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

Bioorganic & Medicinal Chemistry
Harshani R LawrenceSaïd M Sebti

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.

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Citations

Jan 10, 2012·Journal of Medicinal Chemistry·Yiyu GeHarshani R Lawrence
Apr 4, 2013·Journal of Medicinal Chemistry·Sevil OzcanSaïd M Sebti
Nov 26, 2013·European Journal of Medicinal Chemistry·Maria Letícia de Castro BarbosaEliezer J Barreiro
Jul 16, 2014·European Journal of Medicinal Chemistry·Veda PrachayasittikulVirapong Prachayasittikul
Apr 4, 2013·Expert Opinion on Drug Discovery·Yuri PevznerKenyon Daniel
Jun 29, 2017·Journal of Enzyme Inhibition and Medicinal Chemistry·Mauro MarastoniDelia Preti
Jul 12, 2018·Organic & Biomolecular Chemistry·Ramanathan Devenderan, Pitchumani Kasi
Aug 15, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Mohammad M Al-SaneaClaudiu T Supuran
Dec 1, 2019·Chemical Biology & Drug Design·Nilüfer BayrakAmaç Fatih Tuyun
Feb 6, 2014·Biological Chemistry·Fabian NguyenDaniel N Wilson
May 6, 2015·Journal of Enzyme Inhibition and Medicinal Chemistry·Alessandra ScottiMauro Marastoni
Mar 1, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lawrence Nnamdi ObasiAlfred Ezinna Ochonogor
Apr 27, 2016·Bioorganic & Medicinal Chemistry·Tanner J McDanielJetze J Tepe
May 17, 2021·Bioorganic & Medicinal Chemistry·Leandro Rocha SilvaEdeildo Ferreira da Silva-Júnior

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