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Royleanone Derivati...
Royleanone Derivatives From Plectranthus spp. as a Novel Class of P-Glycoprotein Inhibitors
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- Garcia, Catarina (author)
- Univ Lusofona Humanidades & Tecnol, Ctr Res Biosci & Hlth Technol CBIOS, Lisbon, Portugal; Univ Alcala De Henares, Fac Pharm, Dept Biomed Sci, Alcala De Henares, Spain
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- Isca, Vera M. S. (author)
- Univ Lusofona Humanidades & Tecnol, Ctr Res Biosci & Hlth Technol CBIOS, Lisbon, Portugal; Univ Lisbon, Fac Pharm, Inst Invest Med iMed ULisboa, Lisbon, Portugal
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- Pereira, Filipe (author)
- Univ Lusofona Humanidades & Tecnol, Ctr Res Biosci & Hlth Technol CBIOS, Lisbon, Portugal
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- Monteiro, Carlos M. (author)
- Univ Lisbon, Fac Pharm, Inst Invest Med iMed ULisboa, Lisbon, Portugal
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- Ntungwe, Epole (author)
- Univ Lusofona Humanidades & Tecnol, Ctr Res Biosci & Hlth Technol CBIOS, Lisbon, Portugal; Univ Alcala De Henares, Fac Pharm, Dept Biomed Sci, Alcala De Henares, Spain
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- Sousa, Francisco (author)
- Univ Lusofona Humanidades & Tecnol, Ctr Res Biosci & Hlth Technol CBIOS, Lisbon, Portugal
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- Dinic, Jelena (author)
- Univ Belgrade, Inst Biol Res Sinisa Stankovic, Natl Inst Republ Serbia, Belgrade, Serbia
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- Holmstedt, Suvi (author)
- Tampere Univ, Fac Engn & Nat Sci, Tampere, Finland
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- Roberto, Amílcar (author)
- Univ Lusofona Humanidades & Tecnol, Ctr Res Biosci & Hlth Technol CBIOS, Lisbon, Portugal
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- Diaz-Lanza, Ana (author)
- Univ Alcala De Henares, Fac Pharm, Dept Biomed Sci, Alcala De Henares, Spain
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- Reis, Catarina P. (author)
- Univ Lisbon, Fac Pharm, Inst Invest Med iMed ULisboa, Lisbon, Portugal
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- Pesic, Milica (author)
- Univ Belgrade, Inst Biol Res Sinisa Stankovic, Natl Inst Republ Serbia, Belgrade, Serbia
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- Candeias, Nuno R. (author)
- Tampere Univ, Fac Engn & Nat Sci, Tampere, Finland; Univ Aveiro, Dept Chem, LAQV REQUIMTE, Aveiro, Portugal
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- Ferreira, Ricardo J., PhD, 1980- (author)
- Uppsala universitet,Molekylär biofysik,Science for Life Laboratory, SciLifeLab
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- Duarte, Noélia (author)
- Univ Lisbon, Fac Pharm, Inst Invest Med iMed ULisboa, Lisbon, Portugal
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- Afonso, Carlos A. M. (author)
- Univ Lisbon, Fac Pharm, Inst Invest Med iMed ULisboa, Lisbon, Portugal
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- Rijo, Patricia (author)
- Univ Lusofona Humanidades & Tecnol, Ctr Res Biosci & Hlth Technol CBIOS, Lisbon, Portugal; Univ Lisbon, Fac Pharm, Inst Invest Med iMed ULisboa, Lisbon, Portugal
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(creator_code:org_t)
- 2020-11-17
- 2020
- English.
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In: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- Plectranthus
- Diterpenes
- Royleanones
- stability
- Artemia salina
- P-pg activity
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Garcia, Catarina
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Isca, Vera M. S.
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Pereira, Filipe
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Monteiro, Carlos ...
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Ntungwe, Epole
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Sousa, Francisco
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Dinic, Jelena
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Holmstedt, Suvi
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Roberto, Amílcar
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Diaz-Lanza, Ana
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Reis, Catarina P ...
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Pesic, Milica
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Candeias, Nuno R ...
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Ferreira, Ricard ...
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Duarte, Noélia
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Afonso, Carlos A ...
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Rijo, Patricia
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
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Frontiers in Pha ...
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Uppsala University