36010-22-7Relevant academic research and scientific papers
Synthesis and evaluation of cardiac glycoside mimics as potential anticancer drugs
Jensen, Marie,Schmidt, Steffen,Fedosova, Natalya U.,Mollenhauer, Jan,Jensen, Henrik H.
, p. 2407 - 2417 (2011)
The cardiac glycoside digitoxin, consisting of a steroid core linked to a labile trisaccharide, has been used for centuries for the treatment of congestive heart failure. The well known pharmacological effect is a result of the ability of cardiac glycosides to inhibit the Na+, K +-ATPase. Within recent years cardiac glycosides have furthermore been suggested to possess valuable anticancer activity. To mimic the labile trisaccharide of digitoxin with a stabile carbohydrate surrogate, we have used sulfur linked ethylene glycol moieties of varying length (mono-, di-, tri- or tetra-ethylene glycol), and furthermore used these linkers as handles for the synthesis of bivalent steroids. The prepared compounds were evaluated for their potencies to inhibit the Na+, K+-ATPase and for their cytotoxic effect on cancerous MCF-7 cells. A clear trend is observed in both inhibition and cytotoxic effect, where the bioactivity decreases as the size increases. The most potent Na+, K+-ATPase inhibitors are the compounds with the shortest ethylene glycol chain (Kapp 0.48 μM) and thiodigitoxigenin (Kapp 0.42 μM), which both are comparable with digitoxigenin (Kapp 0.52 μM). For the cancer cell viability assay the shortest mimics were found to have highest efficacy, with the best ligand having a monoethylene glycol unit (IC50 0.24 μM), which was slightly better than digitoxigenin (IC50 0.64 μM), while none of the novel cardiac glycoside mimics display an in vitro effect as high as digitoxin (IC50 0.02 μM).
Potential anti-herpes and cytotoxic action of novel semisynthetic digitoxigenin-derivatives
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, Fern?o Castro,Alves, Ricardo José,Maia de Pádua, Rodrigo,Oliveira Sim?es, Cláudia Maria
, p. 546 - 561 (2019/02/25)
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.
