Synthesis of C3-Neoglycosides of digoxigenin and their anticancer activities

  • Eur J Med Chem. 2018 Feb 10:145:252-262. doi: 10.1016/j.ejmech.2017.12.086.
Xiao-San Li  1 ,  Yi-Chang Ren  1 ,  Yu-Zhou Bao  2 ,  Jie Liu  2 ,  Xiao-Kun Zhang  2 ,  You-Wei Zhang  3 ,  Xue-Long Sun  4 ,  Xin-Sheng Yao  5 ,  Jin-Shan Tang  6
Affiliations
  • 1. Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
  • 2. School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, PR China.
  • 3. Department of Pharmacology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
  • 4. Department of Chemistry, Chemical and Biomedical Engineering and Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, 2121 Euclid Avenue, Cleveland, OH 44115, USA.
  • 5. Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China. Electronic address: [email protected].
  • 6. Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China. Electronic address: [email protected].
PMID: 29329000 DOI: 10.1016/j.ejmech.2017.12.086
Abstract

Cardiac glycosides exhibit significant Anticancer effects and the glycosyl substitution at C3 position of digoxigenin is pivotal for their biological activity. In order to study the structure-activity relationship (SAR) of cardiac glycosides toward cancers and explore more potent Anticancer agents, a series of C3-O-neoglycosides and C3-MeON-neoglycosides of digoxigenin were synthesized by the Koenigs-Knorr and neoglycosylation method, respectively. In addition, digoxigenin bisdigitoxoside and monodigitoxoside were prepared from digoxin by sodium periodate (NaIO4) oxidation and 6-aminocaproic acid hydrolysis. The SAR analysis revealed that C3-O-neoglycosides of digoxigenin exhibited stronger cytotoxicity and induction of Nur77 expression of tumor cells than C3-MeON-neoglycosides. Also, 3β-O-glycosides exhibited stronger Anticancer effects than 3α-O-glycosides. Among them, 3β-O-(β-l-fucopyranosyl)-digoxigenin (3i) showed the highest activity on induction of Nur77 expression and translocation from the nucleus to cytoplasm, leading to Cancer cell Apoptosis.

Keywords
Anticancer; Apoptosis; Cytotoxicity; Digoxigenin; MeON-Noeglycosylation; Nur77 nuclear receptor; O-neoglycosylation.
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