Identification of 3-Acetyl-2-aminoquinolin-4-one as a Novel, Nonpeptidic Scaffold for Specific Calpain Inhibitory Activity

Abstract

A series of 3-acetyl-2-aminoquinolin-4-one derivatives selected from the Korean Chemical Bank were screened for calpain inhibitory activity by using a high-throughput fluorimetric calpain assay. We identified a potent and selective mu-calpain inhibitor, compound 17, whose specificity and efficacy for mu-calpain inhibition was better than MDL28170. Docking studies revealed that the efficacy of its inhibitory effect on calpain depended on the size and charge properties of the substitutions on the phenylamino ring.

Chalcones as Novel Non-peptidic μ-Calpain Inhibitors

“…MDL28170 (μ-calpain inhibitor), E64d (μ-calpain inhibitor), CA-074 (cathepsin B inhibitor), and Z-FF-FMK (cathepsin L inhibitor) were used as positive controls for each enzymes. 15 The results are listed in Table 1. Most compounds showed from weak to moderate μ-calpain inhibitory activities regardless of structural modification in the conventional chalcones.…”

“…The fluorimetric assay was performed in 96-well plates as described previously. 15 The substrate used was fluorescence-based probe and designed to possess the calpain-cleavage site in p35 which was [2-Abz]-Ser-Thr-Phe-Ala-Gln-Pro-[3-nitrotyrosine]-NH 2 named pep2. The specific cleavage in pep2 by μ-calpain occurs between phenylalanine and alanine.…”

“…Purification by silica gel column chromatography (eluent: EtOAc/n-hexane = 1:1 → 5:1) gave compound 12 (92.0 mg, 12.9%) as an orange solid. (E)-3-(4-Hydroxy-3-methoxyphenyl)-1-(thiophen-2-yl)-prop-2-en-1-one (15). A mixture of 2-acetylthiophene (0.29 g, 2.3 mmol), 3-methoxy-4-(tetrahydro-2H-pyran-2-yloxy)-benzaldehyde (0.54 g, 2.3 mmol) and 10%-NaOH (0.9 mL, 2.3 mmol) in ethanol (10 mL) was stirred (15 h (E)-1-(Furan-2-yl)-3-(4-hydroxy-2-methoxyphenyl)prop-2-en-1-one (16).…”

Calpains: Attractive Targets for the Development of Synthetic Inhibitors

“…(12)) have been identified by compound screening as potent inhibitors of calpain 1 (with IC 50 values in the high nanomolar range) with good (> 50-fold) and moderate (2.9-15-fold) selectivity over other cysteine proteases, such as cathepsins B and L, respectively. Kinetic studies suggest that (21) is not a competitive inhibitor [296], while modelling studies with (22) and I-II show that it does dock into the active site of calpain [297].…”

Fucoidan promotes mechanosensory hair cell regeneration following amino glycoside-induced cell death

“…chembank.org/) (Kang et al, 2009;Kim et al, 2005) and 10 purified natural compounds (fucoidan, Keumsa Linteusan, saponin, beta-glucan extract, polyhexosamine extract, chito-oligosaccharide extract, terpene extract, flavonoid extract, alkaloid ectract, and lignins) from Kyoungpook National University (Daegu, Korea).…”