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Bioorg Med Chem Lett. 2013 Oct 15;23(20):5624-9. doi: 10.1016/j.bmcl.2013.08.038. Epub 2013 Aug 14.

Syntheses, biological evaluation and SAR of ingenol mebutate analogues for treatment of actinic keratosis and non-melanoma skin cancer.

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Chemical Research, LEO Pharma A/S, 55 Industripaken, DK-2750 Ballerup, Denmark.


Ingenol mebutate is the active ingredient in Picato® a new drug for the treatment of actinic keratosis. A number of derivatives related to ingenol mebutate were prepared by chemical synthesis from ingenol with the purpose of investigating the SAR and potency in assays relating to pro-inflammatory effects (induction of PMN oxidative burst and keratinocyte cytokine release), the potential of cell death induction, as well as the chemical stability. By modifications of the ingenol scaffold several prerequisites for activity were identified. The chemical stability of the compounds could be linked to an acyl migration mechanism. We were able to find analogues of ingenol mebutate with comparable in vitro properties. Some key features for potent and more stable ingenol derivatives have been identified.


Cell death induction; Cytokine release; Immune system activation; Ingenol 3-acylates; Ingenol derivatives; Oxidative burst; PKC activation

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