Cytotoxic Activity, Topoisomerase I Inhibition and In Silico Studies of New Sesquiterpene-aryl Ester Derivatives of (-) Drimenol.

In this study, we aimed to evaluate two sets of sesquiterpene-aryl derivatives linked by an ester bond, their cytotoxic activities, and their capacity to activate caspases 3/7 and inhibit human topoisomerase I (TOP1). A total of 13 compounds were synthesized from the natural sesquiterpene (-)-drimenol and their cytotoxic activity was evaluated in vitro against three cancer cell lines: PC-3 (prostate cancer), HT-29 (colon cancer), MCF-7 (breast cancer), and an immortalized non-tumoral cell line (MCF-10). From the results, it was observed that 6a was the most promising compound due to its cytotoxic effect on three cancer cell lines and its selectivity, 6a was 100-fold more selective than 5-FU in MCF-7 and 20-fold in PC-3. It was observed that 6a also induced apoptosis by caspases 3/7 activity using a Capsase-Glo-3/7 assay kit and inhibited TOP1. A possible binding mode of 6a in a complex with TOP1-DNA was proposed by docking and molecular dynamics studies. In addition, 6a was predicted to have a good pharmacokinetic profile for oral administration. Therefore, through this study, it was demonstrated that the drimane scaffold should be considered in the search of new antitumoral agents.

Biopesticide Activity from Drimanic Compounds to Control Tomato Pathogens.

Tomato crops can be affected by several infectious diseases produced by bacteria, fungi, and oomycetes. Four phytopathogens are of special concern because of the major economic losses they generate worldwide in tomato production; Clavibacter michiganensis subsp. michiganensis and Pseudomonas syringae pv. tomato, causative agents behind two highly destructive diseases, bacterial canker and bacterial speck, respectively; fungus Fusarium oxysporum f. sp. lycopersici that causes Fusarium Wilt, which strongly affects tomato crops; and finally, Phytophthora spp., which affect both potato and tomato crops. Polygodial (1), drimenol (2), isonordrimenone (3), and nordrimenone (4) were studied against these four phytopathogenic microorganisms. Among them, compound 1, obtained from Drimys winteri Forst, and synthetic compound 4 are shown here to have potent activity. Most promisingly, the results showed that compounds 1 and 4 affect Clavibacter michiganensis growth at minimal inhibitory concentrations (MIC) values of 16 and 32 µg/mL, respectively, and high antimycotic activity against Fusarium oxysporum and Phytophthora spp. with MIC of 64 µg/mL. The results of the present study suggest novel treatment alternatives with drimane compounds against bacterial and fungal plant pathogens.

Effect of drimenol and synthetic derivatives on growth and germination of Botrytis cinerea: Evaluation of possible mechanism of action.

The aim of this study was to determine the antifungal activity of Drimenol (1) and its synthetic derivatives, nordrimenone (2), drimenyl acetate (3), and drimenyl-epoxy-acetate (4), and to establish a possible mechanism of action for drimenol. For that, the effect of each compound on mycelial growth of Botrytis cinerea was assessed. Our results showed that compounds 1, 2, 3 and 4 are able to affect Botrytis cinerea growth with EC50 values of 80, 92, 80 and 314ppm, respectively. These values suggest that the activity of these compounds is mainly determined by presence of the double bond between carbons 7 and 8 of the drimane ring. In addition, germination of B. cinerea in presence of 40 and 80ppm of drimenol is reduced almost to a half of the control value. Finally, in order to elucidate a possible mechanism by which drimenol is affecting B. cinerea, the determination of membrane integrity, reactive oxygen species production and gene expression studies of specific genes were performed.