title: Betulin Derivatives Effectively Suppress Inflammation in Vitro and in Vivo.
abstract: Betulin is a pharmacologically active triterpenoid found in the bark of the birch tree (Betula sp. L.). Betulin and betulinic acid are structurally related to anti-inflammatory steroids, but little is known about their potential anti-inflammatory properties. In the present study, the inflammatory gene expression and the anti-inflammatory properties of betulin, betulinic acid, and 16 semisynthetic betulin derivatives were investigated. Betulin derivatives 3, 4, and 5 selectively inhibited the expression of the inducible nitric oxide synthase (iNOS) in a post-transcriptional manner. They also inhibited nitric oxide (NO) production but had no effect on the other inflammatory factors studied. More interestingly, a new anti-inflammatory betulin derivative 9 with a wide-spectrum anti-inflammatory activity was discovered. Compound 9 was found to suppress the expression of cytokines interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1), as well as that of prostaglandin synthase-2 (COX-2) in addition to iNOS. The in vivo anti-inflammatory effect of compound 9 was indicated via significant suppression of the carrageenan-induced paw inflammation in mice. The results show, for the first time, that the pyrazole-fused betulin derivative (9) and related compounds have anti-inflammatory properties that could be utilized in drug development.
authors.affiliation: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital , FI-33014 Tampere, Finland.
authors.forename: Mirka
authors.initials: M
authors.lastname: Laavola
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.
authors.forename: Raisa
authors.initials: R
authors.lastname: Haavikko
authors.affiliation: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital , FI-33014 Tampere, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Hämäläinen
authors.affiliation: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital , FI-33014 Tampere, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Leppänen
authors.affiliation: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital , FI-33014 Tampere, Finland.
authors.forename: Riina
authors.initials: R
authors.lastname: Nieminen
authors.affiliation: Process Chemistry and Environmental Engineering, VTT Technical Research Centre of Finland , FI-02044 Espoo, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Alakurtti
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.
authors.forename: Vânia M
authors.initials: VM
authors.lastname: Moreira
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Yli-Kauhaluoma
authors.affiliation: The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital , FI-33014 Tampere, Finland.
authors.forename: Eeva
authors.initials: E
authors.lastname: Moilanen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D029662:Betula; D002351:Carrageenan / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D000094062:Betulinic Acid; D000093242:Interleukin-6 Inhibitors
chemical_list: D000893:Anti-Inflammatory Agents; D002351:Carrageenan; D018932:Chemokine CCL2; D051546:Cyclooxygenase 2; D016207:Cytokines; D015232:Dinoprostone; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D000094062:Betulinic Acid; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C002503:betulin