Acyl Derivatives of Eudesmanolides To Boost their Bioactivity: An Explanation of Behavior in the Cell Membrane Using a Molecular Dynamics Approach

• Published in: ChemMedChem 2021-04, Vol.16 (8), p.1297-1307
• Main Authors: Mejías, Francisco J. R., Durán, Alexandra G., Zorrilla, Jesús G., Varela, Rosa M., Molinillo, José M. G., Valdivia, Manuel M., Macías, Francisco A.
• Format: Article
• Language: English
• Subjects: acyl derivative; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - metabolism; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic drugs; Antitumor agents; Apoptosis - drug effects; Biological activity; Caspase; caspases; Cell lines; Cell Membrane - metabolism; Cell membranes; Cell Proliferation - drug effects; Computer applications; Drugs; Etoposide; eudesmanolide; HEK293 Cells; HeLa Cells; Humans; Lactones; Membrane processes; Membranes; Mode of action; Molecular dynamics; Molecular Dynamics Simulation; Molecular Structure; Natural products; Physicochemical properties; Selectivity; Sesquiterpene lactones; Sesquiterpenes - chemical synthesis; Sesquiterpenes - metabolism; Sesquiterpenes - pharmacology; Structure-Activity Relationship
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.202000783

Semisynthetic analogs of natural products provide an important approach to obtain safer and more active drugs and they can also have enhanced physicochemical properties such as persistence, cross‐membrane processes and bioactivity. Acyl derivatives of different natural product families, from sesquiterpene lactones to benzoxazinoids, have been synthesized and tested in our laboratories. These compounds were evaluated against tumoral and nontumoral cell lines to identify selective derivatives with a reduced negative impact upon application. The mode of action of these compounds was analyzed by anti‐caspase‐3 assays and molecular dynamics simulations with cell membrane re‐creation were also carried out. Aryl derivatives of eudesmanolide stand out from the other compounds and are better than current anticancer drugs such as etoposide in terms of selectivity and activity. Computational studies provide evidence that lipophilicity plays a key role and the 4‐fluorobenzoyl derivative can pass easily through the cell membrane. Acyl derivatives of different natural product have been synthesized and tested against tumoral and nontumoral cell lines to select those with reduced negative impacts upon application. The mode of action of these compounds was analyzed and molecular dynamics simulations provide evidence that lipophilicity plays a key role, where 4‐fluorobenzoyl derivative highlight as the most relevant compound.