33014-68-5Relevant 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
Design, synthesis and primary activity assay of bi- or tri-peptide analogues with the scaffold l-arginine as amino-peptidase N/CD13 inhibitors
Mou, Jiajia,Fang, Hao,Liu, Yingzi,Shang, Luqing,Wang, Qiang,Zhang, Lei,Xu, Wenfang
scheme or table, p. 887 - 895 (2010/05/02)
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).
Fabrication of luminescent cds nanoparticles on short-peptide-based hydrogel nanofibers: Tuning of Optoelectronic Properties
Palui, Goutam,Nanda, Jayanta,Ray, Sudipta,Banerjee, Arindam
supporting information; experimental part, p. 6902 - 6909 (2010/03/02)
The pH-induced self-assembly of three synthetic tripeptides in water medium is used to immobilize luminescent CdS nanoparticles. These peptides form a nanofibrillar network structure upon gelation in aqueous medium at basic pH values (pH 11.013.0), and th
Design and synthesis of a novel class of furan-based molecules as potential 20S proteasome inhibitors
Fu, Yiqiu,Xu, Bo,Zou, Xiaomin,Ma, Chao,Yang, Xiaoming,Mou, Ke,Fu, Gang,Lue, Yang,Xu, Ping
, p. 1102 - 1106 (2007/10/03)
A novel class of furan-based compounds as potential 20S proteasome inhibitors have been designed and synthesized, among which nine compounds are peptide derivatives and six molecules are statine peptidomimetics. The C-terminal furanyl moiety was introduced to target molecules as furan-based amino acids. All the compounds were obtained steadily with moderate to high yield. Compound 12 was a selective moderate potent proteasome peptidomimetic inhibitor. It inhibited HepG2 and HL-60 proliferation effectively.
A novel and efficient method for cleavage of phenacylesters by magnesium reduction with acetic acid
Kokinaki, Stella,Leondiadis, Leondios,Ferderigos, Nikolas
, p. 1723 - 1724 (2007/10/03)
(Equation Presented) In the present study, we use magnesium turnings as a new deprotection reagent for the phenacyl group during orthogonal organic synthesis in the presence of other esters and sensitive protecting groups. By applying the new magnesium turnings/acetic acid deprotection method, phenacyl group can be more easily combined with other protecting groups that are not compatible with the zinc/acetic acid method.
Synthesis of small cyclic peptides constrained with 3-(3-aminomethylphenyl) propionic acid linkers using free radical-mediated macrocyclization
Balraju,Reddy, D. Srinivasa,Periasamy, Mariappan,Iqbal, Javed
, p. 5207 - 5210 (2007/10/03)
In this letter, we report that small peptides (di- and tri-) having a 3-bromobenzyl group at the C-termini and an acryloyl group at the N-termini undergo an efficient Bu3SnH-AIBN mediated intramolecular free radical cyclization to afford cyclic
β-Turn mimic in tripeptide with Phe(1)-Aib(2) as corner residues and β-strand structure in an isomeric tripeptide: An X-ray diffraction study
Dutt, Anita,Froehlich, Roland,Pramanik, Animesh
, p. 661 - 665 (2007/10/03)
A single crystal X-ray diffraction study of the tripeptide Boc-Phe-Aib-Leu-OMe (Aib = α-aminoisobutyric acid) reveals that it forms structurally one of the best type II β-turns so far reported in tripeptides, stabilized by 10 atom intramolecular hydrogen
Synthesis, characterization and biological evaluation of cyclic peptides: Viscumamide, yunnanin A and evolidine
Poojary, Boja,Belagali
, p. 1313 - 1320 (2008/02/08)
Three biologically active cyclic peptides, viscumamide, yunnanin A and evolidine were synthesized and the structures were established on the basis of analytical, IR, NMR and mass spectral data. These newly synthesized cyclic peptides were evaluated for an
Synthesis of a novel cis-proline-derived cyclic type VI β-turn mimic via ring-closing metathesis
Boruah, Anima,Rao, I. Nageshwar,Nandy, Jyoti Prokash,Kumar, S. Kiran,Kunwar,Iqbal, Javed
, p. 5006 - 5008 (2007/10/03)
A cis-proline derived cyclic mimic of a type VI β-turn is synthesized via a ring-closing metathesis reaction. The solution NMR conformational study indicates that the major conformer of the cyclic peptide adopts a type VIa β-turn in CDCl3 and a type VIb β-turn in DMSO-d6.
