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

Content Provider	PubMed Central
Author	Gozzi, Gustavo Jabor Bouaziz, Zouhair Winter, Evelyn Daflon-yunes, Nathalia Honorat, Mylène Guragossian, Nathalie Marminon, Christelle Valdameri, Glaucio Andre, Bollacke Guillon, Jean Pinaud, Noël Mathieu, Marchivie Cadena, Silvia M. Jose, Joachim Borgne, Marc Le Pietro, Attilio Di
Copyright Year	2015
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 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.
Related Links	http://dx.doi.org/10.2147/dddt.s84982
Ending Page	3495
Starting Page	3481
File Format	PDF
ISSN	11778881
e-ISSN	11778881
Journal	Drug Design, Development and Therapy
Volume Number	9
Language	English
Publisher	Dove Medical Press
Publisher Date	2015-07-01
Access Restriction	Open
Rights Holder	Dove Medical Press
Subject Keyword	Pharmacology Drug Discovery Pharmaceutical Science Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Pharmacology Pharmaceutical Science

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