The Synergistic Cytotoxic Effect of the Two Enantiomers of 6-Prenylflavanones in the HeLa Cell Line

This research performed a structure-activity relationship (SAR) study, which involved the synthesis of 16 (<i>2R/S</i>)-6-PFVNs and evaluating their cytotoxic effects on the HeLa cell line. This investigation concentrated on the length of the prenyl side chain at the C-6 position of the A-ring and the substitution patterns of the methoxy and hydroxy groups on the B-ring. Accordingly, several (<i>2R/S</i>)-6-PFVNs were identified as having strong cytotoxic effects on HeLa cells. Among them, (<i>2R/S</i>)-6-(3,3-diethylallyl)-naringenin (6-DEANG) emerged as a standout candidate, demonstrating an IC₅₀ value of 12 μM and a selectivity index (SI) exceeding 10. Furthermore, the synergistic effect of (<i>2R</i>)-6-DEANG and (<i>2S</i>)-6-DEANG on the treatment of HeLa cells with (<i>2R/S</i>)-6-DEANG was determined by comparing the IC₅₀ value of (<i>2R/S</i>)-6-DEANG to those of the individual enantiomers, which were isolated through chiral chromatography. This synergistic effect was further confirmed through the median-effect plot and the combination index versus the fraction of affected cells (CI-Fa) plot. Additionally, molecular docking studies revealed that (<i>2S</i>)-6-DEANG had a higher affinity for various proteins, while (<i>2R</i>)-DEANG demonstrated stronger binding to other proteins. A similar effect of (<i>2S</i>)-KTt-45 and (<i>2R</i>)-KTt-45 was also observed. Overall, the findings of this study clearly highlight the potential of (<i>2R/S</i>)-6-PFVNs as effective agents in the treatment of cervical cancer.