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Folic acid acceptor mediated molecular targeted photosensitizer and preparation method thereof

A technology of molecular targeting and photosensitizers, applied in the field of tumor-targeting photodynamic therapy, can solve the problems of diamino compound instability, reduced bioavailability, shortened cycle time, etc., to achieve active targeting and improve stability The effect of simple and convenient preparation method

Inactive Publication Date: 2012-09-12
INST OF FIELD OPERATION SURGERY NO 3 MILITARY MEDICL UNIV PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, since the amino group is an active group, it is easily oxidized by air, so the bisamino compound is unstable and difficult to preserve, and during synthesis, it is necessary to protect one end of the amino group first, and then remove the protection after the chemical reaction of the other end of the amino group. follow-up reaction
In addition, because the ester bond and amide bond in the molecule are easily hydrolyzed by the hydrolase in the body, the stability in the body is reduced, the circulation time in the body is shortened, and the bioavailability is reduced.

Method used

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  • Folic acid acceptor mediated molecular targeted photosensitizer and preparation method thereof
  • Folic acid acceptor mediated molecular targeted photosensitizer and preparation method thereof
  • Folic acid acceptor mediated molecular targeted photosensitizer and preparation method thereof

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preparation example Construction

[0046] like figure 2 As shown, the preparation method of the molecularly targeted photosensitizer of the present invention comprises the following steps:

[0047] (1), monohydroxyporphyrin reacts nucleophilically with dihaloalkane under alkali catalysis to generate halogenated porphyrin; wherein, the monohydroxyporphyrin has three substituents R 1 , R 2 and R 3 The monohydroxyporphyrin, the R1, R2 and R3 are each independently a methoxy group; the dihaloalkane is C 1-20 1, n-dihaloalkane, wherein n=1-20;

[0048] (2), the halogenated porphyrin obtained by step (1) undergoes a Gabriel reaction with potassium phthalimide to generate amide porphyrin, which is then hydrolyzed with hydrazine in an aprotic solvent to generate primary amine porphyrin;

[0049] (3) The primary amino porphyrin obtained in step (2) reacts with the activated γ-carboxyl of folic acid to generate the target compound folic acid porphyrin.

experiment example 1

[0050] Experimental example 1: Synthesis of bromoporphyrin

[0051] In 110mL of N,N-dimethylformamide solution, add 16.1mmol of freshly baked potassium carbonate, 2.1mmol of monohydroxyporphyrin and 30mmol of 1,3 dibromopropane, N 2 Stir and react at 80°C for 2h, wait for the reaction liquid to cool slightly, pour it into 100mL of sodium chloride aqueous solution, let stand for 2h, filter with suction, wash with a large amount of water, wash with a small amount of 95% (volume ratio) ethanol, and dry in vacuo to obtain crude product. The crude product was separated by column chromatography (silica gel H, chloroform elution), the first purple band was collected, concentrated under reduced pressure and then recrystallized with chloroform-petroleum ether to obtain 1.77g of brominated porphyrin, yield: 88%, purple-red solid. 1 HNMR (CDCl 3 )δ: 8.85 (s, 8H, β-H), 8.77-8.21 (d, 8H, Ar-H), 7.30-7.25 (d, 8H, Ar-H), 4.34-4.13 (t, 2H, BrCH 2 ), 4.10(s, 9H, 3×OCH 3 ), 3.83-3.69 (t, 2...

experiment example 2

[0052] Experimental example 2: Synthesis of primary amine porphyrin

[0053] In 100mL of N,N-dimethylformamide solution, add 924mg of bromoporphyrin and 375mg of potassium phthalimide, stir and react at 100°C for 9h under the protection of argon, then pour the reaction solution into NaCl solution Stand in the middle for several hours, filter with suction, wash with water three times and wash twice with a small amount of ethanol, and vacuum dry to obtain a purple solid, namely the crude product of amide porphyrin. The crude product was separated by column chromatography (SiO 2 , CHCl 3 ), the second purple band was collected and concentrated to obtain 880 mg of the intermediate. After adding 50ml of tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dioxane or dichloromethane to the intermediate, add hydrazine hydrate under the protection of argon, stir and react in an oil bath at 75°C for 6 hours, pump Dry the reaction solution, then use CHCl 3 Dissolve the solid, dry...

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Abstract

A molecular targeted photosensitizer and a preparation method thereof are disclosed. The molecular targeted photosensitizer consists of folic acid porphyrin, R1, R2 and R3 in the molecular structural formula of folic acid porphyrin are independently hydroxyl, straight-chain or branched-chain hydrocarbon, n in the molecular structural formula ranges from 1 to 20. The preparation method is as follows: alkylation reaction is carried out on monohydric porphyrin and dihalohydrocarbon to generate halogen porphyrin, and then Gabriel reaction is carried out with phthalimide potassium to generate amideporphyrin which is hydrolyzed by hydrazine to obtain primary amine porphyrin; finally, amination reaction is carried out on primary amine porphyrin and folic acid to obtain the folic acid porphyrin.The raw materials used by the preparation method of the invention are stable and accessible, the reaction condition is mild, the yield is high, the generated reactant has good targeted therapy to tumor cell, partial photosensitizer in vitro photodynamic antitumor activity result shows strong effect, thus being suitable for tumor targeted photodynamic therapy and having good clinical application value.

Description

technical field [0001] The invention relates to a molecularly targeted photosensitizer and a preparation method thereof, in particular to a molecularly targeted photosensitizer for tumor-targeted photodynamic therapy mediated by folic acid receptors and a preparation method thereof. Background technique [0002] In my country, the annual incidence of tumors is 2.3 million, and an average of 3 people die of tumors every minute, which has seriously threatened human health. Tumor photodynamic therapy (Photodynamic Therapy, PDT) is the latest development in the field of minimally invasive or non-invasive treatment of modern tumors. , and show strong vitality. In 1996, it was approved by the US FDA for clinical use. In May 2003, the Chinese SFDA approved this treatment system to enter clinical application. This therapy is mainly used in the treatment of body surface tumors, digestive tract tumors, liver cancer, lung cancer and bladder cancer, and an important factor determining...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/519A61K41/00C07D519/00A61P35/00C07D487/22C07D475/04
Inventor 李东红刁俊林刘建仓
Owner INST OF FIELD OPERATION SURGERY NO 3 MILITARY MEDICL UNIV PLA
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