Hydrazone- and imine-containing [PdPtL4]4+ cages: a comparative study of the stability and host–guest chemistry

Abstract

A new [PdPtL₄]⁴⁺ heterobimetallic cage containing hydrazone linkages has been synthesised using the sub-component self-assembly approach. ¹H and DOSY nuclear magnetic resonance (NMR) spectroscopy and electrospray ionisation mass spectrometry (ESIMS) data were consistent with the formation of the [PdPtL₄]⁴⁺ architecture. The cage was stimulus-responsive and could be partially disassembled and reassembled by the addition of dimethylaminopyridine (DMAP) and p-tolenesulfonic acid (TsOH), respectively. Additionally, the stability of the hydrazone cage against hydrolysis in the presence of water and nucleophilic decomposition in the presence of guest molecules was compared to a previously synthesised imine-containing [PdPtL₄]⁴⁺ cage. It was established that the hydrazone linkage was more resistant to hydrolysis. Furthermore, the host–guest (HG) chemistry with a series of drug and drug-like molecules was examined. The hydrazone cage was shown to interact with cisplatin while the smaller imine cage was shown to interact with 5-fluorouracil and oxaliplatin in CD₃CN. No HG interactions were observed in the more polar d₆-DMSO. In vitro antiproliferative activity studies demonstrated both cages were active against the cancer cell lines tested and displayed half-maximal inhibitory (IC₅₀) values in the range of 25–35 μM. Most [PdPtL₄]⁴⁺-drug mixtures tested had higher IC₅₀ values than the hosts. However, the [PdPtL₄]⁴⁺ cages, and [PdPtL₄]⁴⁺:drug mixtures were less cytotoxic than the well established anticancer drugs cisplatin, oxaliplatin and 5-fluorouracil.