73994-87-3Relevant articles and documents
New cysteine protease inhibitors: Electrophilic (Het)arenes and unexpected prodrug identification for the trypanosoma protease rhodesain
Barthels, Fabian,Distler, Ute,Engels, Bernd,Hellmich, Ute A.,Johe, Patrick,Jung, Sascha,Kühlborn, Jonas,Klein, Philipp,Opatz, Till,Schirmeister, Tanja,Tenzer, Stefan,Wagner, Annika,Waigel, Waldemar
, (2020/03/27)
Electrophilic (het)arenes can undergo reactions with nucleophiles yielding π- or Meisenheimer (σ-) complexes or the products of the SNAr addition/elimination reactions. Such building blocks have only rarely been employed for the design of enzyme inhibitors. Herein, we demonstrate the combination of a peptidic recognition sequence with such electrophilic (het)arenes to generate highly active inhibitors of disease-relevant proteases. We further elucidate an unexpected mode of action for the trypanosomal protease rhodesain using NMR spectroscopy and mass spectrometry, enzyme kinetics and various types of simulations. After hydrolysis of an ester function in the recognition sequence of a weakly active prodrug inhibitor, the liberated carboxylic acid represents a highly potent inhibitor of rhodesain (Ki = 4.0 nM). The simulations indicate that, after the cleavage of the ester, the carboxylic acid leaves the active site and re-binds to the enzyme in an orientation that allows the formation of a very stable π-complex between the catalytic dyad (Cys-25/His-162) of rhodesain and the electrophilic aromatic moiety. The reversible inhibition mode results because the SNAr reaction, which is found in an alkaline solvent containing a low molecular weight thiol, is hindered within the enzyme due to the presence of the positively charged imidazolium ring of His-162. Comparisons between measured and calculated NMR shifts support this interpretation.
Naphthoquinones as covalent reversible inhibitors of cysteine proteases—studies on inhibition mechanism and kinetics
Barthels, Fabian,Distler, Ute,Engel, Volker,Engels, Bernd,Hellmich, Ute A.,Johe, Patrick,Klein, Philipp,Le, Thien Anh,Opatz, Till,Schirmeister, Tanja,Schmid, Paul,Tenzer, Stefan,Wagner, Annika
, (2020/05/16)
The facile synthesis and detailed investigation of a class of highly potent protease inhibitors based on 1,4‐naphthoquinones with a dipeptidic recognition motif (HN‐L‐Phe‐L‐Leu‐OR) in the 2‐position and an electron‐withdrawing group (EWG) in the 3‐positio
Environmentally benign peptide synthesis using liquid-assisted ball-milling: Application to the synthesis of Leu-enkephalin
Bonnamour, Julien,Metro, Thomas-Xavier,Martinez, Jean,Lamaty, Frederic
, p. 1116 - 1120 (2013/06/05)
This paper describes an original methodology for peptide bond synthesis avoiding toxic solvents and reactants. Ball-milling stoichiometric amounts of Boc-protected α-amino acid N-carboxyanhydrides (Boc-AA-NCA) or Boc-protected α-amino acid N-hydroxysuccin
Synthesis of a novel series of L-isoserine derivatives as aminopeptidase N inhibitors
Yang, Kanghui,Fen, Jinghong,Fang, Hao,Zhang, Lei,Gong, Jianzhi,Xu, Wenfang
, p. 302 - 310 (2012/07/02)
A series of novel L-isoserine derivatives were synthesised and evaluated for their ability to inhibit aminopeptidase N (APN)/CD13. In our preliminary biological results, some of these compounds possessed a potent inhibitory activity against the APN. Within this series, compound 14b not only showed similar enzyme inhibition (IC50 of 12.2μM) compared with the positive control bestatin (half maximal inhibitory concentration (IC 50) of 7.3μM), but also had a potent antiproliferative activity against human cancer cell lines cells.
Bitter Taste of H-Val-Val-Val-Pro-Pro-Phe-Leu-OH Corresponding to the Partial Sequence (Positions 82-88) of Bovine β-Casein, and Related Peptides
Shinoda, Ichizo,Okai, Hideo,Fukui, Sakuzo
, p. 1255 - 1260 (2007/10/02)
A heptapeptide, H-Val-Val-Val-Pro-Pro-Phe-Leu-OH, corresponding to the partial sequence of bovine β-casein, positions 82-88, was synthesized and its bitter taste was measured.Its threshold value of bitterness was 0.14 mM.We previously reported that H-Arg-
Synthesis and biological evaluation of phosphonamidate peptide inhibitors of enkephalinase and angiotensin-converting enzyme
Elliott,Marks,Berg,Portoghese
, p. 1208 - 1216 (2007/10/02)
The effectiveness of phosphonamidate peptide analogues as inhibitors of rat kidney or human brain metallo-endopeptidase (enkephalinase, E.C. 3.4.24.11) and angiotensin-converting enzyme (ACE, 3.4.15.1) has been explored with a series of enkephalin analogu
Studies on Amino Acids and Peptides. Part 6. Methods for Introducing Thioamide Bonds into the Peptide Backbone: Synthesis of the Four Monothio Analogues of Leucine Enkephalin
Clausen, Kim,Thorsen, Michael,Lawesson, Sven-Olov,Spatola, Arno F.
, p. 785 - 798 (2007/10/02)
A methodology for preparing peptide analogues in which a thioamide bond replaces the normal amide bond is described.Thus, the synthesis of the three leucine enkephalin analogues 4>-, 2>-, and 1>-leucine enke
PEPTIDE SYNTHESIS BY USING PHENYLPHOSPHONIC ESTER AS A COUPLING REAGENT
Watanabe, Yutaka,Morito, Naoya,Kamekawa, Ken-ichi,Mukaiyama, Teruaki
, p. 65 - 68 (2007/10/02)
Synthesis of peptides containing various functions was efficiently accomplished by treatment of the tetrabutylammonium salts of N-protected amino acids (or peptides) with amino acid esters in the presence of bis(o- or p-nitrophenyl) phenylphosphonate.Synthesis of leucine-enkephalin was successfully achieved by the above method employing a (3+2) or (4+1) fragment coupling approach.
Novel Analogues of Enkephalin: Identification of Functional Groups Required for Biological Activity
Gorin, Fredric A.,Balasubramanian, T. M.,Cicero, Theodore J.,Schwietzer, John,Marshall, Garland R.
, p. 1113 - 1122 (2007/10/02)
Novel tri- and tetrapeptide analogues of enkephalin, in conjunction with earlier structure-activity data, confirm that chemical substituents present in the first and fourth residues of enkephalin are required for in vitro biological activity.A class of ar
