A potent fluorescent transmembrane HCl transporter perturbs cellular pH and promotes cancer cell death

Abstract

A series of fluorescent coumarin-based bis-ureas have been synthesised. These compounds show strong HCl cotransport properties in model vesicle systems. Cellular localisation studies show that cytotoxic compound 4 localises in lysosomes and perturbs cellular pH.

Furazan bis-ureas: a heterocyclic scaffold for anion binding and transport

“…22 1,2-Hydrogen bonding motifs centred around cyclic structures have proven to be highly potent anion carriers, but the anion binding and transport ability of these derivatives based around a five-membered ring is relatively unknown. [23][24][25] The croconamide series provided the first example of an anion receptor employing an ortho-hydrogen bonding arrangement around a five-membered scaffold. 26 However, Jolliffe and coworkers highlighted that the potential application of these systems was hindered by the receptor's facile deprotonation, even in the absence of basic species.…”

N,N′-Dimethylsquaramide as a central scaffold for anionophore design

“…5 This central group can provide additional hydrogen bond donors to the binding site or possess complementary properties, such as fluorescence. 6…”

Molecular clips with spatially proximal urea residues for efficient transmembrane co-transport of H+/Cl− ions

“…[19][20][21] For instance, Gale and co-workers have recently reported a coumarin-based fluorescent transporter consisting of a bis(urea) moiety that allows for the co-transport of H + /Cl − across lipid bilayer membranes, resulting in organelle deacidification and apoptosis in cancer cells. 22 Amongst the series of macrocyclic chloride ion channels developed by Madhavan and co-workers, 23 the one with optimal lipophilicity (clog P = 11.7) showed the highest Cl − transport efficiency in lipid vesicles.…”