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Discovery and kinetic evaluation of 6-substituted 4-benzylthio-1,3,5- triazin-2(1H)-ones as inhibitors of cathepsin B
Sosič, Izidor (Avtor), Mirković, Bojana (Avtor), Turk, Samo (Avtor), Štefane, Bogdan (Avtor), Kos, Janko (Avtor), Gobec, Stanislav (Avtor)

URLURL - Predstavitvena datoteka, za dostop obiščite http://www.sciencedirect.com/science/article/pii/S0223523411005770 Povezava se odpre v novem oknu

Izvleček
Cathepsin B is a lysosomal cysteine protease that has various physiological and pathophysiological functions. We present here the discovery of 6-substituted 4-benzylthio-1,3,5-triazin-2(1H)-ones as inhibitors of cathepsin B, starting from screening of a library of variously 2,4,6-trisubstituted 1,3,5-triazines and 1,3,5-triazin-2(1H)-ones on three different human cathepsins. The synthesis and enzymatic evaluation of a focused library of new 1,3,5-triazin-2(1H)-ones is also described. The detailed kinetics analyses have shown that these compounds can act as reversible, partial mixed-type inhibitors of cathepsin B, with Ki and Ki' values in the low micromolar range. The inhibitory activities of selected compounds were also assessed against two related cysteine proteases, cathepsinH and cathepsin L, to estimate their selectivity; these compounds have a selective profile for catB and catL over catH. Highlights A focused library of 6-substituted 4-benzylthio-1,3,5-triazin-2(1H)-ones was synthesized. The compounds inhibited cathepsin B in the low micromolar range. The detailed kinetics analyses showed that these compounds act as reversible, partial mixed-type inhibitors of cathepsin B. Molecular docking predicted binding in the S1' and S2' subsites of the enzyme.

Jezik:Angleški jezik
Ključne besede:katepsin B, cisteinske proteaze, nonkovalentni inhibitorji
Vrsta gradiva:Delo ni kategorizirano (r6)
Tipologija:1.01 - Izvirni znanstveni članek
Organizacija:FFA - Fakulteta za farmacijo
Leto izida:2011
Št. strani:str. 4648-4656
Številčenje:Vol. 46, iss. 9
UDK:542+615
ISSN pri članku:0223-5234
DOI:10.1016/j.ejmech.2011.08.005 Povezava se odpre v novem oknu
COBISS.SI-ID:3068017 Povezava se odpre v novem oknu
Število ogledov:456
Število prenosov:139
Metapodatki:XML RDF-CHPDL DC-XML DC-RDF
 
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Naslov:European journal of medicinal chemistry
Skrajšan naslov:Eur. j. med. chem.
Založnik:Elsevier
ISSN:0223-5234
COBISS.SI-ID:25429760 Povezava se odpre v novem oknu

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