Leaving groups prolong the duration of 20S proteasome inhibition and enhance the potency of salinosporamides
| Autor: | Saskia Theodora Cornelia Neuteboom, Katherine A McArthur, Vito J Palombella, Michael Groll, Ta-Hsiang Chao, G Kenneth Lloyd, Janid A. Ali, Barbara Christine Potts, Rama Rao Manam, Venkat R Macherla, Michael A Palladino, Jeffrey Weiss |
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| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Proteasome Endopeptidase Complex Lactams chemistry.chemical_compound Lactones Structure-Activity Relationship Drug Discovery medicine Potency Structure–activity relationship Animals Pyrroles Enzyme Inhibitors Molecular Structure Chemistry Hydrolysis Leaving group Biological activity Stereoisomerism In vitro Rats Kinetics Protein Subunits Proteasome Mechanism of action Biochemistry Molecular Medicine medicine.symptom Salinosporamide A Proteasome Inhibitors |
| Zdroj: | Journal of medicinal chemistry. 51(21) |
| ISSN: | 1520-4804 |
| Popis: | Salinosporamide A ( 1 (NPI-0052)) is a potent, monochlorinated 20S proteasome inhibitor in clinical trials for the treatment of cancer. To elucidate the role of the chlorine leaving group (LG), we synthesized analogues with a range of LG potentials and determined their IC 50 values for inhibition of chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-like (C-L) activities of 20S proteasomes. Proteasome activity was also determined before and after attempted removal of the inhibitors by dialysis. Analogues bearing substituents with good LG potential exhibited the greatest potency and prolonged duration of proteasome inhibition, with no recovery after 24 h of dialysis. In contrast, activity was restored after |
| Databáze: | OpenAIRE |
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