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Synthesis and Evaluation of Antitumor Alkylphospholipid Prodrugs



Hemolysis is a serious side effect of antitumor alkylphospholipids (APLs) that limits dose levels and is a constraint in their use in therapeutic regimen. Nine prodrugs of promising APLs (miltefosine, perifosine, and erufosine) were synthesized so as to decrease their membrane activity and improve their toxicity profile while preserving their antineoplastic potency.


The synthesis of the pro-APLs was straightforwardly achieved in one step starting from the parent APLs. The critical aggregation concentration of the prodrugs, their hydrolytic stability under various pH conditions, their blood compatibility and cytotoxicity in three different cell lines were determined and compared to those of the parent antitumor lipids.


The APL prodrugs display antitumor activity which is similar to that of the parent alkylphospholipids but without associated hemolytic toxicity.


The pro-APL compounds may be considered as intravenously injectable derivatives of APLs. They could thus address one of the major issues met in cancer therapies involving antitumor lipids and restricting their utilization to oral and topical administration because of limited maximum tolerated dose.

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Correspondence to Luc Lebeau.

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The detailed description of the materials and methods used to characterize the hydrolytic stability, self-assembly properties, hemolytic activity, and cytotoxicity of the compounds as well as the 1H-, 13C-, and 31P-NMR spectra for compounds Ma, Mb, Mc, Pa, Pb, and Pc are provided as Supplementary Information and can be found at http://… (PDF 10173 kb)

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Gaillard, B., Remy, JS., Pons, F. et al. Synthesis and Evaluation of Antitumor Alkylphospholipid Prodrugs. Pharm Res 37, 106 (2020).

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Key Words

  • alkylphospholipid
  • erufosine
  • hemolytic toxicity
  • miltefosine
  • perifosine
  • prodrug