Reactivity of 7α-acetoxy-6β-hydroxyroyleanone and ability of its derivatives to modulate PKC isoforms

Abstract

Abstract Protein kinase C is a family of kinases that play important roles in carcinogenesis . Medicinal plants from Plectranthus spp. (Lamiaceae) are a well-known source of interesting abietanes, such as the 7α-acetoxy-6β-hydroxyroyleanone (Roy). The aim of this study was to extract and isolate Roy from P. grandidentatus Gürke and compare two extraction methods (the CO2 supercritical extraction and the ultrasound-assisted acetonic extraction). The aim is to designing new royleanone derivatives focused on PKC modulation for breast cancer therapy by molecular modeling. The concentration of Roy in the extracts was determined by HPLC-DAD. Supercritical extraction method afforded an extraction yield of 3.6% w/w, with the presence of 40.69 μg·mg-1 of Roy (yield of 0.14%), while ultrasound-assisted acetonic extraction afforded 2.3% w/w, with the presence of 52.67 μg·mg-1 of Roy (yield of 0.11%). The reactivity of Roy was investigated to synthetize new ester derivatives through Roy benzoylation, affording two different products, Roy-12-Bz and RoyBz. Similarly, from Roy acetylation, Roy-12-Ac and RoyAc were successfully prepared. Thus, a reactivity study pointed to the 12-OH position as the most reactive site for the esterification. It afforded ester derivatives, using mild conditions, with overall good yields (33–86%). For both positions’ derivatization, high temperature (50 °C), excess of reagents, and higher reaction time are recommended. Moreover, some royleanones were evaluated as PKC-α, βI, δ, ε and ζ activators. DeRoy displayed the most promising results with increased PKC activity for all the isoforms comparing to PMA and ARA. The results suggest that slightly changes in the royleanones structures’ may have a great impact in the selectivity towards each PKC isoform. New ester hit derivatives are currently in preparation based on this reactivity report, to be further evaluated as PKC modulators.