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CN-121991049-A - Preparation method and application of engineered I-type photosensitizer

CN121991049ACN 121991049 ACN121991049 ACN 121991049ACN-121991049-A

Abstract

The invention relates to the field of biological medicine and photodynamic therapy, in particular to a preparation method and application of an engineered I-type photosensitizer. The preparation method comprises the following steps of S1, synthesizing a core D-pi-A structural unit taking bithiophene as a framework and cyano indanone as an acceptor, S2, introducing a phenylcarbazole donor unit onto the bithiophene aldehyde framework to form an intermediate 1, S3, connecting a strong acceptor unit with the intermediate 1 to form a D-pi-A photosensitizer, S4, introducing the phenylcarbazole donor unit onto the bithiophene aldehyde framework to form an intermediate 2, S5, reacting the intermediate 2 as a raw material with the strong acceptor unit to obtain CzTTI, and S6, preparing CzPhTTI nano particles. The invention can synchronously regulate and control the treatment strategies of a plurality of core pathological pathways, solves the problem of the existing therapies of anti-inflammatory and repairing disjoint, overcomes the bottleneck of strong oxygen dependence of the traditional II type photosensitizer, and improves the targeting and safety of treatment.

Inventors

  • ZENG JINRONG
  • WU NINGLING
  • ZENG WENBIN
  • DING JIPENG

Assignees

  • 中南大学湘雅三医院

Dates

Publication Date
20260508
Application Date
20251217

Claims (7)

  1. 1. An engineered type I photosensitizer preparation method, characterized by comprising the following steps: s1, synthesizing a core D-pi-A structural unit taking bithiophene as a framework and cyano indanone as a receptor through Knoevenagel condensation reaction, wherein the core D-pi-A structural unit is called TTI for short; s2, introducing a phenylcarbazole donor unit onto a bithiophene aldehyde skeleton by a Suzuki-Miyaura coupling reaction to form an intermediate 1 by adopting a boric acid reagent as an organoboron reagent; S3, connecting a strong receptor unit with the intermediate 1 through Knoevenagel condensation reaction to form a target product D-pi-A type photosensitizer, namely a target product CzPhTTI; S4, introducing a phenylcarbazole donor unit onto a bithiophene aldehyde skeleton by a Suzuki-Miyaura coupling reaction, wherein an organoboron reagent adopts 9-phenyl-9H-carbazole-3-yl-3-boric acid pinacol ester to form an intermediate 2; S5, reacting the intermediate 2 serving as a raw material with a strong receptor unit through Knoevenagel condensation reaction, and purifying to obtain a target photosensitizer CzTTI; S6, preparing CzPhTTI nano particles.
  2. 2. The process for preparing an engineered type I photosensitizer according to claim 1, wherein in S1, the synthesis of TTI comprises the steps of S11, feeding, weighing 5-bromo-2, 2 '-bithiophene-5' -formaldehyde (546.3 mg,2.0 mmol) and 3- (dicyanomethylene) indan-1-one (388.4 mg,2.0 mmol) in a dry flask, adding 15mL of absolute ethanol as a solvent, stirring to dissolve the solid, S12, catalyzing, adding 1 drop of piperidine as a catalyst dropwise to the above mixture, S13, reacting, heating the reaction system to 90 ℃ under nitrogen protection, stirring and refluxing at the temperature for 12 hours, S14, post-treating, cooling the reaction mixture to room temperature after the reaction is finished, removing the solvent ethanol by using a rotary evaporator under reduced pressure to obtain a crude product, and S15, purifying by silica gel column chromatography to obtain a red solid target TTI.
  3. 3. The process for preparing an engineered type I photosensitizer according to claim 1, wherein in S2, the intermediate 1 is formed by adding S21, a charge of 9- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) -9H-carbazole (1107.8 mg,3.0 mmol), 5-bromo-2, 2' -dithiophene-5 ' -carbaldehyde (546.3 mg,2.0 mmol), dichloro (1, 1' -bis (diphenylphosphine) ferrocene) palladium (Pd (dppf) Cl 2 ) (73.2 mg,0.1 mmol) and potassium carbonate (1105.6 mg,8.0 mmol) sequentially into a dry 50mL Schlenk reaction tube, S22, a solvent and oxygen removal by adding a mixed solvent of 1, 4-dioxabicyclo (10 mL) and water (2.5 mL) into the reaction system, then "vacuum-filling" the reaction system with nitrogen gas, cooling the reaction system by a three-time hopper (S23 mg,2.0 mmol), drying the reaction system by a vacuum filtration method, cooling to a dry solid phase of 30℃under a vacuum filtration method, concentrating the filtrate of 30℃under a dry phase, and cooling the filtrate of the mixture to obtain a crude product, and concentrating the crude filtrate by a vacuum filtration of 30℃under a vacuum, and concentrating the dry phase of the dry filtrate of the dry product.
  4. 4. The method for preparing the engineered type I photosensitizer according to claim 1, wherein in S3, the synthesis of the target product CzPhTTI comprises the steps of S31, feeding, namely placing intermediate 1 (867.2 mg,2.0 mmol) and 3- (dicyanomethylene) indan-1-one (388.4 mg,2.0 mmol) into a dry flask, adding 15mL of absolute ethyl alcohol, S32, catalyzing and reacting, namely adding 1 drop of piperidine into the mixture, heating to 90 ℃ under the protection of nitrogen, stirring and refluxing for 12 hours, S33, post-treating and purifying, namely cooling the reaction liquid to room temperature, decompressing and evaporating the solvent, and purifying the crude product by a silica gel column chromatography to obtain the purple solid target photosensitizer CzPhTTI.
  5. 5. The method for preparing the engineered type I photosensitizer according to claim 1, wherein in S6, czPhTTI nanoparticles are prepared from CzTTI, 1, 2-dimyristoyl-sn-glycero-3-phosphorylcholine, cholesterol and DSPEmPEG.
  6. 6. The method for preparing the engineered type I photosensitizer according to claim 5, wherein the preparation of CzPhTTI nanoparticles comprises the steps of S61, dissolving 1, mgCzTTI, 8mg of 1, 2-dimyristoyl-sn-glycero-3-phosphorylcholine, 2mg of cholesterol and 0.5mg of DSPEmPEG2000 in chloroform, evaporating the solution into a thin film in a rotary evaporator, S62, hydrating the thin film with deionized water, then sonicating the thin film with a microtip probe sonicator (Q125, QSONIC, LLC) for 5 minutes at 50% output power, S63, passing the resulting solution through a 0.22 μm polycarbonate filter, S64, transferring the solution into a dialysis bag with a molecular weight cutoff of 3500Da, dialyzing the solution with deionized water for 24 hours, and changing water every 4 hours.
  7. 7. Use of an engineered type I photosensitizer according to any one of claims 1-6 in phototherapy of atopic dermatitis.

Description

Preparation method and application of engineered I-type photosensitizer Technical Field The invention relates to the technical field of biological medicine and photodynamic therapy, in particular to a preparation method and application of an engineered I-type photosensitizer. Background Atopic dermatitis is a common chronic inflammatory skin disease, which is manifested clinically by dry skin, itching, erythema and exudation, severely affecting the quality of life of the patient. The existing treatment means such as glucocorticoid, calcineurin inhibitor and the like have the problems of large side effect, easy recrudescence and the like. Photodynamic therapy has shown good promise in dermatological treatment as a non-invasive therapeutic strategy. The type I photosensitizer generates active oxygen through an electron transfer way under illumination, and has stronger tissue penetration capability and antioxidation stress regulation potential. At present, the existing treatment mechanism can treat the symptoms and not the root cause, and has remarkable side effects, particularly, the existing mainstream medicines (such as glucocorticoid and immunosuppressant) mainly play a role in widely inhibiting immune response, but can not fundamentally restore the skin barrier function and the immune balance. Can cause local side effects such as skin atrophy, telangiectasia, pigmentation, etc. and systemic risks (such as cushing's syndrome, hepatorenal toxicity) caused by systemic absorption after long-term use. The biological agent has stronger targeting property, but has the problems of conjunctivitis, high cost, potential infection risk and the like. The existing photosensitizer material has single mechanism and insufficient penetrability and safety, and is characterized in that the type II photosensitizer (such as porphyrin derivative) used in the traditional photodynamic therapy (PDT) is seriously dependent on oxygen to generate singlet oxygen, and the curative effect is drastically reduced in the low-oxygen microenvironment frequently accompanied by atopic dermatitis. Meanwhile, the photosensitizers are absorbed in the visible light region (such as blue light and green light), have limited tissue penetration depth, and are difficult to effectively act on immune cells of dermis. In addition, they often accompany persistent phototoxic reactions, and patients need to be protected from light for a long period after treatment, severely affecting quality of life. In addition, the existing treatment strategies have high comprehensive management cost and poor patient compliance, and are characterized in that the treatment of AD is a long-term process, and the existing scheme often leads to high total treatment cost (especially biological preparations), high treatment frequency and long time consumption. Frequent medications and review places a heavy economic and energy burden on the patient and his home. The long-term light-shielding requirement in photodynamic therapy also severely affects the daily work and life of the patient, resulting in reduced compliance. Disclosure of Invention The invention aims to solve the problems that a photosensitizer material in the background technology is single in mechanism, insufficient in penetrability and safety, the existing treatment means can not address the symptoms and root causes, and the comprehensive cost is high, and provides an engineering type I photosensitizer preparation method and application thereof. In one aspect, the invention provides a method for preparing an engineered type I photosensitizer, comprising the steps of: s1, synthesizing a core D-pi-A structural unit taking bithiophene as a framework and cyano indanone as a receptor through Knoevenagel condensation reaction, wherein the core D-pi-A structural unit is called TTI for short; s2, introducing a phenylcarbazole donor unit onto a bithiophene aldehyde skeleton by a Suzuki-Miyaura coupling reaction to form an intermediate 1 by adopting a boric acid reagent as an organoboron reagent; S3, connecting a strong receptor unit with the intermediate 1 through Knoevenagel condensation reaction to form a target product D-pi-A type photosensitizer, namely a target product CzPhTTI; S4, introducing a phenylcarbazole donor unit onto a bithiophene aldehyde skeleton by a Suzuki-Miyaura coupling reaction, wherein an organoboron reagent adopts 9-phenyl-9H-carbazole-3-yl-3-boric acid pinacol ester to form an intermediate 2; S5, reacting the intermediate 2 serving as a raw material with a strong receptor unit through Knoevenagel condensation reaction, and purifying to obtain a target photosensitizer CzTTI; S6, preparing CzPhTTI nano particles. Preferably, in S1, the synthesis of the TTI comprises the steps of S11, feeding, namely weighing 5-bromo-2, 2 '-bithiophene-5' -formaldehyde (546.3 mg,2.0 mmol) and 3- (dicyanomethylene) indan-1-one (388.4 mg,2.0 mmol) in a dry flask, adding 15mL of absolute ethyl alcohol as a solvent, stirri