Lipophilic and hydrophilic hypocrellin derivative, preparation method and applications thereof

A technology of hypocretin and derivatives, which is applied in the field of ester-water amphiphilic hypocretin derivatives and its preparation, and can solve the problems of reduced photodynamic activity, weak light absorption ability, blood vessel blockage, etc.

Active Publication Date: 2018-04-20
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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  • Lipophilic and hydrophilic hypocrellin derivative, preparation method and applications thereof
  • Lipophilic and hydrophilic hypocrellin derivative, preparation method and applications thereof
  • Lipophilic and hydrophilic hypocrellin derivative, preparation method and applications thereof

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Experimental program
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Effect test

Embodiment 1

[0074] 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.

[0075] Prepa...

Embodiment 2

[0078] 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.

[0079]

[0080] 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).

[0081] 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

[0084] 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:

[0085] 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 lipophilic and hydrophilic hypocrellin derivative, a preparation method and applications thereof. According to the present invention, the prepared substituted lipophilic andhydrophilic hypocrellin derivative containing ethylene glycol, a quaternary ammonium salt and other groups has significant red shift in the absorption spectrum, has significantly enhanced molar extinction coefficient compared to the hypocrellin precursor, and can efficiently produce singlet state oxygen and other reactive oxygen species under a light-sensitive condition; by regulating the hydrophilicity and the hydrophobicity, the derivative can have different hydrophilicity and lipophilicity while the biological compatibility with cells or tissues can be improved; the lipophilic and hydrophilic hypocrellin derivative can meet different clinical medication requirements so as to solve the contradiction between different administration modes and the requirements on hydrophilicity and lipophilicity of drugs; and under the same condition, the lipophilic and hydrophilic hypocrellin derivative photosensitizer can provide high photodynamic tumor inactivation capacity compared to the first-generation and second-generation commercial photosensitizers.

Description

technical field [0001] 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 [0002] 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. Its advantages lie in its high efficiency and safety. It can continuously generate reactive oxygen species under light irradiation, causing diseased cells and tissues Compared with traditional drugs that can only kill a single target molecule, it has remarkable efficiency. Photodynamic therapy has two-way selectivity of drug targeting and light localization, which re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/38C07D487/08C07C221/00C07C225/32C07C227/18C07C229/14C07C303/30C07C309/69C07C319/20C07C323/25C07C231/12C07C237/08C07D213/53C07D211/58C07C241/02C07C243/22C07C239/14C07C249/02C07C251/18A61K41/00A61P35/00
CPCA61K41/0057A61P35/00C07D241/38
Inventor 汪鹏飞吴加胜郑秀丽顾瑛刘卫敏葛介超张洪艳
Owner TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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