Evaluation of Jatrophane Esters from Euphorbia spp. as Modulators of Candida albicans Multidrug Transporters
Evaluation of Jatrophane Esters from Euphorbia spp. as Modulators of Candida albicans Multidrug Transporters
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DOI：
10.1021/acs.jnatprod.6b00990
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发表时间：
2017-02-01
影响因子：
5.1
通讯作者：
Litaudon, Marc
中科院分区：
文献类型：
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作者：
Esposito, Melissa;Nim, Shweta;Litaudon, Marc
在过度表达相应转运蛋白的酵母菌株中，评价了从大戟属物种中分离的29种jatrophane酯（1-10，12-30）和1种lathyrane（11）二萜类化合物酯抑制白色念珠菌的初级ABC转运蛋白CaCdr 1 p和次级MFS转运蛋白CaMdr 1 p的药物外排活性的能力。这些二萜酯类化合物分别从半叶大戟（Euphorbia semiperfoliata）（1-10）、E. insularis（11）和E. Dendroides（12-30），包括5个新化合物，Euphodendroidins P-T（26-30）。发现Jatrophane酯12和23抑制由两种多药物转运蛋白介导的尼罗红（NR）的外排，CaCdr 1 p为85-64%，CaMdr 1 p为79-65%。相比之下，化合物21对CaCdr 1 p具有选择性，并诱导了强烈的抑制（92%），而化合物8对CaMdr 1 p具有选择性，抑制率为74%。进一步证明，效力和选择性对麻风树烷骨架上的取代模式敏感。然而，这些化合物不被转运，并且与氟康唑细胞毒性没有协同作用。
Twenty-nine jatrophane esters (1-10, 12-30) and one lathyrane (11) diterpenoid ester isolated from Euphorbia species were evaluated for their capacity to inhibit drug-efflux activities of the primary ABC transporter CaCdr1p and the secondary MFS transporter CaMdr1p of Candida albicans, in yeast strains overexpressing the corresponding transporter. These diterpenoid esters were obtained from Euphorbia semiperfoliata (1-10), E. insularis (11), and E. dendroides (12-30) and included five new compounds, euphodendroidins P-T (26-30). The jatrophane esters 12 and 23 were found to inhibit the efflux of Nile Red (NR) mediated by the two multidrug transporters, at 85-64% for CaCdr1p and 79-65% for CaMdr1p. In contrast, compound 21 was selective for CaCdr1p and induced a strong inhibition (92%), whereas compound 8 was selective for CaMdr1p, with a 74% inhibition. It was demonstrated further that potency and selectivity are sensitive to the substitution pattern on the jatrophane skeleton. However, these compounds were not transported and showed no synergism with fluconazole cytotoxicity.