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

Abstract

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 anticaspase-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 4fluorobenzoyl derivative can pass easily through the cell membrane.

Identification of Allelochemicals with Differential Modes of Phytotoxicity against Cuscuta campestris

“…Thus, it is interesting to highlight the role of the halogen substituents in phenyl rings, as also discussed in a previous review [31], and how parameters like stability are improved by factors such as the presence of a fluorine atom in the para-position [31]. Indeed, the halogenation of aromatic compounds is a strategy employed for the design of agrochemicals and drugs [32,33]. By observing the bioactivity profiles in Figure 5, the bioactivity of these compounds could be ordered as: 6 < 19 < 20 < 21, which corresponds to H < F < Cl < Br, indicating the positive effect of exchanging a hydrogen atom by, and halogen in.…”

Effects of Sesquiterpene Lactones on Primary Cilia Formation (Ciliogenesis)

“…From a small library of plant allelochemicals synthesized previously in our lab and based on previous biological studies in human cells [19], two sesquiterpene lactones were selected to elucidate their function in cilia formation: grosheimin [20] isolated from a leaf extract from Cynara scolymus, and costunolide [21] isolated from a root extract from Saussurea lappa. From the former, three eudesmanolide-type sesquiterpene lactones were also obtained by cyclization reaction using p-TsOH (para-toluenesulfonic acid), generating three cyclocostunolides with a characteristic double bound located in different positions (α,β,γ) [22] (Figure 1), which are likewise natural products isolated from plants [23,24].…”

Suppressive Activity of Glechoma hederacea Extracts against the Phytopathogenic Oomycete Plasmopara viticola, and First Screening of the Active Metabolites

“…C logP values of the isolated compounds were calculated using ChemOffice v20.1 (Perkin Elmer, Waltham, MA, USA) by means of the appropriate tool in ChemDraw Professional [32].…”