title: Flavonoid dimers as bivalent modulators for pentamidine and sodium stiboglucanate resistance in leishmania.
abstract: Drug resistance by overexpression of ATP-binding cassette (ABC) transporters is an impediment in the treatment of leishmaniasis. Flavonoids are known to reverse multidrug resistance (MDR) in Leishmania and mammalian cancers by inhibiting ABC transporters. Here, we found that synthetic flavonoid dimers with three (compound 9c) or four (compound 9d) ethylene glycol units exhibited a significantly higher reversing activity than other shorter or longer ethylene glycol-ligated dimers, with approximately 3-fold sensitization of pentamidine and sodium stibogluconate (SSG) resistance in Leishmania, respectively. This modulatory effect was dosage dependent and not observed in apigenin monomers with the linker, suggesting that the modulatory effect is due to its bivalent nature. The mechanism of reversal activity was due to increased intracellular accumulation of pentamidine and total antimony in Leishmania. Compared to other MDR modulators such as verapamil, reserpine, quinine, quinacrine, and quinidine, compounds 9c and 9d were the only agents that can reverse SSG resistance. In terms of reversing pentamidine resistance, 9c and 9d have activities comparable to those of reserpine and quinacrine. Modulators 9c and 9d exhibited reversal activity on pentamidine resistance among LeMDR1(-/-), LeMDR1(+/+), and LeMDR1-overexpressed mutants, suggesting that these modulators are specific to a non-LeMDR1 pentamidine transporter. The LeMDR1 copy number is inversely related to pentamidine resistance, suggesting that it might be involved in importing pentamidine into the mitochondria. In summary, bivalency could be a useful strategy for the development of more potent ABC transporter modulators and flavonoid dimers represent a promising reversal agent for overcoming pentamidine and SSG resistance in parasite Leishmania.
authors.affiliation: Department of Applied Biology and Chemical Technology and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis, The Hong Kong Polytechnic University, Hong Kong, People's Republic of China.
authors.forename: Iris L K
authors.initials: IL
authors.lastname: Wong
authors.forename: Kin-Fai
authors.initials: KF
authors.lastname: Chan
authors.forename: Brendan A
authors.initials: BA
authors.lastname: Burkett
authors.forename: Yunzhe
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yi
authors.initials: Y
authors.lastname: Chai
authors.forename: Hongzhe
authors.initials: H
authors.lastname: Sun
authors.forename: Tak Hang
authors.initials: TH
authors.lastname: Chan
authors.forename: Larry M C
authors.initials: LM
authors.lastname: Chow
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D000967:Antimony Sodium Gluconate / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D047310:Apigenin / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D018313:Leishmania enriettii / Q000187:drug effects* / Q000235:genetics; D013058:Mass Spectrometry; D010419:Pentamidine / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D000981:Antiprotozoal Agents; D005419:Flavonoids; D010419:Pentamidine; D047310:Apigenin; D000967:Antimony Sodium Gluconate