Trans-cis Photoisomerization of a Biomimetic Cyclocurcumin Analogue Rationalized by Molecular Modelling

Abstract

<div> <p>Cyclocurcumin is a natural compound extracted from turmeric and showing, in addition to antiinfective, antibacterial, and intinflammatory capabilities, solvent-dependent phtoswitching ability. The solvent-dependent photochemistry of cyclocurcumin has been rationalized on the basis of a competition between π-π* and n-π* states. Recently we have reported the synthesis of a biomimetic analogue showing enhanced photochemical properties and in particular presenting photoswitching capacity in various media. In the present contribution we rely on the use of molecular modeling and simulation, incuding density functional and wavefunction based methods to explore the excited states potential energy surface landscape. We see that the addition of a carbon-carbon double bond to the core of the natural compounds favors the population of the π-π* state, whatever the choice of the solvent, and hence leads to photoisomerisation, with fluorescence reduced to only a minor channel, rationalizing the experimental observations. In addition, the two photon absorption cross section is also strongly increased compared to the parent compound, paving the way to the use in biologically oriented applications.</p></div>

Biomimetic Photo-Switches Softening Model Lipid Membranes

“…Except from water, all spectra exhibit three broad absorption peaks, centered at around 288, 327 and 374 nm, similar to the ones of natural cyclocurcumin 33 or CyP. 31,32 The highest and the lowest energy absorption band were assigned to the pp* transition of the phenyl-pyrone moiety and the styryl-pyrone moiety, respectively (Figure SI2-A), while the intermediate energy absorption band was assigned to an np* transition. This is consistent with the fact that the additional double bond in the pyrone cycle from CyP is not inducing any extension of the p-conjugation on the styryl-pyrone moiety, as compared to the dihydropyranone cycle from CC.…”

“…Instead, it is favoring an extension of the planarity from one extreme to the other of the molecule as already observed for the parent CyP compound. 31,32 A slight negative solvatochromism (Table SI1), accompanied by a narrowing of the vibrational band, is observed as solvent polarity decreases, and a slight dependency of the molar extinction coefficient (e, Table 1) with the solvent should be pointed out. Despite ultrasonication and addition of 2v% of DMSO, CyP-OBu was not fully solubilized in the water and therefore the value of e is underestimated for this solvent.…”

“…Note that both these systems involve only shorts methoxy and hydroxy substituents on the peripheric aromatic moieties, while their isomerization performances have been previously studied pointing to the superior performance of the biomimetic CyP analogous compared to CC. 31,32 The two chromophores have been inserted into the simulation box, and more specifically in the water buffer. Afterwards, classical equilibrium molecular dynamics (MD) simulations have been performed and, while some temporary interaction of the drug with the polar head region appear, no spontaneous penetration into the lipid membrane, or the formation of stable aggregates at the water/membrane interface can be observed, neither for the Z nor the E-isomer.…”

“…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.…”

“…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. 31 In the present contribution, we resort to a combination of experimental techniques and molecular simulation to understand the specific interaction of the Z and E-isomers of biomimetic cyclocurcumin analogous with lipid bilayers mimicking cellular membranes. The change in the membrane properties, observed in liposomes, vesicles, and monolayers, as well as the results of the enhanced sampling simulations confirm on the one side the internalization of the photoswitches in the lipid environment, and on the other side the efficient alteration of the artificial membrane structural parameters upon irradiation.…”