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
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.