Dendritic Molecular Baskets for Selective Binding of Toxic Methotrexate
Kumar, Nitesh, Finnegan, Tyler J., Taneja, Sagarika, Rostam, Darian C., Hansen, Alexandar L., Ward, Carson E., Ucar, Sefa, Parquette, Jon R., Badjic, Jovica D.
We describe the preparation, assembly, recognition characteristics, and bioactivity of dendritic basket 6(12)-. This novel cavitand has a deep aromatic pocket with three (S)-glutamic acid dendrons at the rim to amplify water solubility and prevent self-association. H-1 NMR spectroscopy, calorimetry (ITC), and mass spectrometry (ESI-MS) measurements validate the formation of an inclusion complex between 6(12)- and anticancer drug methotrexate (MTX2-) in water (K-d = 9.2 mu M). To identify the docking pose, a comparison of computed (DFT and MM) and experimental H-1 NMR chemical shifts suggests that MTX2 folds inside 6(12)- (pi center dot center dot center dot pi), forming HBs with the peptidic dendrons while anchoring (C-H center dot center dot center dot pi) to the aromatic pocket through its N-methyl group. In consequence, 6(12-) selectively binds MTX2- in competition with structurally similar folic acid and leucovorin (reversal poisoning agent). While the host is biocompatible (HEK293; IC50 > 150 mu M) and produces inclusion complex [MTX subset of 6](14)- in cell media, it experiences limitation in pharmacokinetic sequestration of MTX2- as dihydrofolate reductase's affinity to the drug is suggested to prevail over that of 6(12-). Nonetheless, considering the basket's biocompatibility, tunability, and chemoselectivity, it stands as the leading candidate in the pursuit of an effective abiotic antidote for methotrexate poisoning.
- Journal
- ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
- Year
- 2025
- Volume
- 64
- Issue
- 9
- eISSN
- 1521-3773
- DOI
- 10.1002/anie.202420574
- WoS UID
- WOS:001361587000001