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Perfluorinated compounds for non-viral transfer of nucleic acids

A compound and perfluorocarbon technology, which is applied in the direction of introducing foreign genetic material, drug combination, and medical preparations with non-active ingredients by using carriers, etc., can solve problems such as adverse effects, low efficiency, and inability to achieve viral gene transfer efficiency

Active Publication Date: 2017-06-13
康斯坦策·沙费尔 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order to reduce the toxicity of these cationic polymers and lipids, they are increasingly combined with hydrophilic polymers, but no significant improvements have been achieved in this way
[0006] In addition to their low efficiency, previously known transfer molecules for non-viral gene transfer have a second common disadvantage: after transport into the cell they remain in the cytoplasm where they accumulate or react with cellular molecules , or have adverse effects on the cell membrane
[0015] All previous solutions are still far from achieving the efficiency of viral gene transfer

Method used

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  • Perfluorinated compounds for non-viral transfer of nucleic acids
  • Perfluorinated compounds for non-viral transfer of nucleic acids
  • Perfluorinated compounds for non-viral transfer of nucleic acids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach 1

[0177] Sample Embodiment 1: Synthesis of Perfluorinated Nucleobases

[0178] Perfluorination of nucleobases was performed by Williamson ether synthesis. Here, NH 2 groups are relatively easy to reach. Thymine does not have NH 2 group, but six tautomeric structures can occur, four of which have perfluorinatable OH groups.

[0179]

Embodiment approach 2

[0180] Sample embodiment 2: Synthesis of 2'-perfluorinated nucleosides based on 2'perfluorinated uridines

[0181] Uridine is an important component of RNA. Insertion into the RNA chain via the 3' or 5' OH group of the sugar. The 2' position of uridine is therefore particularly suitable for introducing substituents in the case of nucleobase bonding sites. A variety of 2'-substituted uridines are known with attachment via 2' ethers or esters, 2' thioethers or esters, 2' amides or 2' carbamates or even via 2-C; see Scheme 8.

[0182]

[0183] Scheme 8: Examples of 2-substituted uridines suitable for perfluorination at the 2' position

[0184] In order to synthesize uridines with perfluorinated alkenes at the 2' position, a new synthetic method was developed. For example, direct attachment to the 2'-OH group via ether functionality and ester functionality; see Scheme 9.

[0185]

[0186] Scheme 9: Direct attachment to the 2'OH group via ether and ester functions

[018...

Embodiment approach 3

[0199] Sample embodiment 3: Perfluorination via the 2'-amino functional group of 2'-amino-2'-deoxyuridine

[0200] The second synthetic route starts with 2'-amino-2'-deoxyuridine, which is commercially available. This is converted to amides using perfluorinated carboxylic acids. Here, an inert gas is used with the exclusion of moisture. The final product was purified using preparative column chromatography. The primary OH group at the 5' position of uridine is protected by DMT. Appropriate protecting groups may be added or omitted for similar reactions at other positions of the nucleic acid component; see Scheme 13.

[0201]

[0202] Diagram 13

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Abstract

The present invention relates to the compound of general formula (I): A-B-C (F, G')-D-E-F-G-A' or the compound of general formula (II): A-B-C (F ', G')-D-B-E-F-G-A' (II), wherein -A is at least one selected from perfluorocarbons (PFCs), perfluorinated silicon compounds and / or Molecules in the group of further perfluorinated compounds, -B is at least one predetermined breaking point in the form of a physically, chemically or enzymatically cleavable bond, -C is absent or is at least one linking molecule, -D is absent or is at least one spacer Molecule, -E is at least one member selected from the group consisting of nucleobases, nucleosides, nucleotides, oligonucleotides, nucleic acids, modified nucleobases, modified nucleosides, modified nucleotides, modified oligonucleotides , modified nucleic acids, peptide nucleic acid monomers, peptide nucleic acid oligomers and peptide nucleic acids or other nucleic acid analogues in the group of molecules, -F, F' is absent or is at least one ligand, -G, G' is absent Or be at least one marker molecule, -A' does not exist or is the meaning of A, and wherein compounds i), ii), iii), iv), v), vi) are excepted. The present invention also relates to the use of said compound for the non-viral transfer of molecule E into cells, the pharmaceutical composition containing said compound, and the use of said pharmaceutical composition.

Description

technical field [0001] The present invention relates to the compound of general formula (I): A-B-C(F', G')-D-E-F-G-A' or general formula (II): A-B-C(F', G')-D-B-E-F-G-A', the use of the compound, A pharmaceutical composition comprising the compound and uses of the composition. Background technique [0002] Non-viral gene transfer is an important area of ​​interest in basic research and medicine. Possible applications relate in particular to traditional and acquired genetic diseases such as HIV, chronic infectious diseases, tumors, cardiac and circulatory diseases. In the past, attempts to establish gene therapy in medicine have focused on viral vectors. However, they have substantial drawbacks. These applications are not safe enough, it triggers an immune response more after one application in the body, which makes a second application impossible. In addition to this, there have been numerous reports of accidents in which the treatment made the patient seriously ill or e...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/54
CPCA61K49/0002A61K47/52A61K47/54A61P35/00C12N15/85
Inventor 康斯坦策·沙费尔
Owner 康斯坦策·沙费尔
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