Abstract
A computational investigation of the mechanism of dihydrosanguinarine (DHSAN) photoactivation and its conversion into the active drug sanguinarine (SAN) is here reported. The reaction mechanism of DHSAN photoconversion was fully explored by considering its excitation first, essential for generating one of the reactants, the 1O2, and then locating all the minima and transition states involved in the formation of SAN. Both forms of the drug present at physiological pH, namely, iminium cation and alkanolamine, were considered as products of such reaction. The ability of the generated drug SAN to induce cell apoptosis was then explored, taking into consideration two anticancer activities: the induction of DNA conformational and functional changes by intercalation and the absorption of light with proper wavelength to trigger type II photochemical reactions leading to 1O2 sensitization for photodynamic therapy application. Concerning the ability to work as photosensitizers, the outcomes of our calculations prove that DHSAN can easily be converted into the active SAN under visible and NIR irradiation through the application of two-photon excitation, and that the maximum absorption of SAN, once intercalated into DNA, shifts to the near region of the therapeutic window.
Highlights
On the basis of such premises, in the present paper we have focused our attention on the investigation of the photophysical properties of SAN to evaluate whether it can act as Appl
On the basis of such premises, in the present paper we have focused our attention on the investigation of the photophysical properties of SAN to evaluate whether it can act as a photosensitizer in Photodynamic Therapy (PDT), the mode of interaction of SAN with DNA occurring through intercalation and how the spectroscopic properties are influenced by DNA intercalation
The DHSAN photophysical properties, in terms of electronic transitions, singlet–triplet energy gaps and spin–orbit coupling constants were computed by means of density functional theory (DFT) and TD-DFT, in order to ascertain its ability to generate the excited state of molecular oxygen, essential for in situ SAN formation
Summary
Gaussian 16 package was used to perform all quantum mechanical calculations [28]. B3LYP including Grimme’s dispersion correction for nonbonding interactions was employed using atom pair-wise additive scheme [39], the DFT-D3 method. The optimized structure at the B3LYP level in water implicit solvent was used to compute the excitation energies employing several functionals: B3LYP, camB3LYP [44], M06L [45], PBE [46], B3P86 [47], ωB97XD [48], and PW91 [49] including the Grimme dispersion corrections (DFT-D3). Their performances were evaluated comparing S1 absorption peak wavelengths in water and THF for SAN and DHSAN, respectively (Table S1). A difference of no more than 0.02 cm−1 was found for S1–T2 coupling, while S1–T1 remains exactly the same
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