Structure–mutagenicity relationship of kaurenoic acid from Xylopia sericeae (Annonaceae)

Abstract

Kaurane diterpenes are considered important compounds in the development of new highly effective anticancer chemotherapeutic agents. Genotoxic effects of anticancer drugs in non-tumour cells are of special significance due to the possibility that they induce secondary tumours in cancer patients. In this context, we evaluated the genotoxic and mutagenic potential of the natural diterpenoid kaurenoic acid (KA), i.e. (-)-kaur-16-en-19-oic acid, isolated from Xylopia sericeae St. Hill, using several standard in vitro and in vivo protocols (comet, chromosomal aberration, micronucleus and Saccharomyces cerevisiae assays). Also, an analysis of structure-activity relationships was performed with two natural diterpenoid compounds, 14-hydroxy-kaurane (1) and xylopic acid (2), isolated from X. sericeae, and three semi-synthetic derivatives of KA (3-5). In addition, considering the importance of the exocyclic double bond (C16) moiety as an active pharmacophore of KA cytotoxicity, we also evaluated the hydrogenated derivative of KA, (-)-kauran-19-oic acid (KAH), to determine the role of the exocyclic bond (C16) in the genotoxic activity of KA. In summary, the present study shows that KA is genotoxic and mutagenic in human peripheral blood leukocytes (PBLs), yeast (S. cerevisiae) and mice (bone marrow, liver and kidney) probably due to the generation of DNA double-strand breaks (DSB) and/or inhibition of topoisomerase I. Unlike KA, compounds 1-5 and KAH are completely devoid of genotoxic and mutagenic effects under the experimental conditions used in this study, suggesting that the exocyclic double bond (C16) moiety may be the active pharmacophore of the genetic toxicity of KA.

The epimer of kaurenoic acid from Croton antisyphiliticus is cytotoxic toward B-16 and HeLa tumor cells through apoptosis induction

“…Thus, the discovery of drugs from medicinal plants may play an important role in cancer treatment. Kaurane diterpenes are considered important compounds in the development of new highly effective anticancer chemotherapeutic agents (Cavalcanti et al, 2010). Kaurene diterpenes such as EKA have been considered important for the development of new effective anticancer compounds due to their cytotoxic property related to induction of apoptosis via inhibition of NF-κB and activation of caspase 8 (Mongelli et al, 2002).…”

Mikania glomerata and M. laevigata: Clinical and Toxicological Advances

“…and at higher doses (50 and 100 mg/kg) in kidney cells. No DNA breaks were observed after the treatment in spleen cells (Cavalcanti et al, 2010). Finally, genotoxicity in Chinese hamster lung fibroblast cells was also observed using the comet and the micronucleus assays.…”

“…Using a yeast cell model, cytotoxic and mutagenic effects of kaurenoic acid were also observed in the XV185-14c strain: there was an increase in the frequencies of point, frameshift, and forward mutations in the stationary phase at high concentrations (0.5-2 μg/mL). However, these effects were more pronounced when cells were treated in the exponential phase than in growth or non-growth conditions (Cavalcanti et al, 2010). Positive genotoxic effects have also been described testing kaurenoic acid in vivo in multiple organs, such as the liver, kidney and spleen of mice (alkaline comet assay).…”

Review of current and “omics” methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms

“…Genotoxicity can be due to many physico-chemical agents that result in a wide variety of possible damages to the genetic material, ranging from various DNA adducts to single-and double-strand breakages, DNA-DNA and DNA-protein cross-links or even chromosomal breakage (Ogura et al, 2008;Cavalcanti et al, 2010;Wang et al, 2012). The major challenge in genotoxicity testing resides in developing methods that can reliably and sensibly detect either such a vast array of damages or a general cellular response to genotoxic insult.…”