Design, synthesis and biological evaluation of (E)‐kojyl‐styryl‐sulfones: Novel recilisib hybrids as promising radioprotectors

Abstract

Radioprotectors are synthetic compounds, natural products, or biological agents that are administered before irradiation to protect normal cells against ionizing radiation (IR)‐induced injuries. We have designed novel hybrid (E)‐kojyl‐styryl‐sulfones 10a–n by applying the pharmacophore hybridization strategy to combine key structural motifs of the natural antioxidant kojic acid and the emerging radioprotector Ex‐RAD (recilisib sodium). These hybrids were successfully synthesized and characterized with (E)‐geometry. In vitro radioprotective activity along with the corresponding O‐benzylated and O‐methoxylated derivatives (9a–n, 14, and 15) was evaluated on human foreskin fibroblast 1 (HFF‐1) cells irradiated with a 10‐Gy dose of X‐rays. In particular, hybrids 10b, 10d, 10f, 10g, and 10n exhibited the highest radioprotection effect at the 10 µM concentration, more effective than the parent compounds. It should be noted that the 3,4,5‐trimethoxystyryl analog 10n was the most effective compound. Surprisingly, the O‐benzylated 3,4,5‐trimethoxystyryl analog (9n) also showed an excellent radioprotective effect. Moreover, the antioxidant evaluation of these selected hybrids on the IR‐induced reactive oxygen species (ROS) generation and lipid peroxidation in the HFF‐1 cells revealed that they could significantly downregulate IR‐induced oxidative stress in the HFF‐1 cells, while mechanistically recilisib is not a well‐established ROS scavenger. The obtained results suggest that these privileged (E)‐kojyl‐styryl‐sulfones can serve as promising radioprotectors for further studies and development.