Harnessing Pillar[5]arene Host–Guest Complexation To Improve pH Stability and Affect Enzymatic Degradation of the Anticancer Prodrug Capecitabine: A ¹⁹F NMR Study

Cancer is a global health problem, and supramolecular chemotherapy is emerging as a novel strategy to battle the disease. Here, we first evaluated the thermodynamic and kinetic stability of the complexes formed between several water-soluble per-substituted pillar[5]arene derivatives and capecitabine (1), a widely used oral chemotherapeutic prodrug. The exchange rate was studied, for the first time in pillararene chemistry, by the ¹⁹F guest exchange saturation transfer (GEST) NMR technique. Importantly, when we evaluated the effect of complexation on the characteristics of 1, we found that the complexation of 1 with such pillar[5]arene hosts increased capecitabine stability at acidic pH very significantly and slowed its enzymatic degradation by the carboxylesterase enzyme in a manner that depended on the host. These interesting findings could have implications on the clinical use of this heavily used prodrug and might affect the management of cancer patients.