Estudo prospectivo da alga marinha Laurencia obtusa para a atividade antitumoral

Abstract

The Brazilian marine environment has great potential in the search for new bioactive natural products. About 1.000 new compounds, derived from marine organisms, have been discovered in the last decade worldwide. Most marine natural products have cytotoxicity, giving hope as treatment of several types of cancer. Algae play an important role in studies of new treatments for many diseases, such as diabetes, hypertension and bacterial, fungal and viral infections, cancer and another one. Among them, red algae are the main producers of bioactive compounds. Laurencia genus have secondary metabolites known for their cytotoxic and anti-inflammatory action, such as sesquiterpenes, diterpenes and acetogenins. The species Laurencia obtusa has demonstrated in studies antitumor activity against chronic myeloid leukemia, breast cancer, prostate cancer, cervical cancer, skin cancer and liver cancer. Mortality associated with cancer worldwide has been growing over the years, and therefore, the need for new treatments as well. It is estimated that over the next three years more than 60.000 Brazilians will be affected by stomach cancer. Therefore, it is expected that new bioactive compounds, such as those from L. obtuse, are a potential treatment for to fight the disease. So, a bioguided study was conducted from the crude extract dichloromethane:methanol (2:1), obtaining fractions of different polarities. The structural determination of the compounds of the crude extract and fractions was performed by mass spectrometry analysis (ESI-FT-ICR/MS) and demonstrated the presence of terpenes, an acetogenin and a fatty acid. In vitro cytotoxicity assays were performed with gastric adenocarcinoma cell lines to select the most cytotoxic fraction of L. obtusa crude extract. The Hex:AcOEt (3:1) fraction, derived from the AcOEt fraction, was the most cytotoxic with an IC50 of 9.23 μg/ml and selectivity index of 15.56 μg/ml. In silico methods were applied to identify the possible mechanism of action of the compounds, through the analysis of crystallographic complexes and molecular docking calculations. Known compounds from L. obtusa were tested at the active site of the HIF-2α protein and the acetogenin scanlonenyne showed a score of 68.40 indicating affinity for the active site. Among the compounds of the Hex:AcOEt (3:1) fraction, the sesquiterpene chermesiterpenoid B showed the highest affinity with a score of 65.90. Of the 11 proposed substances, 9 are described for the first time in this species. The results obtained indicate that molecules found in L. obtusa fractions have therapeutic potential to be used in the treatment of neoplasms, such as gastric adenocarcinoma.