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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 (tripy) ligands (with amino groups either in the 2-(2A-tripy) or 3-(3A-tripy) positions of the terminal pyridines) and their respective [Pd2(Ltripy)4]4+ cages. These systems have been characterised by 1H, 13C 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 (2A-tripy > 3A-tripy > tripy). Competition experiments with a range of nucleophiles showed that these substitutions lead to more kinetically robust cage architectures, with [Pd2(2A-tripy)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(2A-tripy)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(Ltripy)4]4+ cages was accompanied by loss of cisplatin-binding ability.

There is emerging interest in the anti-proliferative effects of metallosupramolecular systems due to the different size and shape of these metallo-architectures compared to traditional small molecule drugs. Palladium(II)-containing systems are the most abundant class of metallosupramolecular complexes, yet their biological activity has hardly been examined. Here a small series of [Pd2(L)4](BF4)4 quadruply-stranded, dipalladium(II) architectures were screened for their cytotoxic effects against three cancer cell lines and one non-malignant line. The helicates exhibited a range of cytotoxic properties, with the most cytotoxic complex [Pd2(hextrz)4](BF4)4 possessing low micromolar IC50 values against all of the cell lines tested, while the other helicates displayed moderate or no cytotoxicity. Against the MDA-MB-231 cell line, which is resistant to platinum-based drugs, [Pd2(hextrz)4](BF4)4 was 7-fold more active than cisplatin. Preliminary mechanistic studies indicate that the [Pd2(hextrz)4](BF4)4 helicate does not induce cell death in the same way as clinically used metal complexes such as cisplatin. Rather than interacting with DNA, the helicate appears to disrupt the cell membrane. These studies represent the first biological characterisation of quadruply-stranded helicate architectures, and provide insight into the design requirements for the development of biologically active and stable palladium(II)-containing metallosupramolecular architectures.

The syntheses of the 4-n-propyl and 4-phenyl substituted fac-Re(CO)(3) complexes of the tridentate "click" ligand (2,6-bis(4-substituted-1,2,3-triazol-1-ylmethyl)pyridine) are described. The complexes were obtained by refluxing methanol solutions of [Re(CO)(5)Cl], AgPF(6) and either the 4-propyl or 4-phenyl substituted ligand for 16 h. The ligands and the two rhenium(I) complexes were characterised by elemental analysis, HR-ESMS, ATR-IR, (1)H and (13)C NMR spectroscopy and the molecular structures of both complexes were confirmed by X-ray crystallography. The electronic structure of the fac-Re(CO)(3) "click" complexes was probed using UV-Vis, Raman and emission spectroscopy, cyclic voltammetry and DFT calculations. Altering the electronic nature of the ligand's substituent, from aromatic to alkyl, had little effect on the absorption/emission maxima and electrochemical properties of the complexes indicating that the 1,2,3-triazole unit may insulate the metal centre from the electronic modification at the ligands' periphery. Both Re(I) complexes were found to be weakly emitting with short excited state lifetimes. The electrochemistry of the complexes is defined by quasi-reversible Re oxidation and irreversible triazole-based ligand reduction processes.