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Royleanone Derivatives From Plectranthus spp. as a Novel Class of P-Glycoprotein Inhibitors
Catarina Garcia1,2, Vera M S Isca1,3, Filipe Pereira1
1Center for Research in Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, Lisboa, Portugal.
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.
Insights
Natural royleanones were modified to create new P-glycoprotein (P-gp) inhibitors to combat multidrug resistance (MDR) in cancer. Derivative 4 showed significant P-gp inhibition and sensitized resistant cancer cells to chemotherapy.
Area of Science:
- Natural Product Chemistry
- Medicinal Chemistry
- Cancer Pharmacology
Background:
- Cancer remains a leading global cause of death, with multidrug resistance (MDR) posing a significant therapeutic challenge.
- Overexpression of P-glycoprotein (P-gp) is a primary mechanism contributing to MDR, necessitating the development of novel P-gp inhibitors.
- Royleanones, natural compounds from *Plectranthus* species, possess cytotoxic properties and serve as a basis for drug discovery.
Purpose of the Study:
- To synthesize novel P-gp inhibitors by chemically modifying natural royleanones.
- To evaluate the P-gp inhibitory potential of these new derivatives in human non-small cell lung carcinoma models.
- To assess the ability of promising derivatives to overcome chemoresistance and enhance the efficacy of existing chemotherapeutics.
Main Methods:
- Chemical synthesis of four new royleanone derivatives (20-23) from natural precursors 1 and 2.
- Evaluation of P-gp inhibition using MTT assays in NCI-H460 and NCI-H460/R cell lines.
- Assessment of P-gp inhibitory effects via Rhodamine 123 accumulation assays and drug sensitization studies.
Main Results:
- Four new royleanone derivatives (20-23) were synthesized with yields ranging from 21-97%.
- Derivatives 4 and 23 demonstrated significant P-gp inhibitory potential.
- Compound 4 exhibited potent anti-P-gp activity, comparable to Dexverapamil, and sensitized resistant NCI-H460/R cells to doxorubicin.
Conclusions:
- Modification of royleanones, particularly through benzoyl ester formation, is a promising strategy for developing effective P-gp inhibitors.
- Derivative 4 represents a potent P-gp inhibitor with potential to overcome MDR in cancer therapy.
- Further research into benzoyl ester derivatives could lead to enhanced anticancer agents that improve treatment outcomes for resistant cancers.
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