title: Jatrophanes from Euphorbia squamosa as potent inhibitors of Candida albicans multidrug transporters.
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.
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University , 110067 New Delhi, India.
authors.forename: Manpreet Kaur
authors.initials: MK
authors.lastname: Rawal
authors.forename: Yalda
authors.initials: Y
authors.lastname: Shokoohinia
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Chianese
authors.forename: Behzad
authors.initials: B
authors.lastname: Zolfaghari
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.forename: Orazio
authors.initials: O
authors.lastname: Taglialatela-Scafati
authors.forename: Rajendra
authors.initials: R
authors.lastname: Prasad
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000378:metabolism; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D028481:Euphorbia / Q000737:chemistry*; D035264:Flowers / Q000737:chemistry; D015725:Fluconazole / Q000494:pharmacology; D007492:Iran; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D018515:Plant Leaves / Q000737:chemistry; D018547:Plant Stems / Q000737:chemistry; D012235:Rhodamines / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000187:drug effects
chemical_list: D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D004224:Diterpenes; D026901:Membrane Transport Proteins; D012235:Rhodamines; C000595592:euphosquamosin A; C000595591:euphosquamosin B; C000595593:euphosquamosin C; C530345:jatrophane; D015725:Fluconazole