Dendritic Molecular Baskets for Selective Binding of Toxic Methotrexate

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.