New Hybrid Compound Candidate as Photothermal Agent Based on DPP Derivatives and Toluidine Blue: A Theoretical Perspective.

In this article, the synthesis of a new hybrid compound, candidate as photothermal agent, is proposed, based on TDPP (3,6-di(thiophene-2-yl)-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione) and toluidine blue. Electronic structure calculations at the DFT, TD-DFT and CCSD level of theories were performed to obtain ground and excited states molecular structures, photophysical properties and absorption spectrum of the hybrid and the starting compounds. Additionally, ADMET calculations were performed to predict the pharmacokinetic, metabolic and toxicity properties of the proposed compound. The results showed that the proposed compound is a strong candidate for photothermal agent since (1) it absorbs close to the near-infrared region, (2) it has low fluorescence and intersystem crossing rate constants, (3) it has accessible conical intersection with low energy barrier, (4) the compound shows lower toxicity than the well know compound toluidine blue, which is used in photodynamic therapy, (5) the compound does not show carcinogenic potential, and (6) it obeys the Lipinski's rule of five, used as a reference for the design of new pharmaceuticals.

Theoretical Investigation of the 4,5-Dibromorodamine Methyl Ester (TH9402) Photosensitizer Used in Photodynamic Therapy: Photophysics, Reactions in the Excited State, and Interactions with DNA.

Photosensitizer (PS) molecules play a critical role in photodynamic therapy of cancer and the understanding of the molecular mechanism involved in the photophysics of these compounds, and their reactions in the excited state are, therefore, of great interest for the development of this technique. In this article, the photophysics of the cationic PS 4,5-dibromorodamine methyl ester (TH9402), its electron- and energy-transfer reactions in the excited triplet state, with molecular oxygen, nitric oxide, guanosine-5'-monophosphate (GMP), and guanine, and the interaction with DNA were evaluated. Time-dependent density functional theory calculations at the TPSSh/Def2-TZVP//B3LYP/Def2-TZVP level of theory in water solution reveals that the PS has a bright S1 state 2.33 eV above the ground state that produces a fluorescent rate constant of 5.40 × 107 s-1, calculated using Fermi's golden rule within a path integral formalism. Once excited to the bright state, the main intersystem crossing (ISC) channel involves the coupling with the T2 state just below S1 (S1 → T2 → T1) with an overall ISC rate constant of 10.1 × 107 s-1, in good agreement with the experimental data. Excited-state reaction thermodynamics, computed at the M06-2X/Def2-TZVP//B3LYP/Def2-TZVP level of theory in water, showed that from all the excited-state electron-transfer reactions studied, only the transfer from GMP to the PS is thermodynamically favorable, independent of the protonation state of guanosine, which indicates a possible DNA photo-oxidation mechanism for the PS. Triplet-triplet energy-transfer reactions from TH9402 to molecular oxygen, producing reactive singlet oxygen, and to the deprotonated guanosine, producing 3GMP2-, are also thermodynamically favorable, with ΔG = -2.0 and -24.0 kcal//mol, respectively. However, the energy transfer to the monoprotonated guanosine is not favorable, (ΔG = 36.1), suggesting that in the DNA double-strand environment, this energy-transfer process may not be observed. The results show that the PS can act through electron transfer and triplet-triplet energy-transfer reactions involved in mechanism types I and II in photodynamic therapy. Interactions of TH9402 with the d(AGACGTCT)2 octanucleotide revealed that the PS can intercalate between the d(GpC)-d(CpG) base pairs in three different orientations and, upon intercalation, the π → π* transition of the PS shows a bathochromic shift up to 90 nm and up to 60% decrease in intensity. Interactions through groove binding showed a smaller bathochromic shift of 52.2 nm and a 56% decrease in intensity of the main transition band.