Royleanone Derivatives From Plectranthus spp. as a Novel Class of P-Glycoprotein Inhibitors

Abstract

Cancer is among the leading causes of death worldwide. One of the most challenging obstacles in cancer treatment is multidrug resistance (MDR). Overexpression of P-glycoprotein (P-gp) is associated with MDR. The growing incidence of cancer and the development of MDR drive the search for novel and more effective anticancer drugs to overcome the MDR problem. Royleanones are natural bioactive compounds frequently found in Plectranthus spp. The cytotoxic diterpene 6,7-dehydroroyleanone (1) is the main component of the P. madagascariensis (Pers.) Benth. essential oil, while 7α-acetoxy-6β-hydroxyroyleanone (2) can be isolated from acetonic extracts of P. grandidentatus Gürke. The reactivity of the natural royleanones 1 and 2 was explored to obtain a small library of new P-gp inhibitors. Four new derivatives (6,7-dehydro-12-O-tert-butyl-carbonate-royleanone (20), 6,7-dehydro-12-O-methylroyleanone (21), 6,7-dehydro-12-O-benzoylroyleanone (22), and 7α-acetoxy-6β-hydroxy-12-O-benzoylroyleanone (23) were obtained as pure with overall modest to excellent yields (21–97%). P-gp inhibition potential of the derivatives 20–23 was evaluated in human non-small cell lung carcinoma NCI-H460 and its MDR counterpart NCI-H460/R with the P-gp overexpression, through MTT assay. Previously prepared diterpene 7α-acetoxy-6β-benzoyloxy-12-O-(4-chloro)benzoylroyleanone (4), has also been tested. The P-gp inhibiting effects of compounds 1–4 were also assessed through a Rhodamine 123 accumulation assay. Derivatives 4 and 23 have significant P-gp inhibitory potential. Regarding stability and P-gp inhibition potential, results suggest that the formation of benzoyl esters is a more convenient approach for future derivatives with enhanced effect on the cell viability decrease. Compound 4 presented higher anti-P-gp potential than the natural diterpenes 1, 2, and 3, with comparable inhibitory potential to Dexverapamil. Moreover, derivative 4 showed the ability to sensitize the resistant NCI-H460/R cells to doxorubicin.

Preliminary Biological Activity Screening of Plectranthus spp. Extracts for the Search of Anticancer Lead Molecules

“…Many studies have attributed the cytotoxicity of Plectranthus extracts to the presence of royleanone-type abietane diterpenoids with known anticancer activities [ 18 , 36 ]. The abietane-type diterpenoid royleanones are a highly bioactive group of lead molecules, important for the development of new anticancer drugs [ 22 ] Given the good levels of bioactivity of P. hadiensis extract in all the cell lines tested, it was selected to identify its main bioactive component.…”

“…It was also found to induce apoptosis in the H7PX glioma cell line, through the G2/M cell cycle arrest and DSBs (double-strand breaks) [ 39 ]. The cytotoxicity of 7α-acetoxy-6β-hydroxyroyleanone could be due to its royleanone-type scaffold and by its high lipophilicity, which facilitates penetration into the interior of the cell membrane [ 21 , 22 , 29 , 39 ]. Moreover, 7α-acetoxy-6β-hydroxyroyleanone was found to exhibit better activity against Gram-positive bacteria, and more importantly, against MRSA strains than some of the existing antibiotics [ 37 ].…”

“…Moreover, 7α-acetoxy-6β-hydroxyroyleanone was found to exhibit better activity against Gram-positive bacteria, and more importantly, against MRSA strains than some of the existing antibiotics [ 37 ]. Roy is found in many other Plectranthus species like P. madagascariensis , P. grandidentatus , P. actites , P. amboinicus , P. sanguineus , P. argentatus , and thus can be considered as a chemomarker of the Plectranthus genus [ 21 , 22 ].…”

“…Isolated terpenes from Plectranthus species are reported to possess antibacterial [ 12 , 13 , 14 ], antitumoral [ 15 , 16 , 17 , 18 ], antifungal [ 12 , 19 ], insecticidal [ 20 ], and antiplasmodial [ 20 ] activities. Moreover, our group has been focused on the phytochemical study of Plectranthus species and we have reported abietane diterpenoids with diverse bioactivity [ 16 , 17 , 21 , 22 , 23 , 24 , 25 ]. Therefore, the screening of other Plectranthus spp.…”

Self-Assembly Nanoparticles of Natural Bioactive Abietane Diterpenes

“…A multitude of smart linkers (hydrazone, azo, peptide, disulfide, etc.) are available, each with unique advantages and disadvantages [ 11 ], and the most frequently used are redox-sensitive linkers. For instance, the high concentration of glutathione (GSH) in tumor cells cleaves these linkers, and the drug is released.…”