Prospecção de metabólitos secundários citotóxicos oriundos de fungos marinhos isolados de sedimentos do litoral cearense

Abstract

This thesis reports the investigation of marine fungi as producers of cytotoxic secondary metabolites against the human tumor cell line HCT-116 (colon). The fungal strains investigated in this study were isolated from sediments collected in Ceará coast, thirty-five of them from Mucuripe beach (BRF012-BRF046) and forty-eight from Pecém beach (BRF047-BRF094). All strains were subjected to small-scale cultivation (100 mL of potato-dextrose medium with synthetic sea water) during fourteen days. After the cultivation, the culture media were partitioned with ethyl acetate (EtOAc) and the organic extracts subjected to cytotoxic activity against the cancer cell line HCT-116. Strains that showed the highest percentage of cell growth inhibition, BRF019 (95.5%), BRF079 (100.0%) and BRF082 (100.0%), were selected for bioguided fractionation of the organic extracts. Phylogenetic analyses have identified them as Aspergillus terreus (BRF019) and Dichotomomyces cejpii (BRF079 and BRF082). BRF019 (A. terreus) was cultivated twice in a large scale (6 L and 12 L medium). The bioguided fractionation of EtOAc extracts from the culture medium led to the isolation of five compounds: Terrein, butyrolactone I, II and V, and 6-hidroxymelein. All of them have already been reported in the literature for A. terreus and none showed cytotoxic activity when bioassayed. BRF082 (D. cejpii) was cultivated under the same conditions (15 L and 20 L medium) of BRF019 (A. terreus). The bioguided fractionation of AcOEt extract from the culture medium led to the isolation of an epipolithiodioxopiperazin, gliotoxin, and four analogues: Acetylgliotoxin G, bis(dethio)bis(methylthio)gliotoxin, acetylgliotoxin, 6-acetylbis(methylthio)gliotoxin, besides the quinazolinic alkaloid fiscalin B. These compounds were tested for cytotoxic activity and suggested gliotoxin (IC50 1.02) and acetylgliotoxin G (IC50 2.39) as responsible for the cytotoxicity of the EtOAc extract of D. cejpii.