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

Abstract

BackgroundA 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.MethodsWe 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.ResultsThe 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.ConclusionThese facts indicate a potential therapeutic application of this novel cytosporone as an important chemotherapeutic adjuvant.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1532-2) contains supplementary material, which is available to authorized users.

Assessment of genetic integrity, splenic phagocytosis and cell death potential of (Z)-4-((1,5-dimethyl-3-oxo-2-phenyl-2,3dihydro-1H-pyrazol-4-yl) amino)-4-oxobut-2-enoic acid and its effect when combined with commercial chemotherapeutics

“…However, this does not contradict the splenic phagocytosis observed for the two lower doses. According to Oliveira et al. (2015a ), splenic phagocytosis can occur efficiently even in the absence of a change in blood cell counts.…”

“…The micronucleus assay in peripheral blood was performed according to Hayashi et al (1990) , with modifications by Oliveira et al. (2015a) .…”

“… Manoharan and Banerjee (1985) and Waters et al (1990) proposed the calculation of percent damage reduction to assess the chemopreventive ability of a substance when it is associated with a substance known to be mutagenic, such as the commercial chemotherapeutic agents used as positive control (PC). According to Oliveira et al (2015a) and Navarro et al (2014) , the same calculation can be used to estimate the increase in DNA damage. Thus, for the present study, both the percent DNA damage reduction and percent DNA damage increase were calculated using the same formula:…”

Cardanol: toxicogenetic assessment and its effects when combined with cyclophosphamide

“…Analyses were performed by epifluorescence microscopy (Bioval®, Model L 2000A, São Paulo, Brazil) at 400x magnification with a 420-490 nm excitation and a 520 nm barrier filter. A total of 100 cells per animal were examined by visual analysis, and DNA fragment migration was determined according to comet class, as described by Kobayashi et al (1995) with modifications ( Oliveira et al , 2015 ): class 0, intact nucleoid without tail; class 1, cell with tail less than the diameter of the nucleoid; class 2, tail size varying between one and two times the diameter of the nucleoid; class 3, tail size more than two times the diameter of the nucleoid. Apoptotic cells that showed a totally fragmented nucleus were not scored.…”

Prevention of DNA damage and anticarcinogenic activity of Activia^® in a preclinical model

“…The total score was calculated by summing the resulting values from the multiplication of the total cells observed in each lesion class. The statistical analysis was performed using ANOVA or the Tukey test (P < 0.05) (Oliveira et al, 2015).…”