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

In recent years, new therapeutic possibilities were proposed for cardiac glycosides traditionally used to treat heart diseases, such as anticancer and antiviral activities. In this sense, this work aimed to synthesize the readily accessible 3β-azido-3-deoxydigitoxigenin (5) from digitoxigenin (1). T...

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Published in:European journal of medicinal chemistry 2019-04, Vol.167, p.546-561
Main Authors: Boff, Laurita, Munkert, Jennifer, Ottoni, Flaviano Melo, Zanchett Schneider, Naira Fernanda, Ramos, Gabriela Silva, Kreis, Wolfgang, Fernandes de Andrade, Saulo, Dias de Souza Filho, José, Braga, Fernão Castro, Alves, Ricardo José, Maia de Pádua, Rodrigo, Oliveira Simões, Cláudia Maria
Format: Article
Language:English
Subjects:
Anti-herpes
Cardenolides
Cytotoxic
Digitoxigenin-derivatives
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Summary:In recent years, new therapeutic possibilities were proposed for cardiac glycosides traditionally used to treat heart diseases, such as anticancer and antiviral activities. In this sense, this work aimed to synthesize the readily accessible 3β-azido-3-deoxydigitoxigenin (5) from digitoxigenin (1). Two new series of compounds were obtained from derivative (5): (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 have 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 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 correlates suitably with the bioactivity demonstrated by those both compounds against the different human cancer cells tested as well as against HSV replication. Moreover, the results showed that specific chemical features of compound 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. [Display omitted] •New cardenolide derivatives (CDs) were synthetized by different approaches.•New CDs showed potent cytotoxicity against different human cancer cell lines.•New CDs showed potent anti-herpes action against different strains of HSV-1 and HSV-2.•Specific chemical features influenced the bioactivity of the new CDs.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2019.01.076