Natural products are an attractive source of new drug candidates. Plectranthus spp. (Lamiaceae) often possess a diversity of biologically active secondary metabolites, namely abietane diterpenoids. One example is the 7α-acetoxy-6β-hydroxyroyleanone (Roy, Figure 1), naturally occurring in P. grandidentatus Gürke, in high yields. Roy proved to be a potential lead molecule for the interaction with protein kinase C (PKC) isoforms and revealed promising activity in breast cancer cell lines of different malignancy. In this work, we isolated Roy in high amounts to be derivatized and thus improve its antitumoral activity. In previous studies, we demonstrated that ester derivatives from royleanones are the most stable and bioactive molecules. Accordingly, herein we investigate the suitable conditions for the preparation of new ester derivatives from Roy, through derivatization of the two hydroxyl groups (Figure 1). Regarding extraction and isolation, the aerial parts of P. grandidentatus were studied through an acetonic ultrasonic extraction (yield of 2.3 %, w/w), yielding 1 g of pure Roy (~ 0.04 %, w/w). Concerning the reactivity study, the 12-OH position allowed the obtention of ester derivatives, using mild conditions, with overall good yields (36-88 %). Thus, this position stands out as the most reactive for esterification. For the derivatization of both positions, it was required high temperature (50 °C), excess of reagents, and higher reaction time. New ester hit derivatives are currently in preparation based on this reactivity report, with the final goal of PKC isoforms modulation.

Exploring the reactivity of a natural diterpenoid to modulate protein kinase C isoforms

ACS Spring 2022

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