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

Radoslav Z. Pavlović, Tyler J. Finnegan, Anna Metlushko, Alexandar L. Hansen, Christopher A. Waudby, Xiuze Wang, Nicole Hoefer, David W. McComb, Aleksandar Pavić, Nikola Plackić, Jovana Novaković, Jovana Bradić, Nevena Jeremić, Vladimir Jakovljević, Biljana Šmit, Sanja Matić, Matias A. Alvarez-Saavedra, Ivan Čapo, Curtis E. Moore, Samuel I. StuppJovica D. Badjić*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

We describe the preparation, dynamic, assembly characteristics of vase-shaped basket 13− 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 1H Nuclear Magnetic Resonance (NMR), 1H 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 1H 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] (Kd=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.

Original languageEnglish (US)
Article numbere202303374
JournalChemistry - A European Journal
Volume29
Issue number68
DOIs
StatePublished - Dec 6 2023

Keywords

  • anticancer agents
  • cavitands
  • mitoxantrone
  • sequesters
  • supramolecular chemistry

ASJC Scopus subject areas

  • General Chemistry
  • Catalysis
  • Organic Chemistry

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