Design and synthesis of new Silybin-carnosine conjugates with antioxidant and cytoprotective effects in LPS-treated RAW264.7 macrophages

Natural compounds are emerging as promising agents in the pharmacology of inflammation, particularly for their ability to treat chronic diseases associated with inflammatory processes. This work focuses on the conjugation of silybins (silybin AB, silybin A and silybin B) extracted from milk thistle with l -carnosine ( l -Car), a dipeptide with immunomodulatory effects. Despite their therapeutic potential, both compounds have pharmacokinetic constraints, which include limited bioavailability due to the low solubility of silybins and the poor stability of L-Car in the bloodstream. To overcome these issues, we designed novel bioconjugates with phosphodiester linkage that retain the pharmacologically significant moieties of both molecules. Starting from properly protected silybins and carnosinol, the new conjugates (Sil p Car) were synthesized following the well-established phosphoramidite chemistry. New Sil p Car conjugates, in addition to being more soluble than silybins also demonstrated high stability in the human serum. Our in vitro investigations showed that these new derivatives outperform their parent drugs in terms of protecting RAW macrophage cell lines against lipopolysaccharide (LPS) damage. This study lays the groundwork for the development of multifunctional drugs that combine antioxidant and cytoprotective actions, with potential relevance to inflammatory conditions.