Structure-ATPase Activity Relationship of Rhodamine Derivatives as Potent Inhibitors of P-Glycoprotein CmABCB1

Sorachi Miwa; Hiroshi Takikawa; Rina Takeuchi; Ryo Mizunuma; Keita Matsuoka; Haruo Ogawa; Hiroaki Kato; Kiyosei Takasu

doi:10.1021/acsmedchemlett.3c00526

Structure-ATPase Activity Relationship of Rhodamine Derivatives as Potent Inhibitors of P-Glycoprotein CmABCB1

ACS Med Chem Lett. 2024 Jan 19;15(2):287-293. doi: 10.1021/acsmedchemlett.3c00526. eCollection 2024 Feb 8.

Authors

Sorachi Miwa¹, Hiroshi Takikawa¹, Rina Takeuchi¹, Ryo Mizunuma¹, Keita Matsuoka¹, Haruo Ogawa¹, Hiroaki Kato^{1

2}, Kiyosei Takasu¹

Affiliations

¹ Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
² RIKEN Harima Institute at SPring-8, Hyogo 679-5148 Japan.

PMID: 38352840
PMCID: PMC10860176 (available on 2025-02-08)
DOI: 10.1021/acsmedchemlett.3c00526

Abstract

Understanding the transport and inhibition mechanisms of substrates by P-glycoprotein (P-gp) is one of the important approaches in addressing multidrug resistance (MDR). In this study, we evaluated a variety of rhodamine derivatives as potential P-gp inhibitors targeting CmABCB1, a P-gp homologue, with a focus on their ATPase activity. Notably, a Q-rhodamine derivative with an o,o'-dimethoxybenzyl ester moiety (Rh_Q-DMB) demonstrated superior affinity and inhibitory activity, which was further confirmed by a drug susceptibility assay in yeast strains expressing CmABCB1. Results from a tryptophan fluorescence quenching experiment using a CmABCB1 mutant suggested that Rh_Q-DMB effectively enters and binds to the inner chamber of CmABCB1. These findings underscore the promising potential of Rh_Q-DMB as a tool for future studies aimed at elucidating the substrate-bound state of CmABCB1.