Synthesis and Photoswitching Properties of Bioinspired Dissymmetric γ-Pyrone, an Analogue of Cyclocurcumin

Abstract

Cyclocurcumin (CC), a turmeric curcuminoid with potential therapeutic properties, is also a natural photoswitch that may undergo E/Z photoisomerization under UV light. To be further exploited in relevant biological applications, photoactivation under near-infrared (NIR) irradiation is required. Such requirement can be met through opportune chemical modifications, by favoring two-photon absorption (TPA) probability. Herein, a general and efficient synthesis of a biomimetic 2,6disubstituted-γ-pyrone analogue of CC is described, motivated by the fact that molecular modeling previews an order of magnitude increase of its NIR TPA compared to CC. Three retrosynthetic pathways have been identified (i) via an aryl-oxazole intermediate or via aryl-diynone through (ii) a bottom-up or (iii) a top-down approach. While avoiding the passage through unstable synthons or low-yield intermediate reactions, only the latest approach could conveniently afford the 2,6-disubstituted-γ-pyrone analogue of CC, in ten steps and with an overall yield of 18%. The photophysical properties of our biomimetic analogue have also been characterized showing an improved photoisomerization yield over the parent natural compound. The potentially improved nonlinear optical properties, as well as enhanced stability, may be correlated to the enforcement of the planarity of the pyrone moiety leading to a quadrupolar D−π−A−π−D system.

Perturbation of Lipid Bilayers by Biomimetic Photoswitches Based on Cyclocurcumin

“…Coherently with the GAFF protocol, and with our previous works, [41][42][43] the electrostatic procedure has been obtained from the Hartree-Fock wavefunction obtained with the 6-31G basis set. Note that the ground state geometry of the chromophore in its trans and cis configuration was previously optimized at Density Functional Theory (DFT) level using B3LYP functional and the 6-31+G* basis set.…”

“…[50][51][52][53] We have also shown that by introducing a g-pyrone analogous not only the absorption wavelength is red-shifted, as well the isomerization solvent-dependency is strongly reduced. 41,42 Finally, by using a combination of experimental and modeling techniques, including enhanced sampling and free energy calculations, we have shown that appending the g-pyrone derivative with a hydrophobic butyl chain (CCBu, Figure 1) leads to the spontaneous penetration inside the lipid bilayer, and more specifically at the interface between the polar heads and the fatty acid core. 54 Interestingly, the free energy profile for the insertion into the bilayer shows important differences between the trans and the cis isomers, with the former developing a more favorable interaction with the lipid bilayer.…”

“…34,35 Recently photoswitches have also been proposed as potential light-controlled regulators of serotonin transporters 36,37 and ion channels as well for potential optogenetics [38][39][40] applications. In previous contributions we have presented the synthesis and characterization of different biomimetic cyclocurcumin (CC)-based photoswitches, 41,42 which can potentially be used in LAC framework. Indeed, CC is a natural and non-toxic component of turmeric, and through it possess a photoisomerizable double bond the isomerization quantum yield is strongly dependent on the solvent polarity.…”

Biomimetic Photo-Switches Softening Model Lipid Membranes

“…In some previous contributions we have shown that natural curcumin and cyclocurcumin may indeed act as molecular photoswitches, undergoing E to Z isomerization under visible light irradiation. [30][31][32] However, in these natural compounds, the isomerization is pretty slow and its chemical quantum yield is strongly environment dependent due to the competition between np* and pp* excited states. 33 As a matter of fact, curcumin may also show interesting properties in term of 1 O 2 generation, due to its efficient intersystem crossing (ISC) coupled with residual fluorescence, which may facilitate its cellular localization.…”

“…33 As a matter of fact, curcumin may also show interesting properties in term of 1 O 2 generation, due to its efficient intersystem crossing (ISC) coupled with residual fluorescence, which may facilitate its cellular localization. 34,35 Recently, 32 we have shown that by opportunely modifying the chemical core of cyclocurcumin, by replacing the 2,3-dihydropyran-4-one core by a 2-6-substitued g-pyrone (Figure 1), the photoisomerization efficiency is strongly enhanced whatever the medium. Experimental findings have also been rationalized and supported by the calculation of the PES of the most important excited state for the natural-occurring and the biomimetic compound.…”