. XVII. Application of Diphenyl Phosphorazidate (DPPA) and Diethyl Phosphorocyanidate (DEPC) to Solid-phase Peptide Synthesis
-
Two coupling reagents for peptide synthesis, diphenyl phosphorazidate (DPPA) and diethyl phosphorocyanidate (DEPC), were tested using the solid-phase method.The reactivities of DPPA and DEPC were examined by coupling Boc-Ile with Gly-resin.In a comparison
- Ikota, Nobuo,Shioiri, Takayuki,Yamada, Shun-Ichi
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p. 3064 - 3069
(2007/10/02)
-