Enhancing Solubility, Dissolution Rate, and Anticancer Activity of Bioactive Genistein via Host–Guest Inclusion Complexation with p-Sulfocalix[4]arene: Collaborate Experimental Findings with Computational Study

Natural phytoconstituents have emerged as potential alternatives to the synthetic drugs, particularly in the treatment of chronic diseases. Genistein (GEN) is a bioflavonoid with potential biological activities such as antioxidant, anticancer, and anti-inflammatory activities. However, it faces limitations like water insolubility and slow dissolution in gastric fluids. p-Sulfocalix[4]arene (SC[4]A), a macrocyclic supramolecule, is being studied for its potential to improve hydrophobic drug properties. In this work, a host–guest inclusion complex (GEN-SC[4]A) was prepared by the solvent evaporation method and analyzed by FTIR, NMR, UV–Vis, DLS, TEM, and DSC techniques. The complex showed concentration, and pH-dependent solubility enhancement showed ~ 31 times more solubility at pH 10 and 8 mM concentration of SC[4]A), thus improving its dissolution. The therapeutic efficacy of native GEN, including its cytotoxicity against A549 cells, was increased after complex formation. The AO/EtBr staining study showed more apoptosis-mediated anticancer activity than pure GEN. This analytical approach offered insights into various aspects, including molecular geometry, stabilizing interactions, release behaviour, and the unwinding pathway of the prepared complex. The computational study, using extended umbrella sampling, supported the experimental findings. Consequently, the GEN-SC[4]A complex emerges as a promising and efficient carrier for the delivery of phytochemicals.