Cytotoxic abietane diterpenes from Peltodon longipes and their mode of action

Peltodon longipes (Labiatae), also known as „baicuru amarelo“ in south of Brazil, has been used in folk medicine as an anti-inflammatory and antiseptic remedy (1). The effective compounds responsible for these effects are still unknown. Here we report the isolation and structure elucidation of 12 diterpenes from the abietane type. 12,14-dihydroxy-11-methoxyabieta-8,11,13-trien-7-one was isolated for the first time, whereas the other diterpenes have already been known. Structure elucidation was based on 1D-(¹H and ¹³C) and 2D NMR experiments (COSY, HMQC, HMBC and NOESY) as well as EIMS. Cytotoxic activity of these compounds was evaluated against two different cancer cell lines, MIA PaCa-2 (Human Pancreatic Carcinoma Cell Line) and MV-3 (Human Melanoma Cell Line). 7α acetoxyroyleanone, the major compound, showed the highest cytotoxic activity with an IC₅₀ value of 4.7 and 7.5µM, respectively. Interestingly, some diterpenes preferentially inhibited topoisomerase-I in the relaxation assay and gave lower IC₅₀ values (2.8 and 4.7µM) than the known classical topoisomerase-I inhibitor camptothecin (IC₅₀ 28µM). Docking experiments revealed that these diterpenes may target topoisomerase-I differenzially to camptothecin. While camptothecin stabilizes type I topoisomerase-DNA complexes, there is evidence that the diterpenes compete with DNA for topoisomerase binding through direct interaction. A new binding side is suggested which allows correlation with the experimental data. Additionally studies are in progress to give further insights in the mechanism of action.

Acknowledgements: Financial support from the government Baden-Württemberg (Zukunftsoffensive IV) is gratefully acknowledged.

References: 1. Mentz, L.A. et al. (1997) Caderno de Farmácia, 13: 25–48.