Dynamic and Assembly Characteristics of Deep-Cavity Basket Acting as a Host for Inclusion Complexation of Mitoxantrone in Biotic and Abiotic Systems

We describe the preparation, dynamic, assembly characteristics of vase-shaped basket 1^3- along with its ability to form an inclusion complex with anticancer drug mitoxantrone in abiotic and biotic systems. This novel cavitand has a deep nonpolar pocket consisting of three naphthalimide sides fused to a bicyclic platform at the bottom while carrying polar glycines at the top. The results of ¹ H Nuclear Magnetic Resonance (NMR), ¹ H NMR Chemical Exchange Saturation Transfer (CEST), Calorimetry, Hybrid Replica Exchange Molecular Dynamics (REMD), and Microcrystal Electron Diffraction (MicroED) measurements are in line with 1 forming dimer [1₂ ]^6- , to be in equilibrium with monomers 1_(R) ^3- (relaxed) and 1_(S) ^3- (squeezed). Through simultaneous line-shape analysis of ¹ H NMR data, kinetic and thermodynamic parameters characterizing these equilibria were quantified. Basket 1_(R) ^3- includes anticancer drug mitoxantrone (MTO²⁺ ) in its pocket to give stable binary complex [MTO⊂1]^- (K_d =2.1 μM) that can be precipitated in vitro with UV light or pH as stimuli. Both in vitro and in vivo studies showed that the basket is nontoxic, while at a higher proportion with respect to MTO it reduced its cytotoxicity in vitro. With well-characterized internal dynamics and dimerization, the ability to include mitoxantrone, and biocompatibility, the stage is set to develop sequestering agents from deep-cavity baskets.