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

Semi-synthetic analogs of natural products provide an important approach to obtain safer and more active drugs and they 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 non-tumoral cell lines to identify selective derivatives with 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 recreation were also carried out. Aryl derivatives of eudesmanolide stand out from the other compounds and are better than current anti-cancer 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.