- Design, synthesis and biological evaluation of dipeptides as novel non-covalent 20S proteasome inhibitors
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Based on the interaction modes of the natural 20S proteasome inhibitors TMC-95A, we have previously discovered a dipeptide 1. To explore the SAR around compound 1, we designed and synthesized a series of dipeptides (8–38) with a fragment-based strategy. Among them, nine compounds showed significant inhibitory activities against the chymotrypsin-like activity of human 20S proteasome with IC50 values at the submicromolar level, which were comparable or even superior to the parent compound 1. Meanwhile, they displayed no significant inhibition against trypsin-like and caspase-like activities of 20S proteasome. The results suggested the feasibility to design dipeptides as novel and potent 20S proteasome inhibitors. (Figure presented.).
- Yang, Ya-Jun,Wang, Ke,Yang, Ying,Lai, Fang-Fang,Chen, Xiao-Guang,Xiao, Zhi-Yan
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p. 436 - 451
(2021/04/22)
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- TRANSGLUTAMINASE 2 (TG2) INHIBITORS
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Described herein are compounds and pharmaceutical compositions containing such compounds which inhibit transglutaminase 2 (TG2). Also described herein are methods for using such TG2 inhibitors, alone or in combination with other compounds, for treating diseases or conditions that would benefit from TG2 inhibition.
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- 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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p. 962 - 977
(2018/09/04)
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- Total synthesis and absolute stereochemistry of the proteasome inhibitors cystargolides A and B
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The absolute stereochemistry of the cystargolides was determined by total synthesis. Evaluation of synthetic cystargolides and derivatives showed that the natural (2S,3R) stereochemistry is essential for activity. Moreover, benzyl esters (-)-10 and (-)-15
- Tello-Aburto, Rodolfo,Hallada, Liam P.,Niroula, Doleshwar,Rogelj, Snezna
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supporting information
p. 10127 - 10130
(2015/10/28)
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- Development of supramolecular organo-gel based on tripeptide skeletons
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Boc-Ser-Val-Gly-OCH2Ph (31) showed high gelation abilities in the aromatic solvents, particularly in toluene. The minimum gelation concentration of 31 in toluene was 10 mg/ml, suggesting that 2500 molecules of toluene were immobilized by each m
- Azuma, Eriko,Kuramochi, Kouji,Tsubaki, Kazunori
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body text
p. 680 - 684
(2010/07/15)
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- A mild Boc deprotection and the importance of a free carboxylate
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We report a facile and rapid removal of Boc protecting groups using microwave heating in H2O, with deprotection only requiring a free carboxylic acid group in the starting material. Unlike previous approaches, no additional reagents are required.
- Thaqi, Ali,McCluskey, Adam,Scott, Janet L.
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supporting information; experimental part
p. 6962 - 6964
(2009/04/07)
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- Self-assembled monolayer of a pepstatin fragment as a sensing element for aspartyl proteases
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A novel disulfide, which carried two pepstatin fragments at both ends, was prepared by the coupling of 11,11′-dithiobisundecanoic acid (DTUA) with a fragment (Val-Val-Sta) carrying a n-hexyl end (Pepsta(h)). The compound obtained (DTUA-Pepsta(h)) formed a
- Kitano, Hiromi,Makino, Yoshinobu,Kawasaki, Hideaki,Sumi, Yusuke
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p. 1588 - 1595
(2008/02/04)
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- Simplified pepstatins: Synthesis and evaluation of N-terminally modified analogues
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The promising strategy of gastric ulcer healing with perorally administered epidermal growth factor (EGF) is so far strongly limited by the pepsinic degradation of this therapeutic polypeptide in the stomach. The incorporation of EGF in a bioadhesive polymer-pepsin inhibitor conjugate used as drug carrier matrix, however, might provide sufficient protection toward pepsinic degradation. The synthesis of appropriate pepsin inhibitors represents a prerequisite for the development of such polymer-inhibitor conjugates. The presented study demonstrates that modifications at the N- terminus of simplified analogues of pepstatin which can be synthesized in a simple and straight way result only in slight variations of the inhibitory activity. These analogues display only 10-fold reduced inhibitory activity, compared to pepstatin A, when bearing a greater N-terminal group like isovaleryl, Boc, or Cbz. Compounds which are substituted at the N-terminus by a shorter N-acyl group like propionyl or cyclopropylcarbonyl show further reduced activity (0.01, compared to pepstatin A). The presence of an amide or a urethane moiety at the N-terminus has no considerable effect on enzyme inhibition. Therefore, the N-terminus of these analogues is able to be modified forming a covalent bond to various bioadhesive polymers via a suitable functionality.
- Kratzel, Martin,Schlichtner, Birgit,Kirchmayer, Roland,Bernkop-Schnürch, Andreas
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p. 2041 - 2045
(2007/10/03)
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- Amino acids and peptides. XVII. Synthesis of peptides related to N-terminal portion of fibrin alpha-chain and their inhibitory effect on fibrinogen/thrombin clotting.
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Various peptides related to N-terminal portion of fibrin alpha-chain were synthesized by the solution method and the solid-phase method, and their inhibitory effect on fibrinogen/thrombin clotting was examined. Extension of peptide chain from N-terminal t
- Kawasaki,Tsuji,Hirase,Miyano,Inouye,Iwamoto
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p. 525 - 528
(2007/10/02)
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- Oxygen alkylation of Schiff base derivatives of amino acids
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Higher imine esters 1a-h and 7a-b of amino acids and dipeptides are prepared in 68-91% yield by saponification of the benzophenone Schiff base methyl esters 3a-d and 6 using phase-transfer techniques followed by O-alkylation with an alkyl halide. The procedure occurs with retention of configuration at the α-carbon except with phenylglycine derivatives.
- O'Donnell,Cook,Rusterholz
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p. 989 - 993
(2007/10/02)
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- Variation in Bitterness Potency When Introducing Gly-Gly Residue into Bitter Peptides
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We previously reported that Gly-Gly-Arg-Pro and Arg-Pro-Gly-Gly, the derivatives of a bitter peptide Arg-Pro, had no bitterness although Gly-Arg-Pro and Arg-Pro-Gly had a bitter taste at the same level as that of Arg-Pro.To elucidate the mechanism of elimination of bitterness by the introduction of the Gly-Gly residues, we synthesized Gly-Gly derivatives of other bitter peptides such as Phe-Phe, Val-Val-Val, Arg-Pro-Phe-Phe, and examined the effectiveness of Gly-Gly residues in eliminating bitterness.We suggest that, for Arg-Pro and Val-Val-Val, the Gly-Gly residue might prevent a hydrophobic group from binding to a taste receptor.
- Shinoda, Ichizo,Nosho, Yasuharu,Kouge, Katsushige,Ishibashi, Norio,Okai, Hideo,et al.
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p. 2103 - 2110
(2007/10/02)
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