Submit Manuscript  

Article Details


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

[ Vol. 19 , Issue. 3 ]

Author(s):

Tatyana S. Khlebnicova*, Yuri A. Piven, Fedor A. Lakhvich, Iryna V. Sorokina, Tatiana S. Frolova, Dmitry S. Baev and Tatyana G. Tolstikova   Pages 254 - 267 ( 14 )

Abstract:


Background: Prevention and treatment of chronic inflammatory diseases require 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, and immunomodulatory activities. Heteroprostanoids have different pleiotropic effects in acute and chronic inflammatory processes.

Objective: The study aimed to develop 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 the transformation of betulin via Jones' oxidation into betulonic acid, reductive amination of the latter and coupling obtained by 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 pain - the acetic acid-induced abdominal writhing and the hotplate 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 a 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 the 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 cases with the azaprostanoid scaffold, but the latter 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:

Analgesic activity, anti-inflammatory activity, azaprostanoids, betulinic acid, cytotoxicity, hybrids.

Affiliation:

Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Acad. Kuprevicha Street 5/2, 220141 Minsk, Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Acad. Kuprevicha Street 5/2, 220141 Minsk, Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Acad. Kuprevicha Street 5/2, 220141 Minsk, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 prosp. Acad. Lavrentieva, 630090 Novosibirsk, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 prosp. Acad. Lavrentieva, 630090 Novosibirsk, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 prosp. Acad. Lavrentieva, 630090 Novosibirsk, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9 prosp. Acad. Lavrentieva, 630090 Novosibirsk



Read Full-Text article