Syntheses, biological evaluation and SAR of ingenol mebutate analogues for treatment of actinic keratosis and non-melanoma skin cancer
| Autor: | Karen Margrethe Engell, Kristoffer Månsson, Martin Stahlhut, Malene Bertelsen, Xifu Liang, Gunnar Grue-Sørensen, Thomas Högberg, Anke Soor, Per Vedsø |
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| Rok vydání: | 2013 |
| Předmět: |
Keratinocytes
Skin Neoplasms Clinical Biochemistry Ingenol mebutate Pharmaceutical Science Antineoplastic Agents Apoptosis Pharmacology Biochemistry Chemical synthesis Cell Line Structure-Activity Relationship chemistry.chemical_compound Drug Discovery medicine Humans Melanoma Molecular Biology Active ingredient Tumor Necrosis Factor-alpha Chemistry Interleukin-8 Organic Chemistry Actinic keratosis medicine.disease In vitro Keratosis Actinic Oxidative Stress Cell Death Induction medicine.anatomical_structure Leukocytes Mononuclear Molecular Medicine Diterpenes Skin cancer Reactive Oxygen Species Keratinocyte |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 23:5624-5629 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2013.08.038 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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