Synthesis and biological evaluation of naphthoquinone analogs as a novel class of proteasome inhibitors.

Abstract

Screening of the NCI Diversity Set-1 identified PI-083 (NSC-45382) a proteasome inhibitor selective for cancer over normal cells. Focused libraries of novel compounds based on PI-083 chloronaphthoquinone and sulfonamide moieties were synthesized to gain a better understanding of the structure-activity relationship responsible for chymotrypsin-like proteasome inhibitory activity. This led to the demonstration that the chloronaphthoquinone and the sulfonamide moieties are critical for inhibitory activity. The pyridyl group in PI-083 can be replaced with other heterocyclic groups without significant loss of activity. Molecular modeling studies were also performed to explore the detailed interactions of PI-083 and its derivatives with the beta5 and beta6 subunits of the 20S proteasome. The refined model showed an H-bond interaction between the Asp-114 and the sulfonamide moiety of the PI-083 in the beta6 subunit.

• Authors: Harshani R Lawrence, Aslamuzzaman Kazi, Yunting Luo, Robert Kendig, Yiyu Ge, Sanjula Jain, Kenyon Daniel, Daniel Santiago, Wayne C Guida, Saïd M Sebti
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 15 Pg. 5576-92 (Aug 01 2010) ISSN: 1464-3391 [Electronic] England
• PMID: 20621484 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Anthracyclines
• Naphthoquinones
• Protease Inhibitors
• Proteasome Inhibitors
• Protein Subunits
• Sulfonamides
• PI 083
• Proteasome Endopeptidase Complex

Topics

• Anthracyclines (chemistry)
• Binding Sites
• Computer Simulation
• Hydrogen Bonding
• Naphthoquinones (chemical synthesis, chemistry, pharmacology)
• Protease Inhibitors (chemical synthesis, chemistry, pharmacology)
• Proteasome Endopeptidase Complex (metabolism)
• Proteasome Inhibitors
• Protein Subunits (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Sulfonamides (chemistry)