Dendritic Molecular Baskets for Selective Binding of Toxic Methotrexate.

Autor: Kumar N; Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH-43210, USA., Finnegan TJ; Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH-43210, USA., Taneja S; Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH-43210, USA., Rostam DC; Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH-43210, USA., Hansen AL; Campus Chemical Instrument Center, The Ohio State University, 100 West 18th Avenue, Columbus, OH-43210, USA., Ward CE; Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH-43210, USA., Uçar S; Atatürk University, Faculty of Science, Department of Chemistry, Erzurum, 25240, Turkey., Parquette JR; Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH-43210, USA., Badjić JD; Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH-43210, USA.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Nov 11, pp. e202420574. Date of Electronic Publication: 2024 Nov 11.
DOI: 10.1002/anie.202420574
Abstrakt: 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. 1 H NMR spectroscopy, calorimetry (ITC), and mass spectrometry (ESI-MS) measurements validate the formation of an inclusion complex between 6 12- and anticancer drug methotrexate (MTX 2- ) in water (K d =9.2 μM). To identify the docking pose, a comparison of computed (DFT and MM) and experimental 1 H NMR chemical shifts suggests that MTX 2- folds inside 6 12- (π⋅⋅⋅π), forming HBs with the peptidic dendrons while anchoring (C-H⋅⋅⋅π) to the aromatic pocket through its N-methyl group. In consequence, 6 12- selectively binds MTX 2- in competition with structurally similar folic acid and leucovorin (reversal poisoning agent). While the host is biocompatible (HEK293; IC 50 >150 μM) and produces inclusion complex [MTX⊂6] 14- in cell media, it experiences limitation in pharmacokinetic sequestration of MTX 2- 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.
(© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
Externí odkaz: