Horin_2023_Chemistry__e202301628

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 the 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 may have implications on clinical use of this heavily used prodrug and may affect the management of cancer patients.