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Lipoid cation function molecule synthesized from natural cholesterol and amino acid and preparation method and application thereof

A technology of natural amino acids and functional molecules, which is applied in the field of synthesizing lipid-like biological carrier materials, can solve the problems of complex and tedious synthesis steps, poor generality of synthetic preparation methods, etc., achieves high gene transfection efficiency, and is easy to scale at low cost. Preparation and application promotion, the effect of low cytotoxicity

Inactive Publication Date: 2012-01-18
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

On the other hand, in practical applications, the synthesis steps of many cholesterol-derived gene delivery vectors are complex and cumbersome, and the generality of their synthetic preparation methods is not good.

Method used

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  • Lipoid cation function molecule synthesized from natural cholesterol and amino acid and preparation method and application thereof
  • Lipoid cation function molecule synthesized from natural cholesterol and amino acid and preparation method and application thereof
  • Lipoid cation function molecule synthesized from natural cholesterol and amino acid and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029]

[0030] Lipid compound CHO-AA-1

[0031] The first step: dissolving hexanediol (12.2g, 0.1mmol) in 30ml of dry dichloromethane, the above solution was slowly added dropwise to cholesterol chloroformate (4.5 ml of triethylamine dissolved in 100ml of dry dichloromethane) g, 0.01 mol) solution, stirred and reacted at 40 °C for 5 h, then distilled off the organic solvent, passed through column chromatography (eluent: ethyl acetate / petroleum ether=1 / 2 v / v), and prepared cholesterol hexylene glycol monolayer The ether carbonate intermediate was synthesized in 80% yield.

[0032] 1 H NMR (CDCl 3 , 300MHz): 5.32 (s, 1H, C=CH, cholesterol), 4.54 (t, 2H, J=6.3 Hz, CH 2 OCO), 4.51(m, 1H, OCOCH), 4.36(t, 2H, J=6.3Hz, CH 2 OCO), 3.79(t, 2H, J=6.3Hz, CH 2 O), 2.30-0.95 (m, 45H, cholesterol) ESI-MS: [M + ]=531.1m / z

[0033] The second step: BOC-lysine (3.5g, 0.01mol) was dissolved in 50ml of dry dichloromethane, and slowly added dropwise to the cholesterol hexanediol monohy...

Embodiment 2

[0037]

[0038] Lipid compound CHO-AA-2

[0039] The first step: dissolving hexanediol (12.2g, 0.1mmol) in 30ml of dry dichloromethane, the above solution was slowly added dropwise to cholesterol chloroformate (4.5 ml of triethylamine dissolved in 100ml of dry dichloromethane) g, 0.01mol) solution, the organic solvent was distilled off after stirring at 40°C for 5h, and then passed through column chromatography (eluent: ethyl acetate / petroleum ether=1 / 2v / v) to prepare cholesterol hexylene glycol monolayer. The ether carbonate intermediate was synthesized in 80% yield.

[0040] 1 H NMR (CDCl 3 , 300MHz): 5.32 (s, 1H, C=CH, cholesterol), 4.54 (t, 2H, J=6.3 Hz, CH 2 OCO), 4.51(m, 1H, OCOCH), 4.36(t, 2H, J=6.3Hz, CH 2 OCO), 3.79(t, 2H, J=6.3Hz, CH 2 O), 2.30-0.95 (m, 45H, cholesterol)

[0041] ESI-MS: [M + ]=531.1m / z

[0042] The second step: BOC-histidine (3.5g, 0.01mol) was dissolved in 50ml of dry organic solvent, and slowly added dropwise to the cholesterol hexanedi...

Embodiment 3

[0046]

[0047] Lipid compound CHO-AA-3

[0048] The first step: dissolving hexanediol (12.2g, 0.1mmol) in 30ml of dry dioxane, the above solution was slowly added dropwise to the cholesterol p-toluenesulfonate ( 5.4g, 0.01mol) solution, stirred and reacted at 80°C for 24h, distilled off the organic solvent, and passed through column chromatography (eluent: ethyl acetate / petroleum ether=1 / 2v / v) to obtain cholesterol hexanediol monoether Intermediate, the synthetic yield is 62%.

[0049] 1 H NMR (CDCl 3 , 300MHz): 5.32 (s, 1H, C=CH, cholesterol), 3.50 (t, 2H, J=6.3 Hz, CH 2 OH), 3.37 (t, 2H, J=5.1 Hz, CHOCH 2 ), 2.30-0.95 (m, 45H, cholesterol)

[0050] ESI-MS: [M + ]=486.4m / z

[0051]The second step: BOC-lysine (3.5g, 0.01mol) was dissolved in 50ml of dry tetrahydrofuran, and slowly added dropwise to the previous step obtained by being dissolved in 20ml of dry tetrahydrofuran under the catalysis of 0.5g of 4-dimethylaminopyridine Cholesterol hexanediol monoether inte...

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Abstract

The invention relates to a lipoid cation function molecule synthesized from natural cholesterol and amino acid and a preparation method and application thereof. The lipoid cation organic function molecule has hydrophobicity and hydrophilicity; a hydrophobic building block comes from rich natural lipoid compound cholesterol; a hydrophilic cation building block comes from natural amino acids having high biocompatibility and derivatives thereof; and a synthesis method is simple and efficient, and is easy for realizing large-scale preparation. Compared with a commercially available gene transfection reagent Bpe1-25k, the invention has the advantages that: the lipoid cation function molecule has remarkably low cell toxicity, can be taken as a gene vector for realizing efficient gene transfection in various cells, can be taken as a novel synthesis lipoid biological vector functional material for applying to loading and in-vivo transmission of genes and medicaments, and can be taken as a low-toxicity efficient cationic surfactant for applying to preparation and production of water aqua or emulsion cosmetics and personal nursing materials.

Description

technical field [0001] The invention relates to the field of synthetic lipid-like biological carrier materials, in particular to the preparation of a lipid-like cationic functional molecule synthesized by coupling natural cholesterol and amino acids and its application in the preparation of gene carriers and functional surfactants. Background technique [0002] In recent years, the research and development of lipid-like functional carrier materials for gene delivery on the surface has become one of the most active research topics in the fields of life science and materials science. These carrier materials can deliver functional genes to specific cells or tissues in the body. Therapeutic effect. At present, most of the materials used as gene carriers are lipid cationic functional molecules. The loading and transporting principle is to use the electrostatic interaction between the positive charge of the protonated amino group in the lipid cationic functional molecule and the n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00C07J43/00A61K47/28B01F17/18B01F17/32C12N15/63C09K23/18C09K23/32
Inventor 曹阿民盛瑞隆罗挺李慧孙景景
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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