Synthesis and biological evaluation of naphthoquinone analogs as a novel class of proteasome inhibitors.
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.
Lawrence
Harshani R
HR
Drug Discovery Department, Moffitt Cancer Center, 12901 Magnolia Drive, Tampa, FL 33612, USA. Harshani.Lawrence@moffitt.org
Kazi
Aslamuzzaman
A
Luo
Yunting
Y
Kendig
Robert
R
Ge
Yiyu
Y
Jain
Sanjula
S
Daniel
Kenyon
K
Santiago
Daniel
D
Guida
Wayne C
WC
Sebti
Saïd M
SM
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
D018943:Anthracyclines; D009285:Naphthoquinones; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D013449:Sulfonamides; C058288:PI 083; D046988:Proteasome Endopeptidase Complex