Synthesis, biological evaluation and SAR of 3-benzoates of ingenol for treatment of actinic keratosis and non-melanoma skin cancer

  • Bioorg Med Chem Lett. 2014 Jan 1;24(1):54-60. doi: 10.1016/j.bmcl.2013.11.073.
Gunnar Grue-Sørensen  1 ,  Xifu Liang  1 ,  Kristoffer Månsson  1 ,  Per Vedsø  1 ,  Morten Dahl Sørensen  1 ,  Anke Soor  1 ,  Martin Stahlhut  2 ,  Malene Bertelsen  2 ,  Karen Margrethe Engell  3 ,  Thomas Högberg  4
Affiliations
  • 1. Chemical Research, LEO Pharma A/S, 55 Industripaken, DK-2750 Ballerup, Denmark.
  • 2. Biological Research, LEO Pharma A/S, 55 Industriparken, DK-2750 Ballerup, Denmark.
  • 3. Product Reprofiling, LEO Pharma A/S, 55 Industriparken, DK-2750 Ballerup, Denmark.
  • 4. Chemical Research, LEO Pharma A/S, 55 Industripaken, DK-2750 Ballerup, Denmark. Electronic address: [email protected].
PMID: 24332494 DOI: 10.1016/j.bmcl.2013.11.073
Abstract

Ingenol 3-benzoates were investigated with respect to chemical stability, pro-inflammatory effects, cell death induction and PKCδ activation. A correlation between structure, chemical stability and biological activity was found and compared to ingenol mebutate (ingenol 3-angelate) used for field treatment of actinic keratosis. We also provided further support for involvement of PKCδ for induction of oxidative burst and cytokine release. Molecular modeling and dynamics calculations corroborated the essential interactions between key compounds and C1 domain of PKCδ.

Keywords
Cell death induction; Cytokine release; Ingenol 3-benzoates; Molecular modeling; Oxidative burst; PKCδ activation.