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Composite lipid comprising cholesterol group and intermediate, preparation method as well as application thereof

A cholesterol group and compound lipid technology, which is applied in the field of biomedical materials, can solve the problems of internal drug leakage, decreased liposome stability, increased mechanical properties, etc., and achieves strong operability, cheap raw materials, and reaction conditions. mild effect

Inactive Publication Date: 2012-01-11
HARBIN INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The relatively ordered state in the membrane will make the membrane denser, thereby increasing the mechanical properties of the membrane and reducing the permeability (Lund-Katz S, Laboda HM, McLean LR, Phillips MC. Biochemistry 1988, 27 (9), 3416- 3423)
In addition, cholesterol in organisms and traditional liposomes is generally in a free state. In the actual research and application process, free cholesterol tends to be quickly transferred out of biomembranes or liposomes (Kan, C.C.; Yan, J. ; Bittman, R.Biochemistry 1992,31,1866-1874; Hamilton, J.A.Curr.Opin.Lipidol.2003,14,263-271), thereby making the stability of liposomes decrease, and causing the leakage of internal package drug

Method used

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  • Composite lipid comprising cholesterol group and intermediate, preparation method as well as application thereof
  • Composite lipid comprising cholesterol group and intermediate, preparation method as well as application thereof
  • Composite lipid comprising cholesterol group and intermediate, preparation method as well as application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] After mixing 1 mmol of compound 1 and 2 mmol of compound 2, dissolved in 40 mL of dimethylformamide, heated to complete dissolution, then added 2 mmol of DCC and 1 mmol of DMAP in turn, stirred at 55 ° C for 20 hours, reduced The solvent was evaporated to dryness under pressure, and the obtained crude product was separated and purified by column chromatography to obtain compound 3 in a yield of 80%.

[0027] C 79 H 133 NO 9

[0028] 1 H NMR (CDCl 3 , 400MHz)δ: 0.85~2.92(m, 15H, CH 3 ), 0.99(s, 3H, CH 3), 1.09~1.60(m, 70H), 1.81~1.85(m, 2H), 2.31(d, J=7.6Hz, 2H, CH 2 ), 2.60~2.68(m, 8H, NCOCH 2 CH 2 CO), 3.22~3.28(m, 4H, NCH 2 ), 3.87~4.51(m, 8H, OCH 2 ), 4.44~4.45(m, 1H, COOCHCH 2 ), 5.35(m, 1H, C=CCH) 5.44(s, 1H, PhCHOCH 2 ), 7.34~7.48(m, 5H, Ph-H). Theoretical value of mass spectrum: 1240.9, experimental value [M] + : 1241.5, [M+Na] + : 1263.6.

Embodiment 2

[0030] The compound 3 of 2mmol (2.48g) was dissolved in the mixed solvent of methanol and tetrahydrofuran with a volume ratio of 1:3, added to a 250mL reactor, then added 1.24g of palladium hydroxide / carbon, and vigorously stirred at 50°C For 48 hours, the solvent was evaporated to dryness under reduced pressure, and the obtained crude product was separated and purified by column chromatography to obtain compound 4 in a yield of 52%.

[0031] C 72 H 129 NO 9

[0032] 1 H NMR (CDCl 3 , 400MHz)δ: 0.85~0.92(m, 15H, CH 3 ), 1.01(s, 3H, CH 3 ), 1.08~1.60(m, 70H), 1.81~1.85(m, 2H), 2.31(d, J=7.6Hz, 2H, CH 2 ), 2.62~2.68(m, 8H, COCH 2 CH 2 CO), 3.19~3.28(m, 4H, NCH 2 ), 3.58(s, 4H, HOOCH 2 ), 4.16~4.19(m, 4H, COOCH 2 ), 4.44~4.45(m, 1H, COOCHCH 2 ), 5.36 (d, J=4Hz, 1H, C=CH). Theoretical value of mass spectrum: 1152.80, experimental value [M] + : 1153.5, [M+Na] + : 1175.5.

Embodiment 3

[0034] Under nitrogen protection, 1 mmol of compound 4 was dissolved in 40 mL of dichloromethane, 2.5 mmol of compound 5 and 0.4 mmol of catalyst dibutyltin dilaurate were added in sequence, and the mixture was stirred at 55° C. for 48 hours. The crude product was separated and purified by column chromatography to obtain compound 6 in a yield of 53.2%.

[0035] C 92 H 171 N 3 O 17 Si 2

[0036] 1 H NMR (CDCl 3 , 400MHz)δ: 0.61(t, J=8.4Hz, 4H, SiCH 2 CH 2 CH 2 NH), 0.67 (s, 3H, CH 3 ), 0.86~1.10(m, 18H, CH 3 ), 1.10~1.35(m, 89H), 1.45~1.62(m, 12H), 1.81~2.30(m, 5H), 2.60~2.65(m, 8H, COCH 2 CH 2 CO), 3.20~3.36(m, 8H, SiCH 2 CH 2 CH 2 NH and CH 3 (CH 2 ) 13 CH 2 CH 2 N), 3.68~3.83(m, 12H, SiOCH 2 CH 3 ), 4.00~4.13(m, 8H, COOCH 2 C), 4.61~4.64 (m, 1H, COOCHCH 2 ), 5.38 (d, J=4Hz, 1H, C=CH). MS theoretical value: 1647.52, experimental value [M] + : 1648.4.

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Abstract

The invention relates to a composite lipid comprising a cholesterol group with a novel structure and an intermediate, relates to a synthesis method and application thereof to a medicament carrier and research on structure and function of a cell membrane as a functional material. The surface of liposome prepared by the composite lipid has a silicate network structure, so that the stability of the liposome is greatly improved; meanwhile, a covalent bond in a formed liposome double-layer membrane structure is connected with the cholesterol group, so that the stability and the permeability of theliposome can be further adjusted.

Description

technical field [0001] The invention belongs to the field of biomedical materials, in particular to a method for preparing a compound lipid containing a cholesterol group with a novel structure and an intermediate thereof, as well as its use as a functional material in drug carrier and cell membrane structure and function research. technical background [0002] Since the 1970s, liposomes have been widely used as drug carriers due to their simple preparation, non-toxicity, no immunogenic response, degradability in vivo, and easy targeting. And prolong the efficacy of drugs, alleviate toxicity, avoid drug resistance and change the route of administration. However, the practical application of liposomes is limited by their stability. The specific performance is that liposomes are destroyed during storage due to drug leakage, particle aggregation, and phospholipids are easily oxidized and hydrolyzed. The liposome may rupture, resulting in the rapid leakage of the encapsulated ...

Claims

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Application Information

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IPC IPC(8): C07J51/00A61K9/127A61K47/28G09B23/36G09B23/38
Inventor 戴志飞梁晓龙岳秀丽
Owner HARBIN INST OF TECH
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