Tellurium-based cysteine protease inhibitors: evaluation of novel organotellurium(IV) compounds as inhibitors of human cathepsin B |
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| Authors: | Cunha Rodrigo L O R Urano Miriam E Chagas Jair R Almeida Paulo C Bincoletto Cláudia Tersariol Ivarne L S Comasseto João V |
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| Affiliation: | 1. Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748 CEP 05508-900, São Paulo, SP, Brazil;2. Centro Interdisciplinar de Investigação Bioquímica, Universidade de Mogi das Cruzes, Prédio I, Centro de Ciências, Tecnológicas, sala 1S-15, Av. Dr. Cândido X. de Almeida Souza, 200, CEP 08780-911, Mogi das Cruzes, SP, Brazil;1. Department of Disease Control, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK;2. Parasitology Department, Indonesian Research Centre for Veterinary Science (Balai Besar Penelitian Veteriner), Bogor, Indonesia;3. Life Sciences Department, Natural History Museum, London SW7 5BD, UK;4. School of Forest Resources and Conservation, University of Florida, Gainesville, FL 32611, USA;1. School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, PR China;2. Department of Radiology, School of Medicine, University of Colorado Denver, Aurora, CO 80045, USA;3. College of Pharmacy, University of New Mexico, Albuquerque, NM 87131, USA;1. Department of Ophthalmology, Kagawa University Faculty of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan;2. Department of Neurobiology, Kagawa University Faculty of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan;3. Department of Pharmacology, Kagawa University Faculty of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan;4. Department of Ophthalmology, Okayama University Graduate School of Medicine, Density and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan |
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| Abstract: | 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. |
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