Phenyltetrazolyl-phenylamides: Substituent impact on modulation capability and selectivity toward the efflux protein ABCG2 and investigation of interaction with the transporter.

Autor: Köhler SC; Pharmazeutisches Institut, Rheinische Friedrich-Wilhelms-Universität Bonn, An der Immenburg 4, 53121 Bonn, Germany., Silbermann K; Pharmazeutisches Institut, Rheinische Friedrich-Wilhelms-Universität Bonn, An der Immenburg 4, 53121 Bonn, Germany., Wiese M; Pharmazeutisches Institut, Rheinische Friedrich-Wilhelms-Universität Bonn, An der Immenburg 4, 53121 Bonn, Germany. Electronic address: mwiese@uni-bonn.de.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2016 Nov 29; Vol. 124, pp. 881-895. Date of Electronic Publication: 2016 Sep 04.
DOI: 10.1016/j.ejmech.2016.09.010
Abstrakt: We recently presented a novel class of ABCG2 modulators based on the third-generation ABCB1 inhibitor tariquidar bearing a 2,5-linked tetrazole instead of an amid linker. We investigated the modulating potential of the compound class by enlarging the substitution pattern on the outer phenyl rings of the scaffold. To identify the structural conditions for achieving a high response, we decided to determine the individual influence of substituents on the scaffold using monosubstituted derivatives. While electron withdrawing groups (with a few exceptions) and bulky moieties decreased the modulating potency, small electron donating groups ensured a high activity level. Interestingly, the unsubstituted derivative 32 reached a similar inhibitory potential as the best derivatives in the previous study. Enzyme kinetic assays indicated that our derivatives have the same binding site as reference inhibitor Ko143. They were found to interact competitively and non-competitively with the substrates Hoechst 33342 and pheophorbide A, respectively.
(Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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