Perturbation of Lipid Bilayers by Biomimetic Photoswitches Based on Cyclocurcumin

The use of photoswitches which may be activated by suitable electromagnetic radiation is an attractive alternative to conventional photodynamic therapy. Here, we report all-atom molecular dynamics simulation of a biomimetic photoswitch derived from cyclocurcumin and experiencing E/Z photoisomerization. In particular, we show that the two isomers interact persistently with a lipid bilayer modeling a cellular membrane. Furthermore, the interaction with the membrane is strongly dependent on the concentration, and a transition between ordered and disordered arrangements of the photoswitches is observed. We also confirm that the structural parameters of the bilayer are differently affected by the two isomers and hence can be modulated through photoswitching, offering interesting perspectives for future applications

Biomimetic Photo-Switches Softening Model Lipid Membranes

We report the synthesis and characterization of a novel photo-switch based on biomimetic cyclocurcumin analogous and interacting with the lipid bilayer, which can be used in the framework of oxygen-independent light-induced therapy. More specifically, by using molecular dynamics simulations and free energy techniques, we show that the inclusion of hydrophobic substituents is needed to allow insertion in the lipid membrane. After having confirmed experimentally that the substituents do not preclude the efficient photoisomerization, we show through UV–vis and dynamic light scattering measurements together with compression isotherms that the chromophore is internalized in both lipid vesicles and monomolecular film, respectively, inducing their fluidification. The irradiation of the chromophore-loaded lipid aggregates modifies their properties due to the different organization of the two diastereoisomers, E and Z. In particular, a competition between a fast structural reorganization and a slower expulsion of the chromophore after isomerization can be observed in the kinetic profiles recorded during E to Z photoisomerization. This report paves the way for future investigations in the optimization of biomimetic photoswitches potentially useful in modern light-induced therapeutic strategies

Synthesis and Anti-Chagas Activity Profile of a Redox-Active Lead 3‑Benzylmenadione Revealed by High-Content Imaging

Chagas disease, or American trypano­somiasis, is a neglected tropical disease which is a top priority target of the World Health Organization. The disease, endemic mainly in Latin America, is caused by the protozoan Trypanosoma cruzi and has spread around the globe due to human migration. There are multiple transmission routes, including vectorial, congenital, oral, and iatrogenic. Less than 1% of patients have access to treatment, relying on two old redox-active drugs that show poor pharmaco­kinetics and severe adverse effects. Hence, the priorities for the next steps of R&D include (i) the discovery of novel drugs/chemical classes, (ii) filling the pipeline with drug candidates that have new mechanisms of action, and (iii) the pressing need for more research and access to new chemical entities. In the present work, we first identified a hit (4a) with a potent anti-T. cruzi activity from a library of 3-benzyl­menadiones. We then designed a synthetic strategy to build a library of 49 3-(4-monoamino)­benzyl­menadione derivatives via reductive amination to obtain diazacyclic benz(o)yl­menadiones. Among them, we identified by high content imaging an anti-amastigote “early lead” 11b (henceforth called cruzidione) revealing optimized pharmaco­kinetic properties and enhanced specificity. Studies in a yeast model revealed that a cruzidione metabolite, the 3-benzoyl­menadione (cruzidione oxide), enters redox cycling with the NADH-dehydrogenase, generating reactive oxygen species, as hypothesized for the early hit (4a)