Phenolic indeno[1,2-b]indoles as ABCG2-selective potent and non-toxic inhibitors stimulating basal ATPase activity.
GOZZI, Gustavo Jabor
Bases moléculaires et structurales des systèmes infectieux [BMSSI]
Department of Biochemistry and Molecular Biology
See more >
Bases moléculaires et structurales des systèmes infectieux [BMSSI]
Department of Biochemistry and Molecular Biology
GOZZI, Gustavo Jabor
Bases moléculaires et structurales des systèmes infectieux [BMSSI]
Department of Biochemistry and Molecular Biology
Bases moléculaires et structurales des systèmes infectieux [BMSSI]
Department of Biochemistry and Molecular Biology
VALDAMERI, Glaucio
Bases moléculaires et structurales des systèmes infectieux [BMSSI]
Department of Biochemistry and Molecular Biology
< Reduce
Bases moléculaires et structurales des systèmes infectieux [BMSSI]
Department of Biochemistry and Molecular Biology
Language
en
Article de revue
This item was published in
Drug Design, Development and Therapy. 2015, vol. 9, p. 3481-3495
Dove Medical Press
English Abstract
Ketonic indeno[1,2-b]indole-9,10-dione derivatives, initially designed as human casein kinase II (CK2) inhibitors, were recently shown to be converted into efficient inhibitors of drug efflux by the breast cancer resistance ...Read more >
Ketonic indeno[1,2-b]indole-9,10-dione derivatives, initially designed as human casein kinase II (CK2) inhibitors, were recently shown to be converted into efficient inhibitors of drug efflux by the breast cancer resistance protein ABCG2 upon suited substitutions including a N (5)-phenethyl on C-ring and hydrophobic groups on D-ring. A series of ten phenolic and seven p-quinonic derivatives were synthesized and screened for inhibition of both CK2 and ABCG2 activities. The best phenolic inhibitors were about threefold more potent against ABCG2 than the corresponding ketonic derivatives, and showed low cytotoxicity. They were selective for ABCG2 over both P-glycoprotein and MRP1 (multidrug resistance protein 1), whereas the ketonic derivatives also interacted with MRP1, and they additionally displayed a lower interaction with CK2. Quite interestingly, they strongly stimulated ABCG2 ATPase activity, in contrast to ketonic derivatives, suggesting distinct binding sites. In contrast, the p-quinonic indenoindoles were cytotoxic and poor ABCG2 inhibitors, whereas a partial inhibition recovery could be reached upon hydrophobic substitutions on D-ring, similarly to the ketonic derivatives.Read less <
Origin
Hal imported