Transmembrane Chloride Transport by Diphosphine‐Pd(II) Complexes: Effect of the Ligand Geometry

Abstract

Transmembrane chloride transport is a fundamental biological process, and its impairment is at the origin of severe genetic diseases such as cystic fibrosis. Synthetic anion carriers able to transport chloride and other anions across biological membranes are considered as putative candidates for treating these syndromes. We have proposed diphosphine–Pd(II) complexes as a new class of anion carriers and in this contribution we have investigated the ionophoric activity of a family of Pd(II) complexes with diphosphine chelating ligands differing for the ligand bite angle that is varied from 71° (dppm) to 98° (dppb). Moreover, in the case of the dppe ligand we also investigated the effect of the introduction in the ligand structure of alkyl substituents of increasing length and hydrophobicity and of electron donor and withdrawing substituents. All the complexes investigated are able to transport chloride across the phospholipid membrane of liposomes and the most important parameter influencing their relative efficacy is the lipophilicity of the complex with the highest activity observed for [Pd(pEt‐dppe)Cl2]. On the contrary the bite angle of the ligand appears to be not relevant while the activity is diminished by the insertion of both EWG and EDG groups on the phenyl substituents of the phosphine ligands. Finally, also Ni(II) and Cu(I) complexes display ionophoric activity demonstrating that the transport ability of metal complexes is not limited to Pd(II) metal ion.

Platinum-based metal complexes as chloride transporters that trigger apoptosis

“…Lipophilicity has been previously shown to be a signicant determinant of the activity of anion transporters, as it directly impacts both the aqueous solubility and the ability to cross the phospholipid bilayer. 19,[48][49][50][51] This strategy of coordinating an anion inside a lipophilic sphere has been previously explored in our group, resulting in highly potent chloride transporters. 52 On the other hand, highly lipophilic complexes typically display diminished aqueous solubility, which is likely responsible for the observed precipitation of complexes 4-8 during the ISE experiments.…”

“…One example of this mechanism was reported for several Pd(II) complexes with the transport properties of this system studied using the 8hydroxypyrene-1,3,6-trisulfonic acid (HPTS) assay. 18,19 Alternatively, the ligands can remain on the metal centre and transport via traditional hydrogen bonding interactions between the ligand and anion. This mechanism was reported for an Ir(III) complex and a number of phosphazane-based complexes with various metal centres, such as Rh(I), Mo(0), and Au(I).…”

Transmembrane transport by platinum-based metal-organic anionophores

“…Lipophilicity has been previously shown to be a significant determinant of the activity of anion transporters, as it directly impacts both the aqueous solubility and the ability to cross the phospholipid bilayer. 27,[41][42][43][44] Due to the presence of four identical isoquinoline ligands, each additional carbon greatly enhances lipophilicity.…”

“…It was determined that the lipophilicity of the complexes was responsible for the changes in transport activity detected. 27 Based on the precipitation of complexes 4-8 in the ISE assay, it is also likely that the longer chain complexes are too lipophilic and end up buried inside the phospholipid bilayer, inhibiting chloride transport.…”