A novel cytosporone 3-Heptyl-4,6-dihydroxy-3H-isobenzofuran-1-one: synthesis; toxicological, apoptotic and immunomodulatory properties; and potentiation of mutagenic damage

Abstract

Background: A large number of studies are attempting to identify alternative products from natural sources or synthesized compounds that effectively interact with cancer cells without causing adverse effects on healthy cells. Resorcinolic lipids are a class of bioactive compounds that possess anticancer activity and are able to interact with the lipid bilayer. Therefore, the objective of this study was to synthesize a novel resorcinolic lipid and test its biological proprieties.

Methods: We aimed to synthesize a novel resorcinolic lipid belonging to the class of cytosporones, AMS049 (3-Heptyl-4,6-dihydroxy-3H-isobenzofuran-1-one) and to evaluate the toxicity of two concentrations of this lipid (7.5 and 10 mg/kg) by determining its genotoxic, mutagenic, immunomodulatory, and apoptotic effects, as well as any biochemical and histopathological alterations in mice treated with cyclophosphamide. The results were analyzed by ANOVA followed by the Tukey test A . level of significance of p < 0.05 was adopted.

Results: The new cytosporone AMS049 was synthesized in only three steps and in satisfactory yields. The results indicate that the compound is neither genotoxic nor mutagenic and does not alter biochemical parameters. The histological alterations observed in the liver and kidneys did not compromise the function of these organs. Histology of the spleen suggested immunomodulation, although no changes were observed in splenic phagocytosis or differential blood cell count. The results also show that AMS049 potentiates the mutagenic effect of the chemotherapy drug cyclophosphamide and that the combination induces apoptosis.

Conclusion: These facts indicate a potential therapeutic application of this novel cytosporone as an important chemotherapeutic adjuvant.

Fig. 1

Retrosynthetic analysis of the novel cytosporone and structures of natural cytosporones C and E. FGI – Functional Group Interconversion

Fig. 2

Synthesis of AMS049

Fig. 3

(a) ESI(+) and (b) ESI(-)FT-ICR mass spectra for compounds 2 and 3, respectively

Fig. 4

Data of mice’ weights represented as graphic. a Initial, final and weight gain. b Absolute weight of the organs. c Relative weight of the organs. Different letters indicate statistically significant differences (p < 0.05; ANOVA/Tukey test)