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Antiviral Activity of Flexibilane and Tigliane Diterpenoids from Stillingia lineata

Olivon, Florent, Palenzuela, Héliciane, Girard-Valenciennes, Emmanuelle, Neyts, Johan, Pannecouque, Christophe, Roussi, Fanny, Grondin, Isabelle, Leyssen, Pieter, Litaudon, Marc
Journal of natural products 2015 v.78 no.5 pp. 1119-1128
Chikungunya virus, Human immunodeficiency virus 1, Human immunodeficiency virus 2, Semliki Forest virus, Sindbis virus, Stillingia, anticarcinogenic activity, antiviral properties, chemical structure, cytotoxicity, diterpenoids, ethyl acetate, leaf extracts, median effective concentration, neoplasms, spectral analysis, virus replication, viruses
In an effort to identify new potent and selective inhibitors of chikungunya virus and HIV-1 and HIV-2 virus replication, the endemic Mascarene species Stillingia lineata was investigated. LC/MS and bioassay-guided purification of the EtOAc leaf extract using a chikungunya virus-cell-based assay led to the isolation of six new (4–9) and three known (1–3) tonantzitlolones possessing the rare C₂₀-flexibilane skeleton, along with tonantzitloic acid (10), a new linear diterpenoid, and three new (11, 13, and 15) and two known (12 and 14) tigliane-type diterpenoids. The planar structures of the new compounds and their relative configurations were determined by spectroscopic analysis, and their absolute configurations were determined through comparison with literature data and from biogenetic considerations. These compounds were investigated for selective antiviral activity against chikungunya virus (CHIKV), Semliki Forest virus, Sindbis virus, and, for compounds 11–15, the HIV-1 and HIV-2 viruses. Compounds 12–15 were found to be the most potent and are selective inhibitors of CHIKV, HIV-1, and HIV-2 replication. In particular, compound 14 inhibited CHIKV replication with an EC₅₀ value of 1.2 μM on CHIKV and a selectivity index of >240, while compound 15 inhibited HIV-1 and HIV-2 with EC₅₀ values of 0.043 and 0.018 μM, respectively. It was demonstrated further that potency and selectivity are sensitive to the substitution pattern on the tigliane skeleton. The cytotoxic activities of compounds 1–10 were evaluated against the HCT-116, MCF-7, and PC3 cancer cell lines.