Efficient singlet oxygen generation photosensitizer based on nitrogenous aliphatic ring size regulation and theoretical calculation design method

Abstract

The invention belongs to the technical field of singlet oxygen generation, and discloses an efficient singlet oxygen generation photosensitizer based on nitrogenous aliphatic ring size regulation and a theoretical calculation design method. A donor is introduced to the meso site of stilbene-BODIPY, the ring tension of the stilbene-BODIPY is effectively changed by adjusting the size of a nitrogen-containing ring, and the larger the ring tension is, the more unstable the molecule is, so that the oxidation potential of the donor is reduced, and the electron donating ability of the stilbene-BODIPY is further improved. The donor with stronger electron donating ability can obviously improve the intersystem crossing efficiency of photosensitizer molecules, thereby improving the quantum yield of singlet oxygen. According to the donor designed by the invention, the electron donating capability of the donor can be enhanced by adjusting the size of the nitrogen-containing aliphatic ring, the spin-orbit coupling is increased, and intersystem crossing is promoted. The calculation result shows that the photosensitizer has lower oxidation potential, smaller single triplet state energy gap, larger spin-orbit coupling coefficient and higher intersystem crossing rate, and shows more excellent potential in the field of singlet oxygen generation.

Description

Technical Field

[0001] The invention belongs to the technical field of singlet oxygen generation, and relates to a high-efficiency singlet oxygen generation photosensitizer based on size regulation of nitrogen-containing aliphatic rings and a theoretical calculation design method. Background Art

[0002] Singlet oxygen is a high-energy oxygen molecule whose electron spin state is different from that of common triplet oxygen. Due to its unique electronic structure, singlet oxygen has strong reactivity and can react with a variety of biological molecules and compounds to generate reactive oxygen species, thus playing an important role in biological and chemical processes. Singlet oxygen has shown potential application value in fields such as photodynamic therapy, water treatment, materials science, and organic synthesis, and can promote chemical reactions and improve reaction selectivity and efficiency. In photodynamic therapy, photosensitizers are excited under light conditions, prompting them to transfer energy and generate singlet oxygen. The generated singlet oxygen has strong oxidizing ability and can react with biological molecules in cells, leading to cell damage or apoptosis. Further studies have shown that by optimizing the structure of photosensitizers (such as adjusting the characteristics of electron donors and acceptors), the generation efficiency of singlet oxygen can be improved, thereby enhancing its effect in treatment.

[0003] Existing photosensitizers include porphyrins, phthalocyanines and certain small molecule compounds, which have been shown to have the ability to generate singlet oxygen. "An exceptionally long-lived triplet state of redlight-absorbing compact phenothiazine-styrylBodipy electron donor / acceptordyads: a better alternative to the heavy atom-effect?" This article reports a DA-type photosensitizer with phenothiazine as donor and diphenylethylene-BODIPY (fluoroboropyrrole) as acceptor, which exhibits strong singlet oxygen generation ability in toluene. Despite significant progress in this field, most DA-type photosensitizer molecules still face the problem that the singlet oxygen quantum yield is lower than the fluorescence quantum yield. At present, the trial and error cost of experiments is high, so it is particularly important to analyze the effect of molecular structure on the performance of photosensitizers through theoretical calculations. The singlet oxygen quantum yield of photosensitizers can be significantly improved by adjusting the molecular structure, especially the design of the electron donor-acceptor (DA) system. However, despite a large number of theoretical studies and some synthetic work, systematic research on new photosensitizer systems is still insufficient, which limits their full potential in the field of singlet oxygen generation. Therefore, it is of great significance to study the mechanism of DA-type photosensitizer molecules through theoretical calculations. Summary of the invention

[0004] The present invention aims to reveal the mechanism of improving the singlet oxygen quantum yield of DA-type photosensitizer molecules and predict and design molecules with stronger singlet oxygen generation ability. Specifically, by introducing a donor group with stronger electron donating ability at the meso position of stilbene-BODIPY, the efficiency of intersystem crossing of photosensitizer molecules can be significantly improved, thereby improving the quantum yield of singlet oxygen. The donor proposed in the present invention is a nitrogen-containing five-membered ring, six-membered ring and seven-membered ring connected to thiophene. This design not only expands the π conjugation degree of the molecule and enhances the electron giving ability of the donor, but also increases the spin-orbit coupling to promote intersystem crossing. In addition, by adjusting the size of the nitrogen-containing ring, its ring tension can be effectively changed. The greater the ring tension, the more unstable the molecule, thereby reducing the oxidation potential of the donor and further improving its electron donating ability. Compared with traditional phenothiazine donors, donors connected to nitrogen-containing five-membered rings, six-membered rings and seven-membered rings on thiophene show stronger electron giving ability, which can effectively promote the intersystem crossing process. Theoretical calculation results show that compared with DA-type photosensitizers with phenothiazine as donor and diphenylethylene-BODIPY (fluoroborylpyrrole) as acceptor, photosensitizers with thiophene and nitrogen-containing five-membered rings, six-membered rings and seven-membered rings connected to the meso position of diphenylethylene-BODIPY have lower oxidation potential, smaller singlet and triplet energy gap, larger spin-orbit coupling coefficient and higher intersystem crossing rate. These superior properties indicate that the photosensitizer designed by the present invention has more outstanding application potential in singlet oxygen generation.

[0005] The technical solution of the present invention:

[0006] A highly efficient singlet oxygen generation photosensitizer based on size regulation of nitrogen-containing aliphatic rings, the structure of which is as follows:

[0007]

[0008] The structure of the nitrogen-containing ring connected by thiophene is as follows:

[0009]

[0010] A theoretical calculation design method for efficient singlet oxygen generation photosensitizer based on size regulation of nitrogen-containing aliphatic rings, the steps are as follows:

[0011] Step 1: Use ChemDraw to draw the photosensitizer molecule, then import the drawn photosensitizer molecular structure into Chem3D, and select Minimize Energy in MOPAC in the menu bar to perform preliminary structural optimization;

[0012] Step 2: Use Gaussian 16 software, select M06-2X functional and 6-31g (d, p) basis set, simulate the properties of photosensitizer molecules in toluene under the SMD solvation model, and calculate the geometric structure optimization and frequency of the ground state, excited singlet state and excited triplet state of the photosensitizer molecular structure;

[0013] Step 3: Confirm that the calculation results obtained in step 2 have no imaginary frequencies, and confirm that the geometric structures of the ground state, excited singlet state and excited triplet state are the most stable structures;

[0014] Step 4: Use BDF software to calculate the spin-orbit coupling constant between the excited singlet state and the excited triplet state to determine the intersystem crossing channel;

[0015] Step 5: After determining the intersystem crossing channel using the spin-orbit coupling constant output from step 4, the energy gap difference between the singlet state and the triplet state where intersystem crossing occurs is obtained according to the structural optimization result of step 2;

[0016] Step 6: Generate a MOMAP input file using the spin-orbit coupling constant obtained in step 4 and the energy gap difference between the singlet state and the triplet state obtained in step 5. Run the MOMAP input file through the MOMAP software. After the calculation is completed, the rate coefficient of the intersystem crossing of the photosensitizer molecule is obtained in the output file. The rate coefficient is proportional to the generation capacity of singlet oxygen.

[0017] Step 7: Perform TD-DFT calculations on the ground state and the first excited singlet state to obtain the maximum absorption wavelength, maximum emission wavelength and fluorescence rate coefficient;

[0018] Step 8: Calculate the ring strain of nitrogen-containing five-membered ring, six-membered ring and seven-membered ring using the homology reaction method;

[0019] Step 9: Use ORCA software to calculate the oxidation potential of these molecules. The smaller the oxidation potential, the stronger the electron donating energy.

[0020] To verify whether the three molecules designed in the present invention (named M5, M6 and M7, respectively) have intersystem crossing ability, we first performed theoretical calculations on the photosensitizer molecules in previous literature that used phenothiazine as donor and diphenylethylene-BODIPY as acceptor. By using photosensitizer molecules known to produce singlet oxygen as a benchmark, we aim to highlight that the three molecules proposed in the present invention may have stronger singlet oxygen generation capabilities. Evaluating newly designed molecules through theoretical calculations is an effective strategy that can provide guidance for subsequent experimental studies and accelerate the development and application of new photosensitizers. Through this theoretical calculation method, we can gain a deep understanding of the photophysical properties of new photosensitizers, providing an important reference for their future application and optimization.

[0021] Beneficial effects of the present invention:

[0022] (1) By introducing donors connected to nitrogen-containing five-membered rings, six-membered rings, and seven-membered rings on thiophene, the electron donating capacity of the donor of the photosensitizer molecule is significantly improved.

[0023] (2) By adjusting the size of the nitrogen-containing ring, the electron donation ability of the donor can be flexibly changed to achieve more precise regulation of the donor.

[0024] (3) The enhanced electron-donating ability effectively improves the intersystem crossing ability of the photosensitizer molecule, and the quantum yield of singlet oxygen is closely related to the intersystem crossing ability. Therefore, this design innovation is expected to significantly improve the singlet oxygen quantum yield of the photosensitizer molecule. DETAILED DESCRIPTION

[0025] The specific implementation of the present invention is further described below in conjunction with the technical solution.

[0026] The present invention uses a unified computational simulation method, and the specific calculation details are shown in steps 1 to 9 above, which reveals the different electronic properties of DA-type photosensitizer molecules in photochemical reactions and provides an important theoretical basis for subsequent research.

[0027] A photosensitizer from the article "An exceptionally long-lived triplet state of redlight-absorbing compact phenothiazine-styrylBodipy electron donor / acceptordyads: a better alternative to the heavy atom-effect?" was selected as a control, with phenothiazine as the donor and stilbene-BODIPY (fluoroborylpyrrole) as the control photosensitizer. The experimental data of the control photosensitizer in toluene showed that the singlet oxygen quantum yield was 0.13, the fluorescence quantum yield was 0.42, the maximum absorption wavelength was 629nm, and the maximum emission wavelength was 640nm, which indicated that the photosensitizer had the ability to generate singlet oxygen.

[0028] The purpose of theoretical calculation of the reference photosensitizer is to obtain a set of theoretical data for comparison, which will help us evaluate the performance of the new molecules M5, M6 and M7. By comparing with the theoretical calculation results of the reference photosensitizer, we can more clearly reveal the potential advantages of the new molecules in terms of singlet oxygen generation ability and photophysical properties. The theoretical calculation data are as follows (the specific calculation details are in the specific implementation method): the donor oxidation potential is 1.703V; the theoretical maximum absorption wavelength is 558.72nm, and the theoretical maximum emission wavelength is 612.63nm. The difference between the calculated value and the experimental value is unavoidable due to theoretical approximation, but its size trend corresponds to the experiment; the theoretical fluorescence rate coefficient is 1.971×10 8 s -1 ; The energy gap between the singlet and triplet states for intersystem crossing is 0.554 eV; The spin-orbit coupling constant for intersystem crossing is 0.40 cm -1 ; The theoretical calculation of the intersystem crossing rate coefficient is 2.324×10 4 s -1 ; These data do support the design concept of the present invention, and subsequent related theoretical calculation data verify that the photophysical properties of M5, M6, and M7 are more excellent, indicating that they are expected to show stronger effects in photodynamic diagnosis and therapy.

[0029] According to the theoretical calculation results, the donor oxidation potentials of embodiments M5-M7 are 1.338V, 1.555V and 1.520V respectively. The lower the donor oxidation potential, the stronger the electron-donating ability. These values ​​are all lower than the control photosensitizer, indicating that the donor groups in M5-M7 have stronger electron-donating properties than the control photosensitizer. In order to study the effect of nitrogen-containing aliphatic rings on the electron-donating ability of M5-M7 molecules, we calculated their ring tension using the same-linked reaction method. The greater the ring tension, the lower the stability, and the easier it is to release electrons. The ring tensions of M5-M7 are 8.643kcal / mol, 2.499kcal / mol and 8.018kcal / mol respectively. In particular, M5 has the largest ring tension and the lowest stability, so it is easiest to release electrons. This is consistent with the result that the donor of M5 has the lowest oxidation potential, indicating that the donor of M5 is the strongest electron-donating group in the present invention.

[0030] Theoretical calculation results show that the theoretically calculated maximum absorption wavelengths of Examples M5-M7 are 562.14nm, 565.26nm and 564.96nm, respectively, which are longer than the maximum absorption wavelength of the control photosensitizer. This result strongly indicates that M5-M7 has the property of being more conducive to deep tissue absorption of light, thereby improving the depth effect of treatment. The theoretically calculated maximum absorption wavelengths of Examples M5-M7 are 618.86nm, 619.43nm and 618.93nm, respectively, which are longer than the maximum absorption wavelength of the control photosensitizer. This indicates that M5-M7 helps reduce light scattering in tissues, making it easier for therapeutic light to concentrate inside the target tissue, improving efficacy and reducing damage to surrounding normal tissues. The red shift of the maximum absorption and emission wavelengths helps to improve the therapeutic effect and safety of photodynamic therapy. The theoretically calculated fluorescence rate coefficients of Examples M5-M7 are 1.912×10 8 s -1 , 1.904×10 8 s -1 and 1.903×10 8 s -1 , which is close to the fluorescence rate coefficient of the control photosensitizer, indicating that it has the potential to emit fluorescence and be used as an imaging agent.

[0031] Theoretical calculation results show that the energy gaps of singlet and triplet states for intersystem crossing of Examples M5-M7 are 0.193 eV, 0.157 eV and 0.163 eV, respectively, which are smaller than the energy gap of the control photosensitizer, which is beneficial to the efficiency of intersystem crossing of Examples M5-M7. The spin-orbit coupling constants for intersystem crossing of Examples M5-M7 are 0.74 cm -1 、0.73cm -1 and 0.73cm -1 In photodynamic therapy, the spin-orbit coupling constant between the singlet state and the triplet state represents the strength of the spin-orbit interaction between different excited states. The larger the spin-orbit coupling constant between the singlet state and the triplet state, the stronger the spin-orbit interaction between the singlet state and the triplet state. This may lead to more efficient intersystem crossing from the singlet state to the triplet state. The spin-orbit coupling constants of M5-M7 are all greater than those of the control photosensitizer, so intersystem crossing from the excited singlet state to the excited triplet state can occur more efficiently. The theoretically calculated intersystem crossing rate coefficients of Examples M5-M7 are 5.350×10 7 s -1 , 2.831×10 6 s -1 and 3.916×10 7 s -1, the larger the intersystem crossing rate coefficient is, the more favorable it is to the generation of the first excited triplet state, and the first excited triplet state can release energy to sensitize oxygen to become singlet oxygen with phototoxicity in the process of returning to the ground state, so the larger the intersystem crossing rate coefficient is, the more favorable it is to the generation of singlet oxygen. In Examples M5-M7, the intersystem crossing rate coefficient is significantly higher than that of the control photosensitizer, indicating that these examples have stronger intersystem crossing ability and are expected to produce more singlet oxygen. By changing the donor structure of the nitrogen-containing ring in Examples M5-M7, its electron donation ability is adjusted, thereby achieving precise regulation of the intersystem crossing process. This design concept is very consistent with the results of the present invention, highlighting that fine-tuning the photosensitizer structure can significantly affect its photodynamic therapy effect. This strategy provides a new idea for the development of more effective photosensitizers, and is expected to achieve better application effects in the field of photodynamic therapy.

Claims

1. A highly efficient singlet oxygen generating photosensitizer based on size regulation of nitrogen-containing aliphatic rings, characterized in that: The structure of the highly efficient singlet oxygen generating photosensitizer is as follows: The structure of the nitrogen-containing ring connected by thiophene is as follows:

2. A theoretical calculation design method for a highly efficient singlet oxygen generating photosensitizer based on size regulation of nitrogen-containing aliphatic rings, characterized in that: Here are the steps: Step 1: Use ChemDraw to draw the photosensitizer molecule, then import the drawn photosensitizer molecular structure into Chem3D, and select Minimize Energy in MOPAC in the menu bar to perform preliminary structural optimization; Step 2: Use Gaussian 16 software, select M06-2X functional and 6-31g (d, p) basis set, simulate the properties of photosensitizer molecules in toluene under the SMD solvation model, and calculate the geometric structure optimization and frequency of the ground state, excited singlet state and excited triplet state of the photosensitizer molecular structure; Step 3: Confirm that the calculation results obtained in step 2 have no imaginary frequencies, and confirm that the geometric structures of the ground state, excited singlet state and excited triplet state are the most stable structures; Step 4: Use BDF software to calculate the spin-orbit coupling constant between the excited singlet state and the excited triplet state to determine the intersystem crossing channel; Step 5: After determining the intersystem crossing channel using the spin-orbit coupling constant output from step 4, the energy gap difference between the singlet state and the triplet state where intersystem crossing occurs is obtained according to the structural optimization result of step 2; Step 6: Generate a MOMAP input file using the spin-orbit coupling constant obtained in step 4 and the energy gap difference between the singlet state and the triplet state obtained in step 5. Run the MOMAP input file through the MOMAP software. After the calculation is completed, the rate coefficient of the intersystem crossing of the photosensitizer molecule is obtained in the output file. The rate coefficient is proportional to the generation capacity of singlet oxygen. Step 7: Perform TD-DFT calculations on the ground state and the first excited singlet state to obtain the maximum absorption wavelength, maximum emission wavelength and fluorescence rate coefficient; Step 8: Calculate the ring strain of nitrogen-containing five-membered ring, six-membered ring and seven-membered ring using the homology reaction method; Step 9: Use ORCA software to calculate the oxidation potential of these molecules. The smaller the oxidation potential, the stronger the electron donating energy.

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