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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.

SUBMITTER: Lawrence HR 

PROVIDER: S-EPMC3530924 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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

Lawrence Harshani R HR   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  

Bioorganic & medicinal chemistry 20100618 15


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 a  ...[more]

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