Natural and semi-synthetic royleanone diterpenoids from Plectranthus spp. as potential anti-tumoral agents

Natural products are an important source of lead compounds for drug discovery. Plectranthus (Lamiaceae family) is an Old-World genus widely used in traditional medicine, whose species are rich in pharmacologically active compounds, specifically diterpenes. Two important lead molecules reported in Plectranthus spp. are the diterpenoids 7α-acetoxy-6β-hydroxyroyleanone (Roy, [Fig. 1]) and 6,7-dehydroroyleanone (DeRoy, [Fig. 1]) [1]. Previous studies reported in vitro activity of Roy and DeRoy against several breast cancer cell lines [1], [2]. Furthermore, in silico studies suggested promising interactions of these natural royleanones with protein kinase C (PKC) isoforms [2].

Fig. 1

The key point of this work was to prepare new functionalized derivatives of Roy and DeRoy and evaluate their effect on two cancer targets, PKC isoforms and the efflux pump, P-glycoprotein (P-gp). New royleanone derivatives were obtained by hemi-synthesis, starting from Roy and DeRoy. Some of these compounds were evaluated as PKC (α, βI, δ, ε and ζ) activators. One benzoylated analogue showed the ability to selectively activate PKC-δ, while DeRoy displayed improved PKC activity, compared with the positive control, in all tested isoforms. Additionally, P-gp inhibitory potential was evaluated in human non-small cell lung carcinoma NCI-H460 and its MDR counterpart NCI-H460/R. Natural royleanones Roy and DeRoy showed similar cytotoxic activity against both NCI-H460 and MDR cancer cell lines. Interestingly, the benzoylated derivatives displayed the most promising results, showing an increased P-gp inhibitory activity and suggesting a relevant role of this moiety for the cytotoxic activity. Several other derivatives are currently under investigation as potential chemotherapeutic agents.

Acknowledgments

This work was financially supported by Fundação para a Ciência e a Tecnologia (FCT, Portugal) under projects UIDB/04 567/2020 and UIDP/04 567/2020 attributed to CBIOS and PhD grant SFRH/BD/137 671/2018

Publikationsverlauf

Artikel online veröffentlicht:
22. Dezember 2022

• References

• 1 Matias D, Nicolai M, Saraiva L. et al. . ACS Omega 2019; 4 (05) 8094
• 2 Isca VMS, Sencanski M, Filipovic N. et al. . Int J Mol Sci 2020; 21: 3671