Isolamento, síntese e avaliação da atividade biológica de diterpenos do tipo labdano

Abstract

From the tree trunk of the Copaifera (Leguminosae) genus is extracted a balm called oleoresin (ORC). The oleoresin consists of a volatile fraction, rich in sesquiterpenes, and a fixed portion, composed predominantly of diterpenes. Among the diterpenes, it is noteworthy the copalic acid (CA), which is present in all oleoresins from the Copaifera genus, being considered a biomarker. Studies have shown that CA and other diterpenes labdans present in ORC have a high biological potential, possessing important antibacterial, cytotoxic and anti-inflammatory activity, being therefore promising prototypes for the development of bioactive molecules. Thus, the objective of the present work consisted in the isolation of the labdanes diterpenes from the Copaifera langsdorffii oleoresin and its use as starting material in the production of semi-synthetic analogs for the evaluation of their potential biological activities and preliminary study of structure-activity relationship (SAR). Four diterpenes of the labdano type were isolated from the oleoresin of C. langsdorffii, as COP1 being described for the first time for Leguminosae family. Of these isolated substances, three of them were subjected to structural modifications at the C-3 (oxidation), C-7 (allyl oxidation), C-15 (methyl esterification) and C-17 (epoxidation) positions, as well as unexpected modifications at C -13. These modifications allowed the obtainment of nine semi-synthetic labdane diterpenes. All these substances, both natural and semi-synthetic, were submitted to an evaluation of their potential biological activities. With regard to the cytotoxic activity, AC and its semisynthetic derivative VM-13 showed the best results, with VM-13 inhibiting more than 90% of the cellular viability of the human alveolar adenocarcinoma (A549) line, at 100 μM. The substances 3-acetoxy-copalic acid (AAC, 50 μM), 3-hydroxy-copalic acid (AHC, 100 μM) and VM-11 (100 μM) reduced in 45-70% nitric oxide (NO) production by macrophages RAW264.7. As for the antibacterial activity, AC showed the highest activity against species of the genus Streptococcus and Staphylococcus, with minimum inhibitory concentration values around 30.45 μg/mL (100 μM). The results allowed to suggest structural units potentially important for the biological activities evaluated, such as the presence of a hydroxyl in C-7 for cytotoxic activity; the presence of an ester or absence of an carboxylic acid in C-15 for anti-inflammatory activity and the presence of the carboxylic acid for antibacterial activity.