Ursolic Acid-Folic Acid Conjugate in the Treatment of Cervical Cancer

Objective: Cervical cancer remains a significant global health concern, necessitating the development of targeted therapies with enhanced efficacy and reduced side effects. Current treatment approaches, such as surgery combined with chemotherapy and radiotherapy, often cause severe adverse effects due to their non-specificity, which drives the need for targeted therapies. The overexpression of folate receptors (FRs) in many cervical cancer cells makes them a promising target for drug delivery. This study focuses on the synthesis and evaluation of a conjugate of ursolic acid and folic acid (UA-FA) as a potential anticancer agent. Methods: In silico studies, including molecular docking and molecular dynamics (MD) simulations, were performed to assess the binding affinity of the UA-FA conjugate to the folate receptor α (FRα; PDB ID: 4LRH). ADME/T predictions were performed. The UA-FA conjugate was synthesized via a multi-step reaction involving the conversion of ursolic acid into its hydrazide derivative, followed by conjugation with the γ-carboxyl group of folic acid. In vitro cytotoxicity assays against HeLa (cervical carcinoma) and Vero (normal kidney epithelial) cell lines were performed. Results and Discussion: Docking results revealed strong interactions with a more favorable binding energy compared to ursolic acid alone. MD simulations confirmed the stability of the receptor-ligand complex over a 100 ns trajectory. ADME/T predictions indicated improved pharmacokinetic properties, including aqueous solubility and oral bioavailability. In vitro cytotoxicity assays demonstrated selective toxicity toward cancer cells, with an IC50 of 105.79 ± 2.23 μg/mL and a selectivity index (SI) of 2.07, compared to UA alone (SI = 1.78). Conclusions: These findings suggest the UA-FA conjugate as a promising candidate for targeted cervical cancer therapy. Further in vivo studies are warranted to confirm its therapeutic potential.