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

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.

• Authors: Gunnar Grue-Sørensen, Xifu Liang, Kristoffer Månsson, Per Vedsø, Morten Dahl Sørensen, Anke Soor, Martin Stahlhut, Malene Bertelsen, Karen Margrethe Engell, Thomas Högberg
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 24 Issue 1 Pg. 54-60 (Jan 01 2014) ISSN: 1464-3405 [Electronic] England
• PMID: 24332494 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzoates
• Cytokines
• Diterpenes
• Protein Kinase Inhibitors
• Protein Kinase C-delta
• ingenol

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Benzoates (chemical synthesis, chemistry, pharmacology)
• Cell Death (drug effects)
• Cytokines (metabolism)
• Diterpenes (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Keratosis, Actinic (drug therapy, metabolism, pathology)
• Models, Molecular
• Molecular Docking Simulation
• Molecular Structure
• Protein Kinase C-delta (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Skin Neoplasms (drug therapy, metabolism, pathology)
• Structure-Activity Relationship