Synthesis and evaluation of cardiac glycoside mimics as potential anticancer drugs

  • Jensen M
  • Schmidt S
  • Fedosova N
 et al. 
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Abstract

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 (K app 0.48 μM) and thiodigitoxigenin (K app 0.42 μM), which both are comparable with digitoxigenin (K app 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 (IC 50 0.24 μM), which was slightly better than digitoxigenin (IC 50 0.64 μM), while none of the novel cardiac glycoside mimics display an in vitro effect as high as digitoxin (IC 50 0.02 μM). © 2011 Elsevier Ltd. All rights reserved.

Author-supplied keywords

  • +, K
  • +-ATPase
  • 1,2 bis(3 digitoxigenin)disulfane
  • 1,2 bis(digitoxigenin 3 ylthio)ethane
  • 1,4 (1,4 dimercapto 1,4 dideoxydiethylene glycol)b
  • 1,6 (1,6 dimercapto 1,6 dideoxytriethylene glycol)
  • 2 (digitoxigenin 3 ylthio)ethanol
  • 3 deoxy 3 mercaptoacetyldigitoxigenin
  • 3 epi o 4 toluenesulfonyldigitoxigenin
  • 3 epidigitoxigenin
  • 3 mercaptodigitoxigenin
  • 4 (digitoxigenin 3 ylthio)diethylene glycol
  • 6 (digitoxigenin 3 ylthio)triethylene glycol
  • 8 (digitoxigenin 3 ylthio)tetraethylene glycol
  • Animals
  • Anti-proliferation
  • Antineoplastic Agents
  • Biomimetic Materials
  • Carbohydrate Sequence
  • Cell Line, Tumor
  • Digitoxin
  • Ethylene glycol
  • Humans
  • IC 50
  • Molecular Sequence Data
  • Na
  • Sodium-Potassium-Exchanging ATPase
  • Tetra
  • adenosine triphosphatase (potassium sodium)
  • adenosine triphosphatase (potassium sodium) inhibi
  • antineoplastic agent
  • article
  • cardiac glycoside
  • cell strain MCF 7
  • cell viability
  • controlled study
  • digitoxigenin
  • digitoxigenone
  • drug cytotoxicity
  • drug mechanism
  • drug screening
  • drug synthesis
  • enzyme inhibition
  • human
  • human cell
  • monoethylene glycol
  • steroid
  • tert butyldimehylsilyl 2 (digitoxigenin 3 ylthio)e
  • tert butyldimehylsilyl 4 (digitoxigenin 3 ylthio)d
  • tert butyldimehylsilyl 6 (digitoxigenin 3 ylthio)t
  • tert butyldimehylsilyl 8 (digitoxigenin 3 ylthio)t
  • tetraethylene glycol
  • thiodigitoxigenin
  • triethylene glycol
  • unclassified drug
  • unindexed drug

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Authors

  • M Jensen

  • S Schmidt

  • N U Fedosova

  • J Mollenhauer

  • H H Jensen

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