Dendritic Molecular Baskets for Selective Binding of Toxic Methotrexate

Area of Science:

• Supramolecular Chemistry
• Medicinal Chemistry
• Materials Science

Background:

• Cavitands are macrocyclic hosts with potential applications in drug delivery and sequestration.
• Methotrexate (MTX) is a crucial anticancer drug with a narrow therapeutic index, necessitating effective management strategies for toxicity.
• Developing synthetic receptors for selective drug binding is a key challenge in medicinal chemistry.

Purpose of the Study:

• To synthesize and characterize a novel dendritic basket cavitand (6^12-) with enhanced water solubility and self-assembly prevention.
• To investigate the binding characteristics and complex formation between the dendritic basket and methotrexate (MTX).
• To evaluate the potential of the dendritic basket as an abiotic antidote for methotrexate poisoning.

Main Methods:

• Synthesis and characterization of the dendritic basket cavitand.
• Binding studies using Isothermal Titration Calorimetry (ITC) and 1H NMR spectroscopy.
• Computational modeling (DFT and MM) to determine the binding pose.
• In vitro biocompatibility assays (HEK293 cell line) and competitive binding assays.

Main Results:

• The dendritic basket 6^12- was successfully prepared and demonstrated high water solubility.
• An inclusion complex between 6^12- and MTX was formed in water with a dissociation constant (Kd) of 9.2 μM.
• Computational and experimental data confirmed MTX binding within the basket via π-π stacking and hydrogen bonding.
• The basket selectively bound MTX over structurally similar compounds like folic acid and leucovorin.
• The host molecule exhibited good biocompatibility (IC50 > 150 μM).

Conclusions:

• The dendritic basket 6^12- is a promising host molecule for selective methotrexate sequestration.
• Its biocompatibility and tunable nature make it a leading candidate for an abiotic antidote against methotrexate poisoning.
• Further pharmacokinetic studies are needed to optimize its efficacy in vivo, as dihydrofolate reductase affinity may prevail.