Lipid-water amphiphilic hypocrellin derivative, preparation method and application thereof

A technology of hypocrellin and its derivatives, which can be used in drug combinations, pharmaceutical formulations, photodynamic therapy, etc., and can solve problems such as blood vessel blockage, low solubility, and low cell uptake rate

Active Publication Date: 2020-10-27
TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the main absorption wavelength range of hypocrellin is 450-550nm, and this wavelength can penetrate less than 1 mm of tissue, and its ability to absorb light in the photodynamic therapy window (600-900nm) is weak
However, hypocretin is a kind of lipophilic organic small molecule, its solubility in water is very low, direct intravenous injection will spontaneously aggregate in the blood and cause blood vessel blockage
Sulfonic acid-substituted derivatives (Liu X, Xie J, Zhang L Y, et al. Optimization of hypocrellin B derivative amphiphilicity and biological activity. Chinese Sci Bull, 2009, 54: 2045-2050) can solve the problem of water solubility well, However, due to its negative charge and the mutual repulsion of a large number of negative charges in cells and tissues, the cellular uptake rate is low, which greatly reduces the photodynamic activity

Method used

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  • Lipid-water amphiphilic hypocrellin derivative, preparation method and application thereof
  • Lipid-water amphiphilic hypocrellin derivative, preparation method and application thereof
  • Lipid-water amphiphilic hypocrellin derivative, preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Extraction of Hypocretin A (HA): 100g of Hypocretin A (HA) was pulverized with a pulverizer, placed in a Soxhlet extractor, and continuously extracted for one day with 1000mL acetone as a solvent until the extract was nearly colorless, and the extract was filtered to remove a small amount of infiltrated The solid insoluble matter was then spin-dried to remove acetone, dissolved with 500mL dichloromethane, washed with 4×400mL distilled water, the organic layer was separated and spin-dried, the solid residue was washed with 5×100mL petroleum ether, the solid was spontaneously ignited and air-dried in the air, and then Recrystallize twice with chloroform-petroleum ether, and the obtained crystal is the target product Hypocretin A (HA), with a purity of more than 98%. Thin-layer silica gel plate chromatography, using petroleum ether: ethyl acetate: absolute ethanol (30:10:1) as a developing solvent, can be further purified to obtain high-purity hypocrellin A.

[0076] Prepa...

Embodiment 2

[0079] The present invention contains long-chain quaternary ammonium salt derivatives and is prepared by the following general method, with H 2 NCH 2 CH 2 -N + (CH 3 ) 2 (C 10 h 21 ) for the column description.

[0080]

[0081] Preparation of intermediate S1: N,N-dimethylethylenediamine (4.4g, 0.05mol) and diethyl carbonate (7.10g, 0.06mol) were mixed in a 100ml round bottom flask, and the reaction solution was reacted at 70°C 48h, and then distilled under reduced pressure to obtain 7.20 g of a light yellow liquid with a yield of 89%. 1 H NMR (CDCl 3 ,δ,ppm):5.45(s,-NH-,1H),4.10(d,J=6.5Hz,-CH 2 O,2H),3.24(s,-NH-CH 2 -,2H),2.39(m,-CH 2 N,2H),2.22(d,J=1.5Hz,CH 3 NCH 3 ,6H),1.23(t,J=6.5Hz,-CH 2 CH 3 ,3H).

[0082] Preparation of Intermediate S2: Intermediate S1 and 1-bromodecane (15.25g, 0.05mol) were reacted at 100°C for 48h and then reacted for 72h. The crude product was treated with acetone-diethyl ether (1:1) to obtain 15.83 g of white crystal 2, with a y...

Embodiment 3

[0085] Hypocretin derivatives modified with aminoethyl glycol (R=-CH 2 CH 2 OCH 2 CH 2 OH) preparation: the synthetic route is attached Figure 4 Shown:

[0086] Dissolve Hypocretin B HB (100mg, 0.18mmol) and aminoethyl glycol (0.40g, 4mmol) in 20mL of anhydrous acetonitrile, mix well, heat to 50°C under nitrogen protection, and stir to react in the dark After 10 h, the reaction was completed, and the solvent was removed by rotary evaporation. The blue-black solid residue was dissolved in 200 mL of dichloromethane, washed once with 100 mL of dilute hydrochloric acid aqueous solution, and washed twice with distilled water. The organic layer was dried with anhydrous magnesium sulfate, filtered, and the organic phase was spin-dried to obtain a crude product. The resulting crude product is further separated by silica gel plate chromatography, and the developing agent is acetone: ethyl acetate (volume ratio is 1:1), and two kinds of blue-black solid products are obtained respe...

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Abstract

The invention discloses a lipid-water amphiphilic hypocrellin derivative, a preparation method and application thereof. Compared with a hypocrellin parent, the hypocrellin derivative containing ethylene glycol, a quaternary ammonium salt and other group substitutions has the advantages that the absorption spectrum of the hypocrellin derivative has significant red shift, the molar extinction coefficient is greatly enhanced, and singlet oxygen and other active oxygen species can be efficiently generated under a photosensitive condition; the hydrophilic and hydrophobic properties of the derivative are adjusted, so that the derivative has different lipid-water amphipathy, and meanwhile, the biocompatibility of the derivative with cells or tissues is improved; the lipid-water amphiphilic hypocrellin derivative can meet the requirements of different clinical medication, and the contradiction between the requirements of different administration modes on the hydrophilicity and lipophilicity ofthe drug is solved; under the same condition, the ester-water amphiphilic hypocrellin derivative photosensitizer provided by the invention has higher photodynamic tumor cell inactivation capacity than first-generation and second-generation commercial photosensitizers.

Description

[0001] The application date is October 13, 2016, the application number is 201610894400.0, the invention name is "ester-water amphiphilic hypocretin derivatives and its preparation method and application", and the applicant is China Institute of Physical and Chemical Technology, Chinese Academy of Sciences A divisional application of an invention patent application. technical field [0002] The invention relates to the technical field of photosensitizer medicine for photodynamic therapy. More specifically, it relates to a class of esterwater amphiphilic hypocretin derivatives and its preparation method and application. Background technique [0003] Photodynamic therapy (PDT) is a new technology for the selective treatment of vascular lesions that has developed rapidly in recent years, and it also has significant curative effects on various tumor diseases. Photodynamic therapy has become the fourth special type of tumor treatment after surgery, radiotherapy and chemotherapy....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/38A61K41/00A61P35/00
CPCA61K41/0057A61P35/00C07D241/38
Inventor 汪鹏飞吴加胜郑秀丽顾瑛刘卫敏
Owner TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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