TY - JOUR
T1 - Jatrophanes from Euphorbia squamosa as potent inhibitors of Candida albicans multidrug transporters
AU - Rawal, Manpreet Kaur
AU - Shokoohinia, Yalda
AU - Chianese, Giuseppina
AU - Zolfaghari, Behzad
AU - Appendino, Giovanni
AU - Taglialatela-Scafati, Orazio
AU - Prasad, Rajendra
AU - Di Pietro, Attilio
N1 - Publisher Copyright:
© 2014 The American Chemical Society and American Society of Pharmacognosy.
PY - 2014/12/26
Y1 - 2014/12/26
N2 - A series of structurally related jatrophane diterpenoids (1-6), including the new euphosquamosins A-C (4-6), was purified from the Iranian spurge Euphorbia squamosa and evaluated for its capacity to inhibit drug efflux by multidrug transporters of Candida albicans. Three of these compounds showed an interesting profile of activity. In particular, deacetylserrulatin B (2) and euphosquamosin C (6) strongly inhibited the drug-efflux activity of the primary ABC-transporter CaCdr1p, an effect that translated, in a yeast strain overexpressing this transporter, into an increased sensitivity to fluconazole. These compounds were transported by CaCdr1p, as shown by the observation of an 11-14-fold cross-resistance of yeast growth, and could also inhibit the secondary MFS-transporter CaMdr1p. In contrast, euphosquamosin A (4) was selective for CaCdr1p, possibly as a result of a different binding mode. Taken together, these observations suggest jatrophane diterpenes to be a new class of potent inhibitors of multidrug transporters critical for drug resistance in pathogenic yeasts.
AB - A series of structurally related jatrophane diterpenoids (1-6), including the new euphosquamosins A-C (4-6), was purified from the Iranian spurge Euphorbia squamosa and evaluated for its capacity to inhibit drug efflux by multidrug transporters of Candida albicans. Three of these compounds showed an interesting profile of activity. In particular, deacetylserrulatin B (2) and euphosquamosin C (6) strongly inhibited the drug-efflux activity of the primary ABC-transporter CaCdr1p, an effect that translated, in a yeast strain overexpressing this transporter, into an increased sensitivity to fluconazole. These compounds were transported by CaCdr1p, as shown by the observation of an 11-14-fold cross-resistance of yeast growth, and could also inhibit the secondary MFS-transporter CaMdr1p. In contrast, euphosquamosin A (4) was selective for CaCdr1p, possibly as a result of a different binding mode. Taken together, these observations suggest jatrophane diterpenes to be a new class of potent inhibitors of multidrug transporters critical for drug resistance in pathogenic yeasts.
UR - http://www.scopus.com/inward/record.url?scp=84920128973&partnerID=8YFLogxK
U2 - 10.1021/np500756z
DO - 10.1021/np500756z
M3 - Article
SN - 0163-3864
VL - 77
SP - 2700
EP - 2706
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 12
ER -