Antiviral Activity of Flexibilane and Tigliane Diterpenoids from Stillingia lineata

Abstract

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.

Tonantzitlolone A and other cytotoxic constituents of Sapium macrocarpum (Euphorbiaceae)

“…Sitostenone (3) was previously reported to possess anti-proliferation and anti-tyrosinase activities in melanoma cells [35]. The activities displayed by tonantzitlolone A (7) were similar to those reported previously for tonantzitlolones B-F [36]. Recently, tonantzitlolone A (7) was C8, C9, C10…”

Diterpenes as lead molecules against neglected tropical diseases

“…Otherwise, diterpenes (tonantzitlolone A, B, C; ent-12α-hydroxy-3,7-dioxoisopimara-8,15-diene and 4′acetoxytonantzitlolone) from Stillingia lineata are evident to have strong anti-CHKIV activity with an EC 50 < 0.8 μg/mL (Techer et al, 2015). A number of promising anti-CHKIV diterpenes have been reported till date (Bourjot et al, 2012;Allard et al, 2012a;Allard et al, 2012b;Bourjot et al, 2014;Corlay et al, 2014;Olivon et al, 2015;Nothias-Scaglia et al, 2015a;Nothias-Scaglia et al, 2015b;Nothias-Scaglia et al, 2015c).…”

Environmentally-Friendly Workflow Based on Supercritical Fluid Chromatography and Tandem Mass Spectrometry Molecular Networking For the Discovery of Potent Anti-Viral Leads From Plants

“…Thus, as it is the case for prostratin, compounds 15 and 18 could be devoid of any tumor-promoting activity, making these compounds very attractive for further biological investigation. These results highlight that Euphorbia plants are a remarkable source of potent antiviral diterpene esters 27,41,[44][45][46]. In the present study, an SFC-MS/MS based workflow was developed to analyze the diterpene esters content of E. semiperfoliata.…”