Indole-based perenosins as highly potent HCl transporters and potential anti-cancer agents

Abstract

Prodigiosin is one of the most potent anion transporters in lipid bilayer membranes reported to date. Inspired by the structure of this natural product, we have recently designed and synthesised a new class of H+/Cl− cotransporters named ‘perenosins’. Here we report a new library of indole-based perenosins and their anion transport properties. The new transporters demonstrated superior transmembrane transport efficiency when compared to other indole-based transporters, due to favourable encapsulating effects from the substituents on the perenosin backbone. Anion transport assays were used to determine the mechanism of chloride transport revealing that the compounds function as ‘strict’ HCl cotransporters. Cell viability studies showed that some compounds specifically trigger late-onset cell death after 72 h with a unique correlation to the position of alkyl chains on the perenosins. Further investigations of cell death mechanism showed a mixture of cell cycle arrest and apoptosis was responsible for the observed decrease in cell viability.

New Insights into the Anion Transport Selectivity and Mechanism of Tren‐based Tris‐(thio)ureas

“…Compound 7 , which shows both electrogenic and electroneutral chloride transport mechanisms, also showed improved transport with the EC 50 (Gra) , 0.0031 mol %, being lower than the EC 50 , 0.020 mol %. Compounds that can facilitate H + /Cl − cotransport in an electroneutral transport process should be largely unaffected by the addition of gramicidin which proved to be the case with these compounds …”

Apoptosis-inducing activity of a fluorescent barrel-rosette M+/Cl− channel

“…Along with these ndings, the renewed interest in the eld of synthetic ion transport systems has emerged aer anticancer activity was observed in prodigiosin, [23][24][25] a naturally occurring ionophore, which acts as a chloride and HCl carrier. Aerward, various synthetic chloride ion carriers [26][27][28][29][30] and chloride channels 9 were evaluated for anticancer activity and were found to induce apoptosis in cancer cells through the caspasedependent intrinsic pathway. In the eld of symporters, the rst synthetic KCl symporter was reported by Smith and coworkers, using a ditopic receptor for NaCl and KCl transport.…”

Supramolecular methods: the chloride/nitrate transmembrane exchange assay

“…One potential use for this family of compounds could be in targeting transporters to acidic cellular organelles such as lysosomes. We have also explored the possibility of tuning the pKa of a protonatable nitrogen atom in the perenosins, 28,29 and probed the effect subtle differences in the pH environment have on the chloride transport abilities. Here, the Cl -/NO3exchange ISE assay was run at Chloride, bicarbonate and phosphate are the most abundant anions in the body, 8 but other anions, such as fluoride, 36 sulfate 37 and nitrate, 38 and cations, such as sodium, potassium, magnesium and calcium, 39 are biologically relevant.…”

“…Our group has used the Cl -/NO3exchange ISE assay extensively for a wide range of small molecule chloride transporters, including urea and thiourea tren-based compounds 2a and 2b, figure 2, 21,22 squaramide and thiosquaramide compounds, 23,24 ortho-phenylenediamine compounds, 25,26 and indole-based anionophores. [27][28][29] Figure 2. Two compounds tested in the Cl -/NO3exchange ISE assay.…”