A potent fluorescent transmembrane HCl transporter perturbs cellular pH and promotes cancer cell death
Publication Name
Organic and Biomolecular Chemistry
Abstract
A series of fluorescent coumarin bis-ureas 1-4 have been synthesised, and their anion transport properties studied. The compounds function as highly potent HCl co-transport agents in lipid bilayer membranes. Single crystal X-ray diffraction of compound 1 showed antiparallel stacking of the coumarin rings, stabilised by hydrogen bonds. Binding studies, using 1H-NMR titration, showed moderate chloride binding in DMSO-d6/0.5% with 1 : 1 binding mode (for transporter 1) and 1 : 2 binding mode (host: guest, for transporters 2-4). We examined the cytotoxicity of compounds 1-4 against three cancer cell lines, lung adenocarcinoma (A549), colon adenocarcinoma (SW620) and breast adenocarcinoma (MCF-7). The most lipophilic transporter, 4 showed a cytotoxic effect against all three cancer cell lines. Cellular fluorescence studies showed compound 4 crossed the plasma membrane and localised in the cytoplasm after a short time. Interestingly, compound 4, lacking any lysosome targeting groups, was co-localised with LysoTracker Red at 4 and 8 h in the lysosome. Cellular anion transport of compound 4 was assessed by measuring intracellular pH and showed a decrease in cellular pH, which may be due to the capacity of transporter 4 to co-transport HCl across biological membranes, as evidenced by the liposomal studies.
Open Access Status
This publication may be available as open access
Volume
21
Issue
12
First Page
2509
Last Page
2515
Funding Number
DP200100453
Funding Sponsor
Australian Research Council