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

Abstract

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.

• Authors: Xifu Liang, Gunnar Grue-Sørensen, Kristoffer Månsson, Per Vedsø, Anke Soor, Martin Stahlhut, Malene Bertelsen, Karen Margrethe Engell, Thomas Högberg
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 20 Pg. 5624-9 (Oct 15 2013) ISSN: 1464-3405 [Electronic] England
• PMID: 23993332 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• 3-ingenyl angelate
• Antineoplastic Agents
• Diterpenes
• Interleukin-8
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha

Topics

• Antineoplastic Agents (chemical synthesis, therapeutic use, toxicity)
• Apoptosis (drug effects)
• Cell Line
• Diterpenes (chemistry, therapeutic use, toxicity)
• Humans
• Interleukin-8 (metabolism)
• Keratinocytes (drug effects, metabolism)
• Keratosis, Actinic (drug therapy, metabolism)
• Leukocytes, Mononuclear (metabolism)
• Melanoma (pathology)
• Oxidative Stress (drug effects)
• Reactive Oxygen Species (metabolism)
• Skin Neoplasms (drug therapy, metabolism, pathology)
• Structure-Activity Relationship
• Tumor Necrosis Factor-alpha (metabolism)