Compound and nucleic acid complex molecule and nucleic acid complex and preparation method and application thereof

A compound molecule and compound technology, applied in the field of preparation of small interfering nucleic acid drugs, can solve the problems of small specific gravity, toxicity and other safety indicators that cannot be fully trusted, and achieve the goal of reducing toxicity, reducing dosage, and improving tissue specificity. Effect

Active Publication Date: 2016-09-21
KUNSHAN RNAI INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] In the currently reported technology, in the siRNA complex molecules constructed for drug administration, the proportion of siRNA with medicinal effect is very small, and the auxiliary medium occupies a large mass ratio, and the safety indicators such as the toxicity of these mediums cannot be completely determined. trust

Method used

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  • Compound and nucleic acid complex molecule and nucleic acid complex and preparation method and application thereof
  • Compound and nucleic acid complex molecule and nucleic acid complex and preparation method and application thereof
  • Compound and nucleic acid complex molecule and nucleic acid complex and preparation method and application thereof

Examples

Experimental program
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Embodiment approach

[0039] According to a preferred embodiment of the present invention, the compound has a structure represented by formula V,

[0040] Formula V,

[0041] Wherein, B is selected from N, P=O, C-X 5 -A 5 or C-R 8 ;A 1 、A 2 、A 3 、A 4 and A 5 Each independently is a group shown in formula I or a group shown in formula II; X 1 、X 2 、X 3 、X 4 and X 5 Each independently is an optionally substituted C1-C20 alkylene group or a group represented by formula III;

[0042] Formula III,

[0043] Among them, R 6 and R 37 is a bond or an optionally substituted C1-C14 alkylene group;

[0044] R 7 is an optionally substituted C1-C20 hydrocarbyl or targeting group; R 8 is H, an optionally substituted C1-C20 hydrocarbon group or a targeting group.

[0045] In the present invention, the three or more first connection structures are the basis for the compound to be used as a carrier to form a spatial topology, and the three or more are preferably 3-6, such as 3, 4, 5 or 6 ...

Embodiment 1

[0225] This example is used to illustrate the synthesis of the central molecule

[0226] (1) Compound (2Z, 2′Z, 2″Z)-4,4′, 4″-(2,2′, 2″-nitrilo three (ethane-2,1 Synthesis of -diyl)tri(azanediyl))tri(4-carbonylbut-2-enoic acid)

[0227]

[0228] Add compound (1) (13.38mmol, 2.016g) into a dry 500mL round bottom flask, then add 200mL of anhydrous dichloromethane, stir evenly with electromagnetic. Add maleic anhydride (45.16mmol, 4.435g) into the round bottom flask, increase the stirring speed, and heat to reflux at 50°C for 2h. The solvent dichloromethane was removed by rotary evaporation to obtain 4.984 g of compound (4) as a yellow solid with a yield of 83%.

[0229] (2) Compound 1,1',1"-(2,2',2"-nitrilotri(ethane-2,1-diyl))tri(1H-pyrrole-2 , 5-diketone) synthesis

[0230]

[0231] Add compound (4) (5mmol, 2.204g), triethylamine (4.158mmol, 420mg), sodium acetate (4.085mmol, 335mg) respectively into a dry 100mL round bottom flask, then add 10mL of acetone, and stir...

Embodiment 2

[0234] This embodiment is used to illustrate the preparation of the nucleic acid complex molecule N1 of the present invention

[0235] Dissolve the terminal sulfhydryl-modified oligonucleotide R1 in 100 microliters of RNase-free water, add Tri-HCl buffer (pH=8.0, final concentration is 20mM), the final concentration of R1 is 1mM, and mix well; 0.11 mM compound (5), placed in a flowing high-purity argon atmosphere for 5 min, and incubated at 45° C. for 2 h. Repeat the above steps of adding compound (5) and argon protection and reacting for 2 h twice. Afterwards, polyacrylamide (6% urea) electrophoresis and gel purification were carried out, and a single band corresponding to the position of the 90nt natural oligonucleotide was cut out for gel elution. After 2 hours, it was washed with 0.3M sodium acetate and 75% ethanol precipitation. Dehydration for 1h. Centrifuge at 13000 rpm for 15 min at 4°C, discard the supernatant to obtain N1.

[0236] N1 was detected by 6% and 15% po...

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Abstract

The present invention provides a nano particle of a nucleic acid. The nano particle of a nucleic acid is composed of a plurality of single chain nucleic acid units, the single chain nucleic acid units comprising three-head single chain nucleic acid units and optionally also comprising two-head single chain nucleic acid units and one-head single chain nucleic acid units. The nano particle of a nucleic acid has high nucleic acid loading and relatively high stability. In addition, the present invention also provides a process for preparing the nano particles of a nucleic acid and the use thereof in the preparation of small interfering nucleic acid drugs.

Description

technical field [0001] The present invention relates to a compound, a nucleic acid complex molecule and a nucleic acid complex, the preparation method of the compound, the nucleic acid complex molecule and the nucleic acid complex, and the use of the compound, the nucleic acid complex molecule and the nucleic acid complex in preparing small interfering nucleic acid drugs in the application. Background technique [0002] RNA interference (RNA interference, RNAi) is a process in which double-stranded RNA (double-stranded RNA, dsRNA) molecules shut down the expression of the corresponding gene or silence the gene at the mRNA level. RNA interference technology, also known as gene knockdown (knock-down) or gene silencing (gene silencing), is a typical post-transcriptional gene regulation method, also known as post-transcriptional gene silencing (PTGS). ). It was first elucidated by Fire and Mello in Caenorhabditis elegans (A.Fire, S.Xu, M.K.Montgomery, S.A.Kostas, S.E.Driver, C...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/38C07C231/02C07C231/12C07D207/452C07H21/00C07H1/00C07C229/08C07C227/18C07C227/20C07K16/00C07K5/083C12N15/115C12N15/113C12N15/10A61K48/00
CPCC07H1/00C07D207/452C07H21/00C12N15/111C12N15/113C12N2310/11C12N2310/14C12N2310/52C12N2320/32C12Q1/6811
Inventor 席真章骏斌魏绿
Owner KUNSHAN RNAI INST
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