title: 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.affiliation: Drug Discovery Department, Moffitt Cancer Center, 12901 Magnolia Drive, Tampa, FL 33612, USA. Harshani.Lawrence@moffitt.org
authors.forename: Harshani R
authors.initials: HR
authors.lastname: Lawrence
authors.forename: Aslamuzzaman
authors.initials: A
authors.lastname: Kazi
authors.forename: Yunting
authors.initials: Y
authors.lastname: Luo
authors.forename: Robert
authors.initials: R
authors.lastname: Kendig
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Ge
authors.forename: Sanjula
authors.initials: S
authors.lastname: Jain
authors.forename: Kenyon
authors.initials: K
authors.lastname: Daniel
authors.forename: Daniel
authors.initials: D
authors.lastname: Santiago
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Guida
authors.forename: Saïd M
authors.initials: SM
authors.lastname: Sebti
mesh_terms: D018943:Anthracyclines / Q000737:chemistry; D001665:Binding Sites; D003198:Computer Simulation; D006860:Hydrogen Bonding; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D018943:Anthracyclines; D009285:Naphthoquinones; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D013449:Sulfonamides; C058288:PI 083; D046988:Proteasome Endopeptidase Complex