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Lipid-modified spermine derivative and liposome prepared by using the derivative

A lipid modification and derivative technology, which is applied in the preparation of carbamate derivatives, liposome delivery, and preparation of carboxylic acid amides, can solve problems such as inability to achieve therapeutic effects, and achieve long-term circulation performance and targeting. The effect of cost reduction and strong gene transfer ability

Active Publication Date: 2017-05-17
GUANGZHOU NANOTIDES PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Taking small interfering nucleic acid (siRNA) as an example, its physical and chemical properties determine that it is difficult to enter and pass through the cell wall (small interfering nucleic acid has a molecular weight of 13KDa, is highly negatively charged, and is highly hydrophilic), and is easily degraded by the body or cells, thereby failing to achieve to the therapeutic effect

Method used

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  • Lipid-modified spermine derivative and liposome prepared by using the derivative
  • Lipid-modified spermine derivative and liposome prepared by using the derivative
  • Lipid-modified spermine derivative and liposome prepared by using the derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Compound 1 was synthesized.

[0047] Weighed 100 mg of compound 12 into a 100 ml round bottom flask, added 3 ml of trifluoroacetic acid, stirred at room temperature for 12 hours, and evaporated the trifluoroacetic acid to dryness. The pre-treated ion exchange resin is used to pass through the column, and the obtained liquid is freeze-dried to obtain the obtained product. Yield 98%.

[0048] 1H NMR (400MHz, CDCl 3 ):δ=0.880(t,6H,j1=7.2Hz,j2=6.4Hz),1.25-1.33(m,44H),1.41-1.57(m,10H),1.96-2.00(m,10H),2.63- 3.10(m,12H),5.32-5.38(m,4H);13CNMR(400MHz,CDCl 3 ): δ=14.147, 22.710, 27.256, 29.347, 29.563, 29.798, 31.930, 129.744, 129.777, 130.006, 130.044. HRMS (MALDI) found 731.7142 [M + H] + (Calculated mass for C 46 h 90 N 4 o 2 was 731.7142[M+H]+).

[0049] The reaction scheme is as follows:

[0050]

Embodiment 2

[0052] Compound 2 was synthesized.

[0053] Weighed 100 mg of compound 16 into a 100 ml round bottom flask, added 3 ml of trifluoroacetic acid, stirred at room temperature for 12 hours, and evaporated the trifluoroacetic acid to dryness. The pre-treated ion exchange resin is used to pass through the column, and the obtained liquid is freeze-dried to obtain the obtained product. Yield 98%.

[0054] 1 H NMR (400MHz, DMSO-d6): δ = 0.835-0.868 (t, 6H, j1 = 7.2, j2 = 6), 1.236-1.403 (m, 48H), 1.530-1.563 (m, 8H), 1.956-1.986 (m,8H),2.321-2.397(m,12H),2.621-2.715(m,8H),3.347-3.558(m,4H),3.963-3.996(t,4H,j1=6.4,j2=6.8), 5.321-5.357 (m, 2H).

[0055] 13 C NMR (400MHz, CDCl 3 ): δ=14.143, 22.711, 25.764, 27.244, 29.260-29.797, 31.933, 32.838, 63.122, 129.987. HRMS (ESI) found 847.8009[M+H]+(Calculated mass for C 52 h 102 N 4 o 4 was 847.7936[M+H]+).

[0056]

Embodiment 3

[0058] Compound 3 was synthesized.

[0059] Weighed 100 mg of compound 11 into a 100 ml round bottom flask, added 3 ml of trifluoroacetic acid, stirred at room temperature for 12 hours, and evaporated the trifluoroacetic acid to dryness. The pre-treated ion exchange resin is used to pass through the column, and the obtained liquid is freeze-dried to obtain the obtained product. Yield 98%.

[0060] 1 H NMR (400MHz, CDCl 3 ):δ=0.880(t,6H,j1=7.2Hz,j2=6.4Hz),1.26-1.41(m,44H),1.58(br,8H),1.90-2.0(m,8H),2.12-2.27( m, 4H), 2.92 (br, 4H), 3.30-3.56 (m, 8H), 5.30-5.38 (m, 4H).

[0061] 13 C NMR (400MHz, CDCl 3 ): δ=14.138, 22.711, 27.189, 27.245, 29.283, 29.352, 29.529, 29.585, 29.728, 29.801, 31.937, 52.553, 53.464, 129.794, 129.952. C 46 h 94 N 4 was703.7557[M+H]+).

[0062] The reaction scheme is as follows:

[0063]

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Abstract

The invention provides a liposome-modified spermine derivative and a liposome prepared by the derivative. The spermine derivative is directly applied or is mixed with one or more selected from cholesterol, neutral lipids and polyethylene glycol (PEG)-modified lipids, which can be adopted as a carrier for entrapping or absorbing bioactive molecular drugs to be loaded into cells. In this way, the effect of regulation, intervention or treatment is realized. In a general formula (1), X1 represents -(CH2)- or carbonyl group, wherein n represents 1, 2 or 3; X2 represents -(CH2)-, ester group, amide group, oxygen, or sulfur; R1 and R2 independently represent C6-C18 alkyl group or lipophilic cholesterol molecules, respectively.

Description

technical field [0001] The present invention relates to the field of drug carriers, more particularly to a lipid-modified spermine derivative and a preparation method thereof, and a liposome using the derivative, which can introduce or deliver exogenous nucleotides to In cells (in vitro) or in animals / humans (in vivo) to play a specific role, the exogenous nucleotides include small interfering nucleotides (siRNA), DNA, messenger RNA (mRNA), microRNA (miRNA) or anti Antisense oligonucleotides, aptamers, etc. Background technique [0002] Any DNA sequence in the genome, as well as every non-coding or coding RNA transcriptome molecule, can regulate its expression through specific exogenous nucleotides (including DNA and RNA), so as to achieve specific disease-specific treat. These treatment methods include gene therapy at the DNA level and nucleic acid interference (RNAinterference, RNAi) therapy at the RNA level. [0003] Gene therapy is to deliver specific sequences of nuc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/38C07C231/12C07C229/16C07C227/20C07C211/20C07C211/14C07C209/62C07C217/08C07C213/08C07C271/20C07C269/04C07C269/06A61K47/18A61K9/127A61K45/00A61K48/00
Inventor 张丽霞俞跃钟天翼徐军陆阳
Owner GUANGZHOU NANOTIDES PHARMA
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