Jatrophane diterpenes as modulators of multidrug resistance. Advances of structure-activity relationships and discovery of the potent lead pepluanin A.
From the whole plant of Euphorbia peplus L., five new diterpenes based on a jatrophane skeleton (pepluanins A-E, 1-5) were isolated, together with two known analogues (6 and 7), which served to divulge in detail the structure-activity relationships within this class of P-glycoprotein inhibitors. The results revealed the importance of substitutions on the medium-sized ring (carbons 8, 9, 14, and 15). In particular, the activity is collapsed by the presence of a free hydroxyl at C-8, while it increases with a carbonyl at C-14, an acetoxyl at C-9, and a free hydroxyl at C-15. The most potent compound of the series, pepluanin A, showed a very high activity for a jatrophane diterpene, outperforming cyclosporin A by a factor of at least 2 in the inhibition of Pgp-mediated daunomycin transport.
Corea
Gabriella
G
Dipartimento di Chimica delle Sostanze Naturali, Università di Napoli "Federico II", Via D. Montesano 49, I-80131 Napoli, Italy.
Fattorusso
Ernesto
E
Lanzotti
Virginia
V
Motti
Riccardo
R
Simon
Pierre-Noël
PN
Dumontet
Charles
C
Di Pietro
Attilio
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D001692:Biological Transport; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D003630:Daunorubicin / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009539:Nicotinic Acids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004224:Diterpenes; D009539:Nicotinic Acids; C483201:pepluanin A; D016572:Cyclosporine; D003630:Daunorubicin