Betulinic Acid-Azaprostanoid Hybrids: Synthesis and Pharmacological Evaluation as Anti-inflammatory Agents

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Author(s): Tatyana S. Khlebnicova*, Yuri A. Piven, Fedor A. Lakhvich, Iryna V. Sorokina, Tatiana S. Frolova, Dmitry S. Baev, Tatyana G. Tolstikova.

Journal Name: Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

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Abstract:

Background: Prevention and treatment of chronic inflammatory diseases requires effective and low-toxic medicines. Molecular hybridization is an effective strategy to enhance the biological activity of new compounds. Triterpenoid scaffolds are in the focus of attention owing to their anti-inflammatory, antiviral, antiproliferative, immunomodulatory activities. Heteroprostanoids have different pleiotropic effects in acute and chronic inflammatory processes.

Objective: Development of structurally new and low toxic anti-inflammatory agents via hybridization of betulinic acid with azaprostanoic acids.

Methods: A series of betulinic acid−azaprostanoid hybrids was synthesized. The synthetic pathway included a transformation of betulin via Jones' oxidation into betulonic acid, a reductive amination of the latter and coupling obtained 3β-amino-3-deoxybetulinic acid with the 7- or 13-azaprostanoic acids and their homo analogues. The hybrids 1-9 were investigated in vivo on histamine-, formalin- and concanavalin A-induced mouse paw edema models and two models of a pain ̶ the acetic acid-induced abdominal writhing and the hot-plate test. The hybrids were in vitro evaluated for cytotoxic activity on cancer (MCF7, U−87 MG) and non-cancer humane cell lines.

Results: In the immunogenic inflammation model, the substances showed pronounced anti-inflammatory effect, which was comparable to that of indomethacin. In the models of the exudative inflammation, none of the compounds displayed a statistically significant effect. The hybrids produced weak or moderate analgesic effects. All agents revealed low cytotoxicity on human immortalized fibroblasts and cancer cell lines compared with 3β-amino-3-deoxybetulinic acid and doxorubicin.

Conclusion: The results indicate that the principal anti-inflammatory effect of hybrids is substantially provided with the triterpenoid scaffold and in some measure with the azaprostanoid scaffold, but the last one makes a significant contribution to reducing the toxicity of hybrids. Hybrid 1 is of interest as a potent low toxic agent against immune-mediated inflammation.

Keywords: Betulinic acid, azaprostanoids, hybrids, anti-inflammatory activity, analgesic activity, cytotoxicity

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(E-pub Ahead of Print)
DOI: 10.2174/1871523018666190426152049