Jatrophanes From Euphorbia Squamosa As Potent Inhibitors of Candida Albicans Multidrug Transporters Publisher Pubmed



Rawal MK¹ ; Shokoohinia Y² ; Chianese G³ ; Zolfaghari B⁴ ; Appendino G⁵ ; Taglialatelascafati O³ ; Prasad R¹ ; Di Pietro A⁶ Show Affiliations
Source: Journal of Natural Products Published:2014

Abstract

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. © 2014 The American Chemical Society and American Society of Pharmacognosy.