GOZZI, Gustavo Jabor; BOUAZIZ, Zouhair; WINTER, Evelyn; DAFLON-YUNES, Nathalia; HONORAT, Mylène; GURAGOSSIAN, Nathalie; MARMINON, Christelle; VALDAMERI, Glaucio; BOLLACKE, Andre; GUILLON, Jean; PINAUD, Noël; MARCHIVIE, Mathieu; CADENA, Silvia M.; JOSE, Joachim; LE BORGNE, Marc; DI PIETRO, Attilio

doi:10.2147/DDDT.S84982

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GOZZI, Gustavo Jabor
Bases moléculaires et structurales des systèmes infectieux [BMSSI]
Department of Biochemistry and Molecular Biology

BOUAZIZ, Zouhair
Biomolécules Cancer et Chimiorésistances [B2C]

WINTER, Evelyn
Department of Pharmaceutical Sciences [ PGFAR]

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Drug Design, Development and Therapy. 2015, vol. 9, p. 3481-3495

Dove Medical Press

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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.< Réduire

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Phenolic indeno[1,2-b]indoles as ABCG2-selective potent and non-toxic inhibitors stimulating basal ATPase activity.

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