Betulin Derivatives Effectively Suppress Inflammation in Vitro and in Vivo

  • J Nat Prod. 2016 Feb 26;79(2):274-80. doi: 10.1021/acs.jnatprod.5b00709.
Mirka Laavola  1 ,  Raisa Haavikko  2 ,  Mari Hämäläinen  1 ,  Tiina Leppänen  1 ,  Riina Nieminen  1 ,  Sami Alakurtti  3 ,  Vânia M Moreira  2 ,  Jari Yli-Kauhaluoma  2 ,  Eeva Moilanen  1
Affiliations
  • 1. The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital , FI-33014 Tampere, Finland.
  • 2. Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , FI-00014 Helsinki, Finland.
  • 3. Process Chemistry and Environmental Engineering, VTT Technical Research Centre of Finland , FI-02044 Espoo, Finland.
PMID: 26915998 DOI: 10.1021/acs.jnatprod.5b00709
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.