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 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.
Corea
Gabriella
G
Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli Federico II, Via D. Montesano 49, I-80131 Naples, Italy.
Fattorusso
Ernesto
E
Lanzotti
Virginia
V
Taglialatela-Scafati
Orazio
O
Appendino
Giovanni
G
Ballero
Mauro
M
Simon
Pierre-Noël
PN
Dumontet
Charles
C
Di Pietro
Attilio
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification*; D028481:Euphorbia / Q000737:chemistry*; D011485:Protein Binding; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004224:Diterpenes