Phorbol Esters from the Latex of Euphorbia umbellata: Bioguided Isolation of Highly Potent HIV-1 Latency Interrupters in Virus Reservoir Cells
| Autor: | Amilcar Tanuri, João Batista de Freitas Tostes, Átila Duque Rossi, Pedro Junior P Mourão, Antonio Carlos Siani, Andressa L D Carvalho, Antonio Jorge Ribeiro da Silva |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Chromatography Lymphoblast Organic Chemistry Pharmaceutical Science medicine.disease High-performance liquid chromatography Virus In vitro Analytical Chemistry chemistry.chemical_compound Complementary and alternative medicine chemistry Drug Discovery Virus latency medicine Molecular Medicine Bioassay Lead compound Two-dimensional nuclear magnetic resonance spectroscopy |
| Zdroj: | Journal of Natural Products. 84:1666-1670 |
| ISSN: | 1520-6025 0163-3864 |
| DOI: | 10.1021/acs.jnatprod.0c01092 |
| Popis: | Three known compounds, 20-deoxyphorbol-5β-hydroxy-12-tiglate-13-isobutyrate (1), 20-deoxyphorbol-5β-hydroxy-12-tiglate-13-phenylacetate (2), and 4-deoxy-4β-phorbol-12-tiglate-13-phenylacetate (3), were reisolated from the latex of Euphorbia umbellata through a bioguided fractionation process to target HIV-1 latency reactivation. The in vitro bioassay using infected T-cell lymphoblasts (J-Lat 10.6), complemented with surface CD4 receptor downregulation assessment, led to isolation of the compounds as a highly active ternary mixture. Effective purification of the individual compounds was achieved by first subjecting a phorbol-enriched fraction (previously prepared from crude latex) to MPLC, followed by semipreparative HPLC and characterization by 1D and 2D NMR spectroscopy and (+)-HRESIMS. Compared with a positive control, the isolated compounds were effective in reactivating 68-75% of the virus latency in the range of 9.7-0.097 μM for compound 1, 8.85-0.088 μM for compound 2, and 9.1-0.091 μM for compound 3, with the latter maintaining steady effectiveness down to a 10-5 dilution. Accordingly, compound 3 may serve as a promising lead compound for the development of anti-HIV drugs based on latency reactivation therapy. |
| Databáze: | OpenAIRE |
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