1383471-07-5Relevant academic research and scientific papers
Novel heat shock protein 90 inhibitors suppress P-glycoprotein activity and overcome multidrug resistance in cancer cells
Dini?, Jelena,Podolski-Reni?, Ana,Jovanovi?, Mirna,Musso, Loana,Tsakovska, Ivanka,Pajeva, Ilza,Dallavalle, Sabrina,Pe?i?, Milica
, (2019/10/22)
Heat Shock Protein 90 (Hsp90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents due to their high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer drugs. Eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in two MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (human non-small cell lung carcinoma and colorectal adenocarcinoma). We investigated the effect of Hsp90 inhibitors on cell growth inhibition, P-gp activity and P-gp expression. Structure-activity relationship analysis was performed in respect to cell growth and P-gp inhibition. Compounds 5, 7, and 9 directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was identified by molecular docking studies. In addition, these compounds downregulated P-gp expression in MDR colorectal carcinoma cells, showed good relative selectivity towards cancer cells, while compound 5 reversed resistance to doxorubicin and paclitaxel in concentration-dependent manner. Therefore, compounds 5, 7 and 9 could be promising candidates for treating cancers with P-gp overexpression.
Isoxazolo(aza)naphthoquinones: A new class of cytotoxic Hsp90 inhibitors
Bargiotti, Alberto,Musso, Loana,Dallavalle, Sabrina,Merlini, Lucio,Gallo, Grazia,Ciacci, Andrea,Giannini, Giuseppe,Cabri, Walter,Penco, Sergio,Vesci, Loredana,Castorina, Massimo,Milazzo, Ferdinando Maria,Cervoni, Maria Luisa,Barbarino, Marcella,Pisano, Claudio,Giommarelli, Chiara,Zuco, Valentina,De Cesare, Michelandrea,Zunino, Franco
experimental part, p. 64 - 75 (2012/07/30)
A series of 3-aryl-naphtho[2,3-d]isoxazole-4,9-diones and some of their 6-aza analogues were synthesized and found to inhibit the heat shock protein 90 (Hsp90). The compounds were tested for their binding to Hsp90 and for their effects on Hsp90 client pro
