Jatrophane Diterpenes as Inhibitors of Chikungunya Virus Replication: Structure–Activity Relationship and Discovery of a Potent Lead

Nothias, Louis Félix; Retailleau, Pascal; Paolini, Julien; Pannecouque, Christophe; Neyts, Johan; Dumontet, Vincent; Roussi, Fanny; Leyssen, Pieter; Costa, Jean; Litaudon, Marc

doi:10.1021/np500271u

Cited by 64 publications

(97 citation statements)

References 28 publications

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“…From these observations, it could be stated that the HMBC spectrum exhibited an ABX system for H-11, H-12, and H-13. Taking into account the known absolute configuration of related jatrophane esters previously isolated in this plant, 33 it can be proposed that they have the same absolute The NMR spectroscopic data of compound 2 were found to be similar to those of jatrophane esters belonging to "group B", i.e., esters of 9-oxojatropha-6(17),11E-diene that have been isolated previously, 23,33 but with an oxygenated methylene group located at C-10 (δ H 3.77 and 3.45, each d, J = 10.7 Hz, H-19a and H-19b, respectively) instead of the usual CH 3 -19 group (Table 1). In the HMBC spectrum, correlations from H-19 to C-10, C-11, and C-18 and from H-18 to C-9, C-10, and C-19 were used to confirm the attachment of the oxymethylene group at C-10.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Advanced Structural Determination of Diterpene Esters Using Molecular Modeling and NMR Spectroscopy

et al. 2015

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Three new jatrophane esters (1-3) were isolated from Euphorbia amygdaloides ssp. semiperfoliata, including an unprecedented macrocyclic jatrophane ester bearing a hemiketal substructure, named jatrohemiketal (3). The chemical structures of compounds 1-3 and their relative configurations were determined by spectroscopic analysis. The absolute configuration of compound 3 was determined unambiguously through an original strategy combining NMR spectroscopy and molecular modeling. Conformational search calculations were performed for the four possible diastereomers 3a-3d differing in their C-6 and C-9 stereocenters, and the lowest energy conformer was used as input structure for geometry optimization. The prediction of NMR parameters ((1)H and (13)C chemical shifts and (1)H-(1)H coupling constants) by density functional theory (DFT) calculations allowed identifying the most plausible diastereomer. Finally, the stereostructure of 3 was solved by comparison of the structural features obtained by molecular modeling for 3a-3d with NMR-derived data (the values of dihedral angles deduced from the vicinal proton-proton coupling constants ((3)JHH) and interproton distances determined by ROESY). The methodology described herein provides an efficient way to solve or confirm structural elucidation of new macrocyclic diterpene esters, in particular when no crystal structure is available.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Advanced Structural Determination of Diterpene Esters Using Molecular Modeling and NMR Spectroscopy

et al. 2015

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“…53 Keeping in mind that 27 elicited no anti-CHIKV activity and the fact that the hydrophobicity of phorbol esters played a preeminent role, the present results may suggested that the pattern of PKC translocation could be an important factor in the mechanism of action of diterpene esters against CHIKV replication. 10,54 In conclusion, the current study has allowed the development of preliminary SAR observations among tigliane diterpene esters for CHIKV replication. It has also revealed that ingenane-type esters can exhibit anti-CHIKV activity.…”

Section: Journal Of Natural Productsmentioning

confidence: 81%

Antiviral Activity of Diterpene Esters on Chikungunya Virus and HIV Replication

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Recently, new daphnane, tigliane, and jatrophane diterpenoids have been isolated from various Euphorbiaceae species, of which some have been shown to be potent inhibitors of chikungunya virus (CHIKV) replication. To further explore this type of compound, the antiviral activity of a series of 29 commercially available natural diterpenoids was evaluated. Phorbol-12,13-didecanoate (11) proved to be the most potent inhibitor, with an EC50 value of 6.0 ± 0.9 nM and a selectivity index (SI) of 686, which is in line with the previously reported anti-CHIKV potency for the structurally related 12-O-tetradecanoylphorbol-13-acetate (13). Most of the other compounds exhibited low to moderate activity, including an ingenane-type diterpene ester, compound 28, with an EC50 value of 1.2 ± 0.1 μM and SI = 6.4. Diterpene compounds are known also to inhibit HIV replication, so the antiviral activities of compounds 1-29 were evaluated also against HIV-1 and HIV-2. Tigliane- (4β-hydroxyphorbol analogues 10, 11, 13, 15, 16, and 18) and ingenane-type (27 and 28) diterpene esters were shown to inhibit HIV replication in vitro at the nanomolar level. A Pearson analysis performed with the anti-CHIKV and anti-HIV data sets demonstrated a linear relationship, which supported the hypothesis made that PKC may be an important target in CHIKV replication.

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“…For example, two jatrophane diterpene ester isolated from E. amygdaloides ssp. semiperfoliata showed anti-CHIKV activities [50].…”

Section: Analysis Of Euphorbia Extracts Using Targeted Lc-ms 2 Methodsmentioning

confidence: 99%

“…Following the results described hereby, the study of the Corsican species Euphorbia amygdaloides ssp. semiperfoliata was carried out [50].…”

Section: Introductionmentioning

confidence: 99%

LC-MS2-Based dereplication of Euphorbia extracts with anti-Chikungunya virus activity

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Recently, phorbol esters from Euphorbiaceae have been shown to elicit potent and selective antiviral activity on the replication of Chikungunya virus (CHIKV) in cell culture. With the objective to found new compounds with anti-CHIKV activities, 45 extracts from various plant parts of 11 Mediterranean Euphorbia and one Mercurialis species were evaluated for selective inhibition of CHIKV replication. All EtOAc extracts, especially those prepared from latex, exhibited significant and selective antiviral activity in a Chikungunya virus-cell-based assay. An LC-MS(2) dereplication method was then developed to investigate whether known diterpenoids with anti-CHIKV activity, such as the potent anti-CHIKV 12-O-tetradecanoylphorbol-13-acetate (TPA), phorbol-12,13-didecanoate, and prostratin as well as 24 other commercially available diterpenoids of tigliane-, ingenane-, and daphnane-type for which the anti-CHIKV activity have been established in advance (Nothias-Scaglia et al. 2015), were present in the Euphorbia extracts. Only ingenol-3-mebutate, 13-O-isobutyryl-12-deoxyphorbol-20-acetate, and ingenol-3,20-dibenzoate, all exhibiting weak anti-CHIKV activities, were detected in the EtOAc extracts of Euphorbia peplus, Euphorbia segetalis ssp. pinea, and Euphorbia pithyusa ssp. pithyusa. Given the potent anti-CHIKV activities of these Euphorbia extracts, the present study suggested that their antiviral activities are probably due to untargeted diterpenoids.

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Jatrophane Diterpenes as Inhibitors of Chikungunya Virus Replication: Structure–Activity Relationship and Discovery of a Potent Lead

Cited by 64 publications

References 28 publications

Advanced Structural Determination of Diterpene Esters Using Molecular Modeling and NMR Spectroscopy

Advanced Structural Determination of Diterpene Esters Using Molecular Modeling and NMR Spectroscopy

Antiviral Activity of Diterpene Esters on Chikungunya Virus and HIV Replication

LC-MS2-Based dereplication of Euphorbia extracts with anti-Chikungunya virus activity

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