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
supporting information, (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.
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).
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.
