Betulinic acid-azaprostanoid hybrids: Synthesis and pharmacological evaluation as anti-inflammatory agents

Betulinic acid-azaprostanoid hybrids: Synthesis and pharmacological evaluation as anti-inflammatory agents Full article

Journal

Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry

Output data

Year: 2020, Volume: 19, Number: 3, Pages: 254-267 Pages count : 14 DOI: 10.2174/1871523018666190426152049

Tags

Analgesic activity; Anti-inflammatory activity; Azaprostanoids; Betulinic acid; Cytotoxicity; Hybrids

Authors

Khlebnicova Tatyana S. ¹ , Piven Yuri A. ¹ , Lakhvich Fedor A. ¹ , Sorokina Iryna V. ² , Frolova Tatiana S. ² , Baev Dmitry S. ² , Tolstikova Tatyana G. ²

Affiliations

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

Background: Prevention and treatment of chronic inflammatory diseases re-quire 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 immunomod-ulatory 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, re-ductive 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 in-vestigated 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 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 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 ef-fect. 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 azapros-tanoid 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 in-flammation. © 2020 Bentham Science Publishers.

Khlebnicova T.S. , Piven Y.A. , Lakhvich F.A. , Sorokina I.V. , Frolova T.S. , Baev D.S. , Tolstikova T.G.
Betulinic acid-azaprostanoid hybrids: Synthesis and pharmacological evaluation as anti-inflammatory agents

Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry. 2020. V.19. N3. P.254-267. DOI: 10.2174/1871523018666190426152049 Scopus РИНЦ

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Published print:

Sep 3, 2020

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