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Alpha helix cationic polypeptide as well as preparation method and application of alpha helix cationic polypeptide

A cationic polymerization and α-helix technology, applied in the field of polymer material technology and pharmacy, can solve the problems of inability to maintain α-helix, poor membrane penetration ability, and poor gene transfection efficiency.

Active Publication Date: 2018-05-08
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, when used as a gene carrier, CPP has a relatively large defect: the length of the main chain of CPP is too short, the positive charge and secondary structure of CPP are shielded after the nucleic acid molecule is loaded, and the ability to penetrate the membrane is significantly reduced, so it is impossible to complete the gene efficiently. deliver
However, the strong electrostatic repulsion between the charged groups in the side chains of cationic polypeptides makes it impossible to maintain the conformation of α-helix, and mainly exists in the form of random coils, so the ability to penetrate membranes is poor, and the efficiency of gene transfection is also poor

Method used

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  • Alpha helix cationic polypeptide as well as preparation method and application of alpha helix cationic polypeptide
  • Alpha helix cationic polypeptide as well as preparation method and application of alpha helix cationic polypeptide
  • Alpha helix cationic polypeptide as well as preparation method and application of alpha helix cationic polypeptide

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Experimental program
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Effect test

Embodiment 1

[0076] (1) Potassium carbonate (15.2 g, 0.11 mol) and p-hydroxybenzyl alcohol (9.3 g, 0.075 mol) were dissolved in 150 mL of acetone, and propyne bromide (10 mL, 0.09 mol) and 18-crown-6 (0.1 mL). The solution was refluxed in an oil bath at 75°C, and the acetone was removed by rotary evaporation after 12 h. Add 200 mL of water to the crude product, extract 3 times with 30 mL of dichloromethane (DCM), and remove the lower organic phase. The organic phase was washed with 15% sodium hydroxide (200 mL) and saturated brine (200 mL), and washed with Na 2 SO 4 Dry, filter, and remove the solvent to obtain compound 1;

[0077] (2) Compound 1 (8.5 g, 52 mmol) was dissolved in dichloromethane, and thionyl chloride (5 mL, 68 mmol) was added dropwise in an ice bath. Stir the reaction at room temperature for 3.5 h, add 100 mL of water to quench thionyl chloride, extract the organic phase three times with 50 mL of water, and wash with MgSO 4 Dry, filter, and remove the solvent to obtai...

Embodiment 2

[0081] (1) Add 1,6-dibromohexane (1.26mL, 8 mmol) and sodium azide (1.6g, 24 mmol) into 19 mL DMF and react at 60°C for 24h. (There will be insoluble matter in the reaction) After adding about 150 mL of water to dissolve it, extract it with 20 mL of ether three times, collect the organic phase, dry it with sodium sulfate, filter, and rotary evaporate to obtain compound 5;

[0082] (2) Take compound 5 (3.33 g, 20 mmol), Et2O (15 mL), EtOAc (15 mL), 5% HCl (30 mL, 5 mL concentrated HCl + 25 mL H 2O), slowly add triphenylphosphine (5.51 g, 22 mmol) under ice-bath conditions (0°C) to ensure two-phase separation, ensure that the reaction is longer than 1 h under ice-water bath, and react at room temperature for 24 h; add 30 mL of 1M HCl (2.5 mL concentrated hydrochloric acid + 27.5 mL water), discard the upper organic phase after stratification occurs, and take the lower aqueous phase; extract the aqueous phase with 20 mL DCM for 3 times, collect the lower aqueous phase; then adjus...

Embodiment 3

[0085] (1) In the glove box, the five-membered ring N-carboxylic acid anhydride of Example 1 was dissolved in N,N-dimethylformamide, and then 5,10,15,20-tetrakis(4-aminobenzene)-porphyrin was added phenoline (TAPP) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene, and precipitated with ice methanol after stirring at room temperature for 72 h; 5,10,15,20-tetra The molar ratio of (4-aminobenzene)-porphyrin (TAPP) to the five-membered ring N-carboxylic acid anhydride of Example 1 is 1:60;

[0086] (2) In the glove box, the intermediate product (20 mg, 0.072 mmol alkynyl) was dissolved in DMF, and the azide terminal compound (0.144 mmol) and pentamethyldiethylenetriamine (15 μL , 0.072 mmol), then copper bromide (2 mg, 0.0144 mmol) was added, and the reaction was stirred at room temperature in the glove box for 48 hours; after the reaction was completed, it was taken out from the glove box, opened and stirred for 20 min, then added 1 mL of 1M hydrochloric acid, dialyzed with water for 3 d...

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Abstract

The invention provides an alpha helix cationic polypeptide as well as a preparation method and application of the alpha helix cationic polypeptide. The alpha helix cationic polypeptide takes a photosensitizer porphyrin as a core and alpha helix polypeptides as four arms, and a nucleotide drug prepared from the polymer can be applied to a nucleotide drug delivery system. The polymer provided by theinvention has good biocompatibility, low cytotoxicity and light activation ability. The polymer provided by the invention is self-assembled in a water solution to form nanoparticles which has good stability, biocompatibility and low cytotoxicity; the preparation method is simple and high in repeatability, and the polymer serving as a carrier is not only capable of protecting nucleic acid such asDNA from being degraded, but also capable of being combined with the scale effect of the nanoparticles so as to be used for treating diseases; and in addition, the transfection promoting effect for different cancer cells can be achieved by virtue of the light activation ability.

Description

technical field [0001] The invention belongs to the fields of polymer material technology and pharmacy, and relates to an alpha-helical cationic polypeptide containing a side chain and a photosensitizer, a preparation method and application thereof. Background technique [0002] Cell penetrating peptides (CPPs) are short-chain polypeptides that can penetrate cell membranes, usually consisting of a few or more than a dozen amino acids. However, when used as a gene carrier, CPP has a relatively large defect: the length of the main chain of CPP is too short, the positive charge and secondary structure of CPP are shielded after the nucleic acid molecule is loaded, and the ability to penetrate the membrane is significantly reduced, so it is impossible to complete the gene efficiently. deliver. Cationic polypeptides, such as polylysine (PLL) and polyarginine (PLR), have long molecular backbones, so they can complex and deliver nucleic acid molecules independently. However, the s...

Claims

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Application Information

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IPC IPC(8): C08G69/48C08G69/40C08G69/32A61K47/42A61K9/14A61K48/00A61K41/00A61P35/00
CPCA61K9/146A61K41/0071A61K48/005C08G69/32C08G69/40C08G69/48
Inventor 殷黎晨许欣
Owner SUZHOU UNIV
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