Rational design of apoptosis signal-regulating kinase 1 inhibitors: discovering novel structural scaffold.

Autor: Volynets GP; Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo Str., 03143 Kyiv, Ukraine., Bdzhola VG, Golub AG, Synyugin AR, Chekanov MA, Kukharenko OP, Yarmoluk SM
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2013 Mar; Vol. 61, pp. 104-15. Date of Electronic Publication: 2012 Sep 21.
DOI: 10.1016/j.ejmech.2012.09.022
Abstrakt: Increased activity of apoptosis signal-regulating kinase 1 (ASK1) is associated with a number of human disorders and the inhibitors of ASK1 may become important compounds for pharmaceutical application. Here we report novel ASK1 inhibitor scaffold, namely 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one, that has been identified using virtual screening and biochemical tests. A series of derivatives has been synthesized and evaluated in vitro towards human protein kinase ASK1. It was revealed that the most active compounds 4-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)butanoic acid and 6-((5Z)-5-{[5-(4-bromophenyl)-2-furyl]methylene}-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)hexanoic acid inhibit ASK1 with IC50 of 0.2 μM. Structure-activity relationships of 33 derivatives of 5-(5-Phenyl-furan-2-ylmethylene)-2-thioxo-thiazolidin-4-one have been studied and binding mode of this chemical class has been predicted.
(Copyright © 2012 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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