Tellurium-based cysteine protease inhibitors: evaluation of novel organotellurium(IV) compounds as inhibitors of human cathepsin B

• Published in: Bioorganic & medicinal chemistry letters 2005-02, Vol.15 (3), p.755-760
• Main Authors: Cunha, Rodrigo L.O.R., Urano, Miriam E., Chagas, Jair R., Almeida, Paulo C., Bincoletto, Cláudia, Tersariol, Ivarne L.S., Comasseto, João V.
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Biological and medical sciences; Cathepsin B; Cathepsin B - antagonists & inhibitors; Cell Survival - drug effects; Cysteine protease inhibitor; Cysteine Proteinase Inhibitors - chemical synthesis; General aspects; HL-60 Cells; Humans; Kinetics; Medical sciences; Organometallic Compounds - chemical synthesis; Organometallic Compounds - pharmacology; Organotellurium; Pharmacology. Drug treatments; Structure-Activity Relationship; Tellurium; Tellurium(IV) compounds
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.11.012

The inhibition of Cathepsin B by a sort of different classes of organotellurium(IV) compounds was described. New organotellurium(IV) compounds with specific cysteine protease inhibitory activity were synthesized. Serine and aspartic protease activity were not affected by any of these compounds. All Te(IV) compounds tested exhibited high specific second-order constant for cathepsin B inactivation. Tellurium(IV) compound 6 was the best inhibitor of the series, showing a second-order constant of 36,000 M −1 s −1. This value is about 100-fold higher than the second-order rate for cysteine protease inactivation shown by the historic Te(IV) compound AS 101 ( 1). The inhibition was irreversible and time and concentration dependent; no saturation kinetics were observed, suggesting a direct bimolecular reaction. The results described in this paper show that the new organotellurium(IV) compounds are powerful inhibitors of cathepsin B, constituting promising potential anti-metastatic agents.