Fluorinated bisbenzimidazoles: a new class of drug-like anion transporters with chloride-mediated, cell apoptosis-inducing activity

Anion transporters have attracted substantial interest due to their ability to induce cell apoptosis by disrupting cellular anion homeostasis. In this paper we describe the synthesis, anion recognition, transmembrane anion transport and cell apoptosis-inducing activity of a series of fluorinated 1,3...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2019-02, Vol.17 (6), p.1558-1571
Main Authors: Yu, Xi-Hui, Hong, Xiao-Qiao, Chen, Wen-Hua
Format: Article
Language:English
Subjects:
Anions
Apoptosis
Apoptosis - drug effects
Atomic properties
Benzene
Biological activity
Bisbenzimidazole - chemistry
Bisbenzimidazole - pharmacology
Cancer
Cell Line, Tumor
Chlorides
Chlorides - chemistry
Cytotoxicity
Disruption
Drug Design
Fluorination
Fluorine
Halogenation
Homeostasis
Humans
Hydrogen Bonding
Hydrophobic and Hydrophilic Interactions
Lipophilicity
Recognition
Structural analysis
Structure-Activity Relationship
Toxicity
Transport
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Summary:Anion transporters have attracted substantial interest due to their ability to induce cell apoptosis by disrupting cellular anion homeostasis. In this paper we describe the synthesis, anion recognition, transmembrane anion transport and cell apoptosis-inducing activity of a series of fluorinated 1,3-bis(benzimidazol-2-yl)benzene derivatives. These compounds were synthesized from the condensation of 1,3-benzenedialdehyde or 5-fluoro-1,3-benzenedialdehyde with the corresponding 1,2-benzenediamines and fully characterized. They are able to form stable complexes with chloride anions, and exhibit potent liposomal and in vitro anionophoric activity. Their anion transport efficiency may be ameliorated by the total number of fluorine atoms, and the enhanced anionophoric activity was a likely consequence of the increased lipophilicity induced by fluorination. Most of these fluorinated bisbenzimidazoles exhibit potent cytotoxicity toward the selected cancer cells. Mechanistic investigations suggest that these compounds are able to trigger cell apoptosis probably by disrupting the homeostasis of chloride anions. Fluorinated bisbenzimidazoles were synthesized as a new class of drug-like anion transporters with chloride-mediated, cell apoptosis-inducing activity.
ISSN:1477-0520
1477-0539
DOI:10.1039/c8ob03036g