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 (2R/S)-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 (2R/S)-6-PFVNs were identified as having strong cytotoxic effects on HeLa cells. Among them, (2R/S)-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 (2R)-6-DEANG and (2S)-6-DEANG on the treatment of HeLa cells with (2R/S)-6-DEANG was determined by comparing the IC50 value of (2R/S)-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 (2S)-6-DEANG had a higher affinity for various proteins, while (2R)-DEANG demonstrated stronger binding to other proteins. A similar effect of (2S)-KTt-45 and (2R)-KTt-45 was also observed. Overall, the findings of this study clearly highlight the potential of (2R/S)-6-PFVNs as effective agents in the treatment of cervical cancer.