Shape Selective Copper-Based Metallo-Tweezer: Bridging Molecular Recognition and Solubility Enhancement of Natural Therapeutics.

Natural bioactive compounds exhibit remarkable therapeutic potential, particularly in combating chronic inflammatory conditions and associated diseases like cancer. However, their clinical application is often constrained by poor aqueous solubility and limited bioavailability, primarily ascribed to their pronounced self-aggregation propensities driven by hydrophobic and hydrogen bonding interactions. To address this challenge, the study introduces a bisimidazole pyridine-based metallo-tweezer (MRE) as a novel strategy to enhance the solubility of three naturally derived therapeutics─camptothecin, luteolin, and riboflavin. Through comprehensive MD simulations, complemented by quantum-level DFT calculations, the study unveils critical insights into the solubilizing mechanism of MRE. MRE disrupts drug assembly by effectively encapsulating the molecules capable of specifically coordinating to the Cu2+ center, combined with strong π-π stacking interactions with its anisole arms. This complexation attenuates the intrinsic clustering tendencies of the drugs, facilitating solute-solvent interactions and promoting solvation. Additionally, the exquisite selectivity of MRE and its varying binding affinities toward different drugs highlights its potential as a selective sensor for natural bioactives, distinguishing it from conventional solubilizing agents. The study provides profound insights at the molecular level and establishes key design principles for the rational development of advanced solubilizing agents, significantly enhancing the clinical utility of natural therapeutics.