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Lathyrol and Epoxylathyrol Derivatives: Modulation of Cdr1p and Mdr1p Drug-Efflux Transporters of Candida Albicans in Saccharomyces Cerevisiae Model

Lathyrol and Epoxylathyrol Derivatives: Modulation of Cdr1p and Mdr1p Drug-Efflux Transporters of Candida Albicans in Saccharomyces Cerevisiae Model

Andreia Mónico, Shweta Nim, Noélia Duarte, Manpreet Kaur Rawal, Rajendra Prasad, Attilio Di Pietro, Maria-José U Ferreira

Bioorg Med Chem. 2017 Jul 1;25(13):3278-3284.

PMID: 28479022

Abstract:

Macrocyclic diterpenes were previously found to be able to modulate the efflux pump activity of Candida albicans multidrug transporters. Most of these compounds were jatrophanes, but only a few number of lathyrane-type diterpenes was evaluated. Therefore, the aim of this study was to evaluate the ability of nineteen structurally-related lathyrane diterpenes (1-19) to overcome the drug-efflux activity of Cdr1p and Mdr1p transporters of C. albicans, and get some insights on their structure-activity relationships. The transport assay was performed by monitoring Nile Red (NR) efflux in a Saccharomyces cerevisiae strain overexpressing the referred efflux pumps from C. albicans. Moreover, a chemosensitization assay was performed in order to evaluate the type of interaction between the inhibitory compounds and the antifungal drug fluconazole. Compounds 1-13 were previously isolated from Euphorbia boetica or obtained by derivatization, and compounds 14-19 were prepared by chemical transformations of compound 4. In the transport assays, compounds 14-19 revealed the strongest inhibitory activity of the Cdr1p efflux pump, ranging from 65 to 85%. Concerning Mdr1p efflux pump, the most active compounds were 1, 3, 6, 8, and 12 (75-85%). When used in combination with fluconazole, epoxyboetirane K (2) and euphoboetirane N (18) revealed synergistic effects in the AD-CDR1 yeast strain, overexpressing the Cdr1p transporter, through their ability to reduce the effective concentration of the antifungal drug by 23- and 52-fold, respectively.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP34420194	Lathyrol		34420-19-4	Price

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