Enhanced kinetic stability of [Pd2L4](4+) cages through ligand substitution

There is considerable interest in exploiting metallosupramolecular cages as drug delivery vectors. Recently, we developed a [Pd2L4](4+) cage capable of binding two molecules of cisplatin. Unfortunately, this first generation cage was rapidly decomposed by common biologically relevant nucleophiles. In an effort to improve the kinetic stability of these cage architectures here we report the synthesis of two amino substituted tripyridyl 2,6-bis(pyridin-3-ylethynyl)pyridine () ligands (with amino groups either in the 2-() or 3-() positions of the terminal pyridines) and their respective [Pd2()4](4+) cages. These systems have been characterised by (1)H, (13)C and DOSY NMR spectroscopies, high resolution electrospray mass spectrometry, elemental analysis and, in one case, by X-ray crystallography. It was established, using model palladium(ii) N-heterocyclic carbene (NHC) probe complexes, that the amino substituted compounds were stronger donor ligands than the parent system ( > > ). Competition experiments with a range of nucleophiles showed that these substitutions lead to more kinetically robust cage architectures, with [Pd2()4](4+) proving the most stable. Biological testing on the three ligands and cages against A549 and MDA-MB-231 cell lines showed that only [Pd2()4](4+) exhibited any appreciable cytotoxicity, with a modest IC50 of 36.4 ± 1.9 μM against the MDA-MB-231 cell line. Unfortunately, the increase in kinetic stability of the [Pd2()4](4+) cages was accompanied by loss of cisplatin-binding ability.