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Isolation of Premyrsinane, Myrsinane, and Tigliane Diterpenoids from Euphorbia pithyusa Using a Chikungunya Virus Cell-Based Assay and Analogue Annotation by Molecular Networking

Esposito, Mélissa, Nothias, Louis-Félix, Retailleau, Pascal, Costa, Jean, Roussi, Fanny, Neyts, Johan, Leyssen, Pieter, Touboul, David, Litaudon, Marc, Paolini, Julien
Journal of natural products 2017 v.80 no.7 pp. 2051-2059
Chikungunya virus, Euphorbia, active ingredients, aerial parts, chromatography, diterpenoids, esters, median effective concentration, nuclear magnetic resonance spectroscopy, spectral analysis
Six new premyrsinol esters (1–6) and one new myrsinol ester (8) were isolated from an aerial parts extract of Euphorbia pithyusa, together with a known premyrsinol (7) and two known dideoxyphorbol esters (9 and 10), following a bioactivity-guided purification procedure using a chikungunya virus (CHIKV) cell-based assay. The structures of the new diterpene esters (1–6 and 8) were elucidated by MS and NMR spectroscopic data interpretation. Compounds 1–10 were evaluated against CHIKV replication, and results showed that the 4β-dideoxyphorbol ester 10 was the most active compound, with an EC₅₀ value of 4.0 ± 0.3 μM and a selectivity index of 10.6. To gain more insight into the structural diversity of diterpenoids produced by E. pithyusa, the initial extract and chromatographic fractions were analyzed by LC-MS/MS. The generated data were annotated using a molecular networking procedure and revealed that dozens of unknown premyrsinane, myrsinane, and tigliane analogues were present.