Potential anti-herpes and cytotoxic action of novel semisynthetic digitoxigenin-derivatives

In recent years, new therapeutic possibilities, such as anticancer and antiviral activities [1], [2] were proposed for cardiac glycosides used to treat heart diseases. The present work aimed to synthesize the readily accessible 3β-azido-3-deoxydigitoxigenin from digitoxigenin. Two new series of compounds were obtained from 3β-azido-3-deoxydigitoxigenin: (i) O-glycosyl trizols through click chemistry with propargyl glycosides; and (ii) compounds substituted in the alpha carbonyl position with different residues linked via an amino-group. All obtained derivatives had their chemical structures confirmed, and their anti-herpes (against HSV-types 1 and 2 replication) and cytotoxic (against PC3, A549, HCT-8 and LNCaP cell lines) activities evaluated. Compounds 10 and 11 [Fig. 1] exhibited the most promising results against HSV-1 (KOS and 29-R strains) and HSV-2 (333 strain) replication with SI values > 1000. Both compounds were also the most cytotoxic for the human cancer cell lines tested with IC₅₀ values similar to those of paclitaxel. They also presented reduced toxicity toward non-cancerous cell lines (MRC-5 and HGF cells). Promising compounds were tested in regard to their ability to inhibit Na ⁺/K ⁺-ATPase. The inhibition rate correlated suitably with the bioactivity demonstrated by both compounds against the different human cancer cells tested as well as against HSV replication. Moreover, the results showed that specific chemical features of compounds 10 and 11 influenced the bioactivities tested. In summary, it was possible to obtain novel digitoxigenin-derivatives with remarkable cytotoxic and anti-herpes activities as well as low toxicity and high selectivity. In this way, they could be considered potential molecules for the development of new drugs.

Fig. 1 Chemical structure of 3β-[(N-(2-hydroxyetil)aminoacetyl] amino-3-deoxydigitoxigenin (compound 10) and 3β-(hydroxyacetyl)amino-3-deoxydigitoxigenin (compound 11).

• References

• 1 Schneider NFZ, Cerella C, Simões CMO. et al. Anticancer and Immunogenic Properties of Cardiac Glycosides. Molecules 2017; 22
• 2 Bertol JW, Rigotto C, de Pádua RM. et al. Antiherpes activity of glucoevatromonoside, a cardenolide isolated from a Brazilian cultivar of Digitalis lanata, Antiviral Res. 2011; 92: 73-80