Phosphodiester Silybin Dimers Powerful Radical Scavengers: A Antiproliferative Activity on Different Cancer Cell Lines

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 5; p. 1702
• Main Authors: Romanucci, Valeria, Pagano, Rita, Lembo, Antonio, Capasso, Domenica, Di Gaetano, Sonia, Zarrelli, Armando, Di Fabio, Giovanni
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05.03.2022; MDPI
• Subjects: Alzheimer's disease; Angiogenesis; Antioxidants; Antioxidants - chemistry; Antioxidants - pharmacology; Antiproliferatives; Apoptosis; Biological activity; Cancer; Cell cycle; Cell Line; Fibroblasts; Flavonoids; flavonolignan dimers; Hydroxyl radicals; Leukemia; leukemia cells; Metastasis; Neoplasms; Oxidative stress; Quercetin; radical scavenger of ROS; Scavenging; Silibinin; silybin; Silybin - pharmacology; Silymarin; Silymarin - chemistry; Silymarin - pharmacology; Stereochemistry; Tumor cell lines; radical scavenger of ROS; apoptosis; silibinin; leukemia cells; flavonolignan dimers; silybin
• DOI: 10.3390/molecules27051702
• ISSN: 1420-3049

Silibinin is the main biologically active component of silymarin extract and consists of a mixture 1:1 of two diastereoisomeric flavonolignans, namely silybin A ( ) and silybin B ( ), which we call here silybins. Despite the high interest in the activity of this flavonolignan, there are still few studies that give due attention to the role of its stereochemistry and, there is still today a strong need to investigate in this area. In this regard, here we report a study concerning the radical scavenger ability and the antiproliferative activity on different cell lines, both of silybins and phosphodiester-linked silybin dimers. An efficient synthetic strategy to obtain silybin dimers in an optical pure form ( , and ) starting from a suitable building block of silybin A and silybin B, obtained by us from natural extract silibinin, was proposed. New dimers show strong antioxidant properties, determined through hydroxyl radical (HO ) scavenging ability, comparable to the value reported for known potent antioxidants such as quercetin. A preliminary screening was performed by treating cells with 10 and 50 μM concentrations for 48 h to identify the most sensitive cell lines. The results show that silibinin compounds were active on Jurkat, A375, WM266, and HeLa, but at the tested concentrations, they did not interfere with the growth of PANC, MCF-7, HDF or U87. In particular, both monomers ( and ) and dimers ( , and ) present selective anti-proliferative activity towards leukemia cells in the mid-micromolar range and are poorly active on normal cells. They exhibit different mechanisms of action in fact all the cells treated with the and go completely into apoptosis, whereas only part of the cells treated with and were found to be in apoptosis.