title: 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.affiliation: Chemical Research, LEO Pharma A/S, 55 Industripaken, DK-2750 Ballerup, Denmark.
authors.forename: Xifu
authors.initials: X
authors.lastname: Liang
authors.forename: Gunnar
authors.initials: G
authors.lastname: Grue-Sørensen
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Månsson
authors.forename: Per
authors.initials: P
authors.lastname: Vedsø
authors.forename: Anke
authors.initials: A
authors.lastname: Soor
authors.forename: Martin
authors.initials: M
authors.lastname: Stahlhut
authors.forename: Malene
authors.initials: M
authors.lastname: Bertelsen
authors.forename: Karen Margrethe
authors.initials: KM
authors.lastname: Engell
authors.forename: Thomas
authors.initials: T
authors.lastname: Högberg
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004224:Diterpenes / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D055623:Keratosis, Actinic / Q000188:drug therapy / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008545:Melanoma / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C486592:3-ingenyl angelate; D000970:Antineoplastic Agents; D004224:Diterpenes; D016209:Interleukin-8; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha
keywords: Cell death induction; Cytokine release; Immune system activation; Ingenol 3-acylates; Ingenol derivatives; Oxidative burst; PKC activation