Molecular Design of Highly Efficient Heavy-Atom-free NpImidazole Derivatives for Two-Photon Photodynamic Therapy and ClO- Detection.

Two-photon photodynamic therapy (TP-PDT), as a treatment technology with deep penetration and less damage, provides a broad prospect for cancer treatment. Nowadays, the development of TP-PDT suffers from the low two-photon absorption (TPA) intensity and short triplet state lifetime of photosensitizers (PSs) used in TP-PDT. Herein, we propose some novel modification strategies based on the thionated NpImidazole (the combination of naphthalimide and imidazole) derivatives to make efforts on those issues and obtain corresponding fluorescent probes for detecting ClO- and excellent PSs for TP-PDT. Density functional theory (DFT) and time-dependent DFT (TD-DFT) are used to help us characterize the photophysical properties and TP-PDT process of the newly designed compounds. Our results show that the introduction of different electron-donating groups at the position 4 of NpImidazole can effectively improve their TPA and emission properties. Specifically, 3s with a N,N-dimethylamino group has a large triplet state lifetime (τ = 699 µs) and TPA cross section value (δTPA = 314 GM), which can effectively achieve TP-PDT; additionally, 4s (with electron-donating group 2-oxa-6-azaspiro[3.3]heptane in NpImidazole) effectively realizes the dual-function of a PS for TP-PDT (τ = 25,122 µs, δTPA = 351 GM) and a fluorescent probe for detecting ClO- (Φf = 29% of the product 4o). Moreover, an important problem is clarified from a microscopic perspective, that is, why the transition property of 3s and 4s (1π-π*) from S1 to S0 is different from that of 1s and 2s (1n-π*). It is hoped that our work can provides valuable theoretical clues for the design and synthesis of heavy-atom-free NpImidazole-based PSs and fluorescent probes for the detection of hypochlorite.

Theoretical Investigation of Ru(II) Complexes with Long Lifetime and a Large Two-Photon Absorption Cross-Section in Photodynamic Therapy.

Two-photon photodynamic therapy (TP-PDT), as a new method for cancer, has shown unique advantages in tumors. A low two-photon absorption cross-section (δ) in the biologic spectral window and a short triplet state lifetime are the important issues faced by the current photosensitizers (PSs) in TP-PDT. In this paper, the photophysical properties of a series of Ru(II) complexes were studied by density functional theory and time-dependent density functional theory methods. The electronic structure, one- and two-photon absorption properties, type I/II mechanisms, triplet state lifetime, and solvation free energy were calculated. The results showed that the substitution of methoxyls by pyrene groups greatly improved the lifetime of the complex. Furthermore, the addition of acetylenyl groups subtly enhanced δ. Overall, complex 3b possess a large δ(1376 GM), a long lifetime (136 µs), and better solvation free energy. It is hoped that it can provide valuable theoretical guidance for the design and synthesis of efficient two-photon PSs in the experiment.

Photophysical Exploration of Zn(II) Polypyridine Photosensitizers in Two-Photon Photodynamic Therapy: Insights from Theory.

The high incidence and difficulties of treatment of cancer have always been a challenge for mankind. Two-photon photodynamic therapy (TP-PDT) as a less invasive technique provides a new perspective for tumor treatment due to its low-energy near-infrared excitation, high targeting, and minor damage. At present, the emerging metal complexes used as the photosensitizers (PSs) in TP-PDT have aroused great interest. However, most metal complexes as PSs in TP-PDT still face some problems, such as slow clearance, unsatisfactory two-photon absorption (TPA) characteristics, high price, low reactivity, and poor solubility. In this work, density functional theory and time-dependent density functional theory were used to characterize the one/two-photon response, solvation free energy, and lipophilicity of a series of novel PSs applied in TP-PDT. The results suggest that based on complex 1, replacing Ru(II) center with Zn(II) (complex 2) can effectively prolong the triplet excited state lifetime while reducing the cost and environmental pollution, and the azetidine heterospirocycles were introduced into the ligand scaffold (complex 3), which effectively reduced the vibration relaxation of the ligand group and improved the water solubility; further, the addition of acetylenyl groups subtly enhanced the light absorption and significantly improved the two-photon response (complex 4). In addition, all complexes met the requirement of a PS and could be used as potential candidates for TP-PDT. In particular, complex 4 has the advantages of high solvation free energy, a large TPA cross-section (1413 GM), a long triplet state lifetime (671 µs), good chemical reactivity, and low cost, and it is easy to be scavenged by organisms. Overall, this contribution may provide an important clue to formulate clear design principles for type I/II PSs and rational design of PSs with high intersystem crossing rates, a long lifetime, and therapeutic excitation wavelengths.

A Theoretical Investigation into the Homo- and Hetero-leptic Cu(I) Phosphorescent Complexes Bearing 2,9-dimethyl-1,10-phenanthroline and bis [2-(diphenylphosphino)phenyl]ether Ligand.

Cu(I) complexes have received widespread attention as a promising alternative to traditional noble-metal complexes. Herein, we systematically study the properties of Cu(I) complexes from homo- to hetero-ligands, and found the following: (1) hetero-ligands are beneficial to regulate phosphorescent efficiency; (2) when the hetero-ligands in a tetracoordinated Cu(I) complex are 1:1, the ligands coordinate along the dx2-y2 direction of Cu(I) ion, which can observably suppress structural deformation; (3) unlike the P^P ligand, the N^N ligand can enhance the participation of Cu(I) during the transition process; (4) the addition of an appropriate amount of P^P ligand can effectively raise the energy level of HOMO (highest occupied molecular orbital), enhance the proportion of LLCT (ligand-ligand charge transfer), and thereby increase the available singlet emission transition moments which can be borrowed, thus promoting the radiative decay process. As a result, this work provides a detailed understanding of the effects of different ligands in Cu(I) complexes, and provides a valuable reference and theoretical basis for regulating and designing the phosphorescent properties of Cu(I) complexes in the future.

Theoretical design and investigation of 1,8-naphthalimide-based two-photon fluorescent probes for detecting cytochrome P450 1A with separated fluorescence signal.

As a type of enzyme with a terminal oxygen, the CYP1A subfamily possesses the ability to catalyze the reactions of many environmental toxins, endogenous substrates and clinical drugs. The development of efficient methods for the rapid and real-time detection of CYP1A enzyme activity in complex biological systems is of considerable significance for identifying potential abnormalities in these cancer-related enzymes. With this goal, we firstly provided a series of 1,8-naphthalimide-based two-photon fluorescent chromophores with large two-photon absorption (TPA) cross-sections (500-7000 GM) and remarkable changes in fluorescence spectra upon recognizing the CYP1A enzyme from its theoretical aspect. Moreover, we have thoroughly studied the effects of cyclic acceptor (dichlorobenzene and benzothiadiazole) and donor (fluorene and carbazole) groups on the one-photon absorption (OPA), TPA, and fluorescence properties of CYP1A enzyme probes and the corresponding reaction products. The connection of a heterocycle as the donor group to a 1,8-naphthalimide-based molecule to form a D-π-A-π-D-type electronic structure can effectively cause red shifts in the absorption and emission wavelengths to facilitate bioimaging in the near infrared (NIR) region, which is attributed to the lower transition energy, larger transition dipole moment and amount of transferred charge. Docking analysis suggests that the two-photon fluorescent probes NCMN-3 and NCMN-5 that were designed will guarantee and achieve excellent selectivity for the CYP1A enzyme.

Theoretical investigation on the origin of yellow-green firefly bioluminescence by time-dependent density functional theory.

The question whether the emitter of yellow-green firefly bioluminescence is the enol or keto-constrained form of oxyluciferin (OxyLH(2)) still has no definitive answer from experiment or theory. In this study, Arg220, His247, adenosine monophosphate (AMP), Water324, Phe249, Gly343, and Ser349, which make the dominant contributions to color tuning of the fluorescence, are selected to simulate the luciferase (Luc) environment and thus elucidate the origin of firefly bioluminescence. Their respective and compositive effects on OxyLH(2) are considered and the electronic absorption and emission spectra are investigated with B3LYP, B3PW91, and PBE1KCIS methods. Comparing the respective effects in the gas and aqueous phases revealed that the emission transition is prohibited in the gas phase but allowed in the aqueous phase. For the compositive effects, the optimized geometry shows that OxyLH(2) exists in the keto(-1) form when Arg220, His247, AMP, Water324, Phe249, Gly343, and Ser349 are all included in the model. Furthermore, the emission maximum wavelength of keto(-1)+Arg+His+AMP+H(2)O+Phe+Gly+Ser is close to the experimental value (560 nm). We conclude that the keto(-1) form of OxyLH(2) is a possible emitter which can produce yellow-green bioluminescence because of the compositive effects of Arg220, His247, AMP, Water324, Phe249, Gly343, and Ser349 in the luciferase environment. Moreover, AMP may be involved in enolization of the keto(-1) form of OxyLH(2). Water324 is indispensable with respect to the environmental factors around luciferin (LH(2)).