Silibinin phosphodiester glyco-conjugates: Synthesis, redox behaviour and biological investigations

• Published in: Bioorganic chemistry Vol. 77; pp. 349 - 359
• Main Authors: Romanucci, Valeria, Agarwal, Chapla, Agarwal, Rajesh, Pannecouque, Christophe, Iuliano, Mauro, De Tommaso, Gaetano, Caruso, Tonino, Di Fabio, Giovanni, Zarrelli, Armando
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.04.2018; Elsevier
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biochemistry & Molecular Biology; Cell Death - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Chemistry; Chemistry, Organic; Dose-Response Relationship, Drug; Flavonolignans; Glyco-conjugates; Glycoconjugates - chemical synthesis; Glycoconjugates - chemistry; Glycoconjugates - pharmacology; HIV - drug effects; Humans; Life Sciences & Biomedicine; Molecular Structure; Organophosphates - chemistry; Organophosphates - pharmacology; Oxidation-Reduction; PC-3 Cells; Phosphoramidite chemistry; Physical Sciences; Science & Technology; Silibinin; Silybin; Silybin - chemistry; Silybin - pharmacology; Structure-Activity Relationship; Glyco-conjugates; Silybin; Flavonolignans; Phosphoramidite chemistry; Silibinin; DRUG; DESIGN; GYMNEMA-SYLVESTRE; HIV REPLICATION; CANCER; ANTIOXIDANT PROPERTIES; PRODRUGS; PHARMACOLOGICAL-ACTIVITIES; SILYMARIN
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.01.026

[Display omitted] •New silibinin glyco-conjugates were synthesized and fully characterized by NMR.•Radical scavenging activity of new derivatives was better than that of silibinin.•Electrochemical behaviour of derivatives was similar to that silibinin.•Serum stability were 40–70 h, making them useful in pro-drug approach.•The glucosamine-phosphodiester silibinin exhibited mild anti-HIV-1 activity. New silibinin phosphodiester glyco-conjugates were synthesized by efficient phosphoramidite chemistry and were fully characterized by 2D-NMR. A wide-ranging study focused on the determination of their pKa and E° values as well as on their radical scavenging activities by different assays (DPPH, ABTS+ and HRSA) was conducted. The new glyco-conjugates are more water-soluble than silibinin, and their radical scavenging activities are higher than those of silibinin. The conjugation therefore improves both the water solubilities and antioxidant activities of the flavonolignan moieties. The serum stability was evaluated under physiological conditions, and the glyco-conjugates degraded with half-lives of 40–70 h, making them useful in pro-drug approaches. We started by treating androgen-dependent prostate cancer (PCa) LNCaP cells and then expanded our studies to androgen-independent PCa PC3 and DU145 cells. In most cases, the new derivatives significantly reduced both total and live cell numbers, albeit at different levels. Anti-HIV activities were evaluated and the glucosamine-phosphate silibinin derivative showed higher activity (IC50 = 73 μM) than silibinin.