Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020;19(3):254-267.
doi: 10.2174/1871523018666190426152049.

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

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

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

Tatyana S Khlebnicova et al. Antiinflamm Antiallergy Agents Med Chem. 2020.

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..

PubMed Disclaimer

Figures

Fig. (1)
Fig. (1)
New synthesized and bioevaluated hybirds.
Scheme 1
Scheme 1
A synthetic route for the preparation of hybirds 1-9.
Scheme 2
Scheme 2
Synthesis of azaprostanoic acids 11-19.
See this image and copyright information in PMC

References

    1. Sun L.D., Wang F., Dai F., Wang Y.H., Lin D., Zhou B. Development and mechanism investigation of a new piperlongumine derivative as a potent anti-inflammatory agent. Biochem. Pharmacol. 2015;95(3):156–169. doi: 10.1016/j.bcp.2015.03.014. - DOI - PubMed
    1. Dinarello C.A. Anti-inflammatory agents: present and future. Cell. 2010;140(6):935–950. doi: 10.1016/j.cell.2010.02.043. - DOI - PMC - PubMed
    1. Azab A., Nassar A., Azab A.N. Anti-inflammatory activity of natural products. Molecules. 2016;21(10):1321. doi: 10.3390/molecules21101321. - DOI - PMC - PubMed
    1. Newman D.J., Cragg C.M. Natural product scaffolds of value in medicinal chemistry. In: Bräse S., editor. Privileged scaffolds in medicinal chemistry. Design, synthesis, evaluation. Cambridge, UK: Royal Society of Chemistry; 2016. pp. 348–378.
    1. Tolstikova T.G., Sorokina I.V., Tolstikov G.A., Tolstikov A.G., Flekhter O.B. [Biological activity and pharmacological prospects of lupane terpenoids: I. Natural lupane derivatives]. Bioorg. Khim. 2006;32(1):42–55. - PubMed

MeSH terms