Jatrophane Diterpenes as P-Glycoprotein Inhibitors. First Insights of Structure−Activity Relationships and Discovery of a New, Powerful Lead

The Mediterranean spurge Euphorbia dendroides L. afforded a series of 10 closely related jatrophane polyesters, nine of which are new, which served as a base for the establishment of structure−activity relationships within this class of P-glycoprotein inhibitors. The results, while pointing to the g...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2003-07, Vol.46 (15), p.3395-3402
Main Authors: Corea, Gabriella, Fattorusso, Ernesto, Lanzotti, Virginia, Taglialatela-Scafati, Orazio, Appendino, Giovanni, Ballero, Mauro, Simon, Pierre-Noël, Dumontet, Charles, Di Pietro, Attilio
Format: Article
Language:English
Subjects:
ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors
ATP-Binding Cassette, Sub-Family B, Member 1 - chemistry
Biochemistry, Molecular Biology
Biological and medical sciences
Diterpenes - chemistry
Diterpenes - isolation & purification
Euphorbia - chemistry
General pharmacology
Life Sciences
Medical sciences
Pharmacognosy. Homeopathy. Health food
Pharmacology. Drug treatments
Protein Binding
Structure-Activity Relationship
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Summary:The Mediterranean spurge Euphorbia dendroides L. afforded a series of 10 closely related jatrophane polyesters, nine of which are new, which served as a base for the establishment of structure−activity relationships within this class of P-glycoprotein inhibitors. The results, while pointing to the general role of lipophilicity for activity, also highlighted the relevance of the substitution pattern at the positions 2, 3, and 5, suggesting the involvement of this fragment in binding. The most powerful compound of the series, euphodendroidin D (4), outperformed cyclosporin by a factor of 2 to inhibit Pgp-mediated daunomycin transport.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm030787e