Demonstration of the first known 1:2 host-guest encapsulation of a platinum anticancer complex within a macrocycle

Abstract

This study examined the ability of the para-sulfonatocalix[8]arene (sCX[8]) macrocycle to encapsulate [Pt(H2O)2(R,R-dach)]2+, the active aquated component of oxaliplatin. Both the free 1R,2R-diaminocyclohexane (dach) ligand and [Pt(H2O)2(R,R-dach)]2+ formed host-guest complexes with sCX[8], as indicated by 1H nuclear magnetic resonance (NMR) spectroscopy and molecular modelling. This interaction uniquely occurred in a 1:2 host-guest stoichiometric ratio, such that one platinum molecule was bound at each of the two sCX[8] pseudo-cavities. The 1H NMR data showed this binding to be predominantly stabilised by hydrophobic effects, hydrogen bonds and electrostatic interactions, the latter of which were evidenced by the lack of host-guest complex formation for the uncharged [PtCl2(R,R-dach)] derivative. Contrastingly, molecular modelling results indicated that host-guest complex formation was predominantly due to hydrogen bonds and electrostatic interactions at the surface of the macrocycle, such that the dach groups of [Pt(H2O)2(R,R-dach)]2+ were projecting away from, and not bound through hydrophobic effects with, the pseudo-cavities of sCX[8]. Guanosine 5′-monophosphate binding studies demonstrated that complexation with the macrocycle did not affect the ability of [Pt(H2O)2(R,R-dach)]2+ to interact with its target, but rather, it was capable of doing so while still bound to sCX[8]. In total, these findings point to the potential role of sCX[8] as a delivery vehicle for other charged platinum complexes.