A method for designing a guanidine salt-modified photosensitizer, and use of the guanidine salt-modified photosensitizer

Abstract

The application belongs to the technical field of photosensitizer design, and particularly relates to a design method and application of a guanidinium salt modified photosensitizer. The design method comprises the following steps: providing a guanidinium salt and a fluorescent molecule, wherein the fluorescent molecule has an electron donor and an electron acceptor structure; and covalently coupling the fluorescent molecule and the guanidinium salt to obtain a guanidinium salt modified photosensitizer. The method changes the position of the guanidinium salt in the molecular structure to make the absorption and emission spectrum of the molecule red shift, increases the total active oxygen yield by increasing the number of guanidinium salts, and successfully prolongs the triplet state lifetime of the photosensitizer and improves the active oxygen yield by changing the number and position of the guanidinium salt. The covalent coupling of the fluorescent molecule without active oxygen and the guanidinium salt makes the final photosensitizer 2AG-TPABT have higher singlet oxygen and superoxide anion yield than the commercialized chlorin e6. The synthesis steps of the application are simple, the molecular structure does not contain heavy metals, the cost is low, and the application can be suitable for other fluorescent molecules without active oxygen.

Description

Technical Field

[0001] This invention belongs to the field of photosensitizer design technology, specifically relating to a design method for guanidine salt modified photosensitizers and the application of guanidine salt modified photosensitizers. Background Technology

[0002] In applications such as antibacterial, antitumor, and photovoltaic, photosensitizers play a crucial role. After being excited by light and absorbing energy, photosensitizer molecules transition from the ground state to a singlet excited state. They then deactivate to the lowest singlet excited state through non-radiative transitions such as vibrational relaxation and internal conversion. Subsequently, they undergo intersystem crossing processes (…). Figure 1 When electrons flip their spins to reach a triplet excited state, they react with surrounding substrates through electron transfer or energy transfer to produce highly toxic reactive oxygen species (ROS). As reactive substances, ROS damage macromolecules such as nucleic acids, proteins, and lipids, thereby killing lesions.

[0003] Introducing heavy atoms into the structure of fluorescent molecules is a method for designing photosensitizers and enhancing photosensitivity. For example, introducing transition metals such as platinum, ruthenium, and iridium into complexes can improve the reactive oxygen species (ROS) yield of the photosensitizer by promoting intersystem crossing. However, introducing heavy metals into the molecular structure may pose biotoxicity issues, limiting its application in fields such as photodynamic therapy, and also presents the potential for high costs associated with heavy metals.

[0004] Therefore, existing technologies still need further improvement. Summary of the Invention

[0005] To address the aforementioned problems, this invention aims to provide a design method for guanidine salt-modified photosensitizers. This design method successfully extends the triplet lifetime of the photosensitizer and improves the reactive oxygen species yield by introducing guanidine salts into reactive oxygen species-free fluorescent molecules with typical donor-acceptor structures.

[0006] The technical solution adopted by the present invention to solve the above-mentioned technical problems is as follows:

[0007] In a first aspect, a method for designing a guanidine salt-modified photosensitizer, wherein the design method includes:

[0008] A guanidine salt and a fluorescent molecule are provided, the fluorescent molecule having an electron donor and an electron acceptor structure;

[0009] The fluorescent molecule is covalently coupled to the guanidine salt to obtain a guanidine salt-modified photosensitizer. The following are preferred technical solutions of the present invention, but are not intended to limit the technical solutions provided by the present invention. Through the following preferred technical solutions, the objectives and beneficial effects of the present invention can be better achieved and realized.

[0010] As a preferred technical solution, the design method of the guanidine salt modified photosensitizer, wherein the fluorescent molecule is a reactive oxygen-free fluorescent molecule.

[0011] As a preferred technical solution, the design method of the guanidine salt-modified photosensitizer, wherein the structural formula of the guanidine salt-modified photosensitizer is:

[0012]

[0013] As a preferred technical solution, the design method of the guanidine salt-modified photosensitizer, wherein the structural formula of the guanidine salt-modified photosensitizer is:

[0014]

[0015] As a preferred technical solution, the design method of the guanidine salt modified photosensitizer specifically includes:

[0016] Provides aldehyde-based triphenylamine;

[0017] Aldehyde-triphenylamine was reacted with N-bromosuccinimide to give brominated aldehyde-triphenylamine;

[0018] The brominated aldehyde triphenylamine and the boron ester were reacted under the catalysis of a catalyst to obtain boron esterified aldehyde triphenylamine;

[0019] Boron-esterified aldehyde triphenylamine and brominated benzothiadiazole were subjected to the Suzuki reaction to obtain aldehyde-modified TPABT.

[0020] The aldehyde-modified TPABT was subjected to an aldehyde-amine condensation reaction with a guanidine amine salt to obtain the final guanidine salt-modified photosensitizer.

[0021] As a preferred technical solution, the design method of the guanidine salt modified photosensitizer specifically includes:

[0022] Provides aldehyde-based triphenylamine;

[0023] Aldehyde-based triphenylamine was reacted with malononitrile to obtain aldehyde-modified TPAMN;

[0024] The aldehyde-modified TPAMN and guanidinoamine salt were subjected to an aldehyde-amine condensation reaction to obtain the final guanidinoamine-modified photosensitizer.

[0025] Secondly, a guanidine salt-modified photosensitizer, wherein the guanidine salt-modified photosensitizer is designed using the design method described above.

[0026] Thirdly, the application of the aforementioned guanidine salt-modified photosensitizer in the preparation of antibacterial or antitumor drugs.

[0027] Beneficial Effects: Compared with existing technologies, the design method for a guanidine salt-modified photosensitizer provided by this invention has simple synthesis steps and wide applicability. By introducing a guanidine salt into a fluorescent molecule with a donor-acceptor structure, the photosensitizer is endowed with a longer triplet lifetime and a high reactive oxygen species (ROS) yield, with a total ROS yield higher than that of the commercially available photosensitizer dihydroporphyrin E6. Furthermore, the guanidine salt-modified photosensitizer prepared using this design method exhibits photodynamic antitumor effects in both in vitro cell experiments and in vivo mouse experiments. Attached Figure Description

[0028] Figure 1 This is a schematic diagram illustrating the mechanism by which photosensitizers generate reactive oxygen species.

[0029] Figure 2 The reactive oxygen species generated under white light irradiation by different guanidine salt modified photosensitizers provided in the embodiments of the present invention are generated.

[0030] Figure 3 This refers to the excited triplet lifetime of different guanidine salt modified photosensitizers provided in the embodiments of the present invention.

[0031] Figure 4 The guanidine salt modified photosensitizer provided in this embodiment of the invention exhibits dark toxicity and phototoxicity to tumor cells.

[0032] Figure 5 This is a graph showing the effect of the guanidine salt modified photosensitizer provided in this embodiment of the invention on the photodynamic therapy of tumors in mice. Detailed Implementation

[0033] The present invention will be further described in detail below with reference to specific embodiments and accompanying drawings. However, the implementation of the present invention is not limited thereto. For process parameters not specifically noted, conventional techniques can be referred to.

[0034] Furthermore, the features, operations, or characteristics described in the specification can be combined in any suitable manner to form various embodiments. Simultaneously, the steps or actions in the method description can be rearranged or adjusted in a manner readily apparent to those skilled in the art. Therefore, the various orders in the specification and drawings are merely for the clear description of a particular embodiment and do not imply a necessary order, unless otherwise stated that a particular order must be followed. The component designations used herein, such as "first," "second," etc., are merely for distinguishing the described objects and do not have any sequential or technical meaning. All instruments and reagents used are commercially available products.

[0035] Unless otherwise defined, all terms used herein (including technical and scientific terms) shall have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. It will also be understood that, unless expressly defined herein, terms such as those defined in a general dictionary shall be interpreted as having the meaning consistent with their meaning in the relevant field context, and not as having an idealized or overly formal meaning.

[0036] The present invention provides a method for designing a guanidine salt-modified photosensitizer, comprising the following steps:

[0037] S10. Provide a guanidine salt and a fluorescent molecule, said fluorescent molecule having an electron donor and an electron acceptor structure.

[0038] Specifically, the photosensitizer uses fluorescent molecules with electron donor and electron acceptor structures and guanidine salts as its structural components. Any fluorescent molecule with an electron donor-electron acceptor structure can be used. Guanidine salts are also common; their function is to provide a guanidine group, a unique functional group with a conjugated structure and specific biological activities.

[0039] Following step S10 is step S20, in which the fluorescent molecule is covalently coupled to the guanidine salt to obtain a guanidine salt-modified photosensitizer.

[0040] Specifically, in an acidic environment, guanidine salts are covalently coupled with fluorescent molecules having an electron donor-electron acceptor structure, introducing a guanidine group into the fluorescent molecule. This red-shifts the absorption and emission spectra of the photosensitizer, prolonging its triplet lifetime and increasing the yield of reactive oxygen species.

[0041] In one embodiment of the present invention, the fluorescent molecule is a reactive oxygen species-free fluorescent molecule, such as TPABT or TPAMN. The structural formulas of TPABT and TPAMN are as follows:

[0042]

[0043] In this invention, the preparation method of the guanidine salt modified photosensitizer includes the following steps:

[0044] S100 provides aldehyde-based triphenylamine;

[0045] S200, reacting aldehyde triphenylamine with N-bromosuccinimide to obtain brominated aldehyde triphenylamine;

[0046] S300. The brominated aldehyde triphenylamine and the borate ester are reacted under the catalysis of a catalyst to obtain borate esterified aldehyde triphenylamine;

[0047] S400, boron-esterified aldehyde triphenylamine and brominated benzothiadiazole are subjected to the Suzuki reaction to obtain aldehyde-modified TPABT.

[0048] S500, aldehyde-modified TPABT is subjected to an aldehyde-amine condensation reaction with guanidineamine salt to obtain the final guanidine salt modified photosensitizer.

[0049] Specifically, using aldehyde-based triphenylamine as a raw material, brominated aldehyde-based triphenylamine was first synthesized via a bromination reaction. Then, boron-esterified aldehyde-based triphenylamine was synthesized via a palladium-catalyzed reaction with boron ester. Next, boron-esterified aldehyde-based triphenylamine and brominated benzothiadiazole were coupled via a Suzuki reaction under palladium catalysis to obtain aldehyde-based triphenylamine benzothiadiazole. Finally, the aldehyde-based triphenylamine benzothiadiazole was reacted with guanidinoamine salt under acid catalysis to obtain the final photosensitizer product.

[0050] Based on the same inventive concept, the present invention also provides a guanidine salt modified photosensitizer, the preparation method of which is as follows:

[0051] Provides aldehyde-based triphenylamine;

[0052] Aldehyde-based triphenylamine was reacted with malononitrile to obtain aldehyde-modified TPAMN;

[0053] The aldehyde-modified TPAMN and guanidinoamine salt were subjected to an aldehyde-amine condensation reaction to obtain the final guanidinoamine-modified photosensitizer.

[0054] Based on the same inventive concept, the present invention also provides the application of the guanidine salt modified photosensitizer in the preparation of antibacterial or antitumor drugs.

[0055] The following specific preparation examples will further explain the preparation method of the guanidine salt modified photosensitizer provided by the present invention.

[0056] Example 1: Preparation of AG-TPABT

[0057] First, 4-(diphenylamine)benzaldehyde is reacted with N-bromosuccinimide to give brominated aldehyde triphenylamine. Then, brominated aldehyde triphenylamine is reacted with borate ester under palladium catalysis to give boronized aldehyde triphenylamine. The boronized aldehyde triphenylamine is then subjected to the Suzuki reaction with brominated benzothiadiazole to give aldehyde triphenylamine benzothiadiazole. The aldehyde triphenylamine benzothiadiazole is then reacted with guanidinoamine salt to give the product AG-TPABT, which is an orange solid. The structural formula of AG-TPABT is as follows:

[0058]

[0059] Example 2 Preparation of 2AG-TPABT

[0060] First, N,N-bis(4-formylphenyl)aniline was reacted with N-bromosuccinimide to yield brominated dialdehyde triphenylamine. Then, brominated dialdehyde triphenylamine was reacted with a borate ester under palladium catalysis to yield boronized dialdehyde triphenylamine. The synthesis of dialdehyde-modified TPABT was similar to that of TPABT; dialdehyde-modified TPABT was reacted with a guanidinoamine salt to give product 2AG-TPABT, a red-orange solid.

[0061] The structural formula of the 2AG-TPABT is as follows:

[0062]

[0063] Example 3: Preparation of TPABT-AG

[0064] First, 4-(diphenylamino)phenylboronic acid pinacol ester and 7-bromo-2,1,3-benzothiadiazole-4-carboxaldehyde were reacted under palladium catalysis to obtain a yellow solid. Then, it was reacted with guanidinoamine salt to obtain the product TPABT-AG, which was a red solid.

[0065] The structural formula of the TPABT-AG is as follows:

[0066]

[0067] Example 4: Preparation of AG-TPAMN

[0068] First, N,N-bis(4-formylphenyl)aniline was reacted with malononitrile to give a yellow solid. Then, it was reacted with guanidinium salt to give the product AG-TPAMN, which was a red solid.

[0069] The structural formula of the AG-TPAMN is as follows:

[0070]

[0071] Example 5 Preparation of 2AG-TPAMN

[0072] Tris(4-formylphenyl)amine was reacted with malononitrile to give a yellow solid. Then it was reacted with guanidinoamine salt to give product 2AG-TPAMN, which was a red solid.

[0073] The structural formula of the 2AG-TPAMN is as follows:

[0074]

[0075] In summary, the guanidine salt-modified photosensitizer, its preparation method, and its applications provided by this invention include: providing a guanidine salt and a fluorescent molecule, wherein the fluorescent molecule has an electron donor and an electron acceptor structure; and covalently coupling the fluorescent molecule with the guanidine salt to obtain the guanidine salt-modified photosensitizer. This method red-shifts the absorption and emission spectra of the molecule by changing the position of the guanidine salt in the molecular structure, and increases the total reactive oxygen species (ROS) yield by increasing the amount of guanidine salt. The changes in the number and position of the guanidine salt successfully prolong the triplet lifetime of the photosensitizer and increase the ROS yield. The covalent coupling of the ROS-free fluorescent molecule with the guanidine salt results in the final photosensitizer 2AG-TPABT exhibiting higher singlet oxygen and superoxide anion yields than commercially available dihydroporphyrin e6. Subsequent in vitro cell experiments and in vivo mouse experiments also demonstrated that 2AG-TPABT has a significant photodynamic therapeutic effect on tumors. The synthesis steps of this invention are simple, the molecular structure is free of heavy metals, the cost is low, and it can be applied to other ROS-free fluorescent molecules.

[0076] The above description outlines the basic principles, main features, and performance advantages of this invention. It should be understood that the performance and applications of this invention are not limited to the examples described above. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims.

Claims

1. A guanidine salt-modified photosensitizer, characterized in that, The structural formula of the photosensitizer is: 、 、 、 or .

2. The use of the guanidine salt modified photosensitizer according to claim 1 in the preparation of antibacterial or antitumor drugs.

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