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

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.