title: 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: Chemical Research, LEO Pharma A/S, 55 Industripaken, DK-2750 Ballerup, Denmark.
authors: Gunnar
authors: G
authors: Grue-Sørensen
authors: Chemical Research, LEO Pharma A/S, 55 Industripaken, DK-2750 Ballerup, Denmark.
authors: Xifu
authors: X
authors: Liang
authors: Chemical Research, LEO Pharma A/S, 55 Industripaken, DK-2750 Ballerup, Denmark.
authors: Kristoffer
authors: K
authors: Månsson
authors: Chemical Research, LEO Pharma A/S, 55 Industripaken, DK-2750 Ballerup, Denmark.
authors: Per
authors: P
authors: Vedsø
authors: Chemical Research, LEO Pharma A/S, 55 Industripaken, DK-2750 Ballerup, Denmark.
authors: Morten
authors: M
authors: Dahl Sørensen
authors: Chemical Research, LEO Pharma A/S, 55 Industripaken, DK-2750 Ballerup, Denmark.
authors: Anke
authors: A
authors: Soor
authors: Biological Research, LEO Pharma A/S, 55 Industriparken, DK-2750 Ballerup, Denmark.
authors: Martin
authors: M
authors: Stahlhut
authors: Biological Research, LEO Pharma A/S, 55 Industriparken, DK-2750 Ballerup, Denmark.
authors: Malene
authors: M
authors: Bertelsen
authors: Product Reprofiling, LEO Pharma A/S, 55 Industriparken, DK-2750 Ballerup, Denmark.
authors: Karen Margrethe
authors: KM
authors: Engell
authors: Chemical Research, LEO Pharma A/S, 55 Industripaken, DK-2750 Ballerup, Denmark. Electronic address: thomas.hogberg@leo-pharma.com.
authors: Thomas
authors: T
authors: Högberg
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D055623:Keratosis, Actinic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D016207:Cytokines; D004224:Diterpenes; D047428:Protein Kinase Inhibitors; D051745:Protein Kinase C-delta; C008125:ingenol
keywords: Cell death induction; Cytokine release; Ingenol 3-benzoates; Molecular modeling; Oxidative burst; PKCδ activation