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Oligonucleotide-disulfide and synthesis method thereof

An oligonucleotide and disulfide technology, applied in the field of oligonucleotide-disulfide and its synthesis, can solve the problems of DNA instability, influence chemical reaction, denaturation, etc., and achieve good DNA integrity, The effect of high conversion rate and good application prospects

Pending Publication Date: 2022-08-05
康龙化成(宁波)科技发展有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this reaction is an intramolecular reaction, which has certain limitations for the construction of diverse disulfide compounds in the synthesis of DELs.
In addition, because the construction of DELs depends on the stability of DNA, DNA must be stable in a certain aqueous phase, pH, temperature, metal ion concentration and inorganic salt concentration (Gironda-Martínez A.; Donckele E.J.; Samain F. et al. DNA-Encoded Chemical Libraries: A Comprehensive Review with Successful Stories and Future Challenges; ACS Pharmacol. Transl. Sci. 2021, 4, 4, 1265–1279.), heating, extreme pH or some organic reagents (such as methanol, ethanol, urea, formamide, etc.) can easily cause DNA denaturation and cause DNA instability; at the same time, DNA will have a certain impact on the reactivity of the compound, thereby affecting the occurrence of chemical reactions; in addition, the reaction applied to the construction of DELs needs to have a higher conversion rate in order to enable it to be applied to genetically encoded libraries

Method used

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  • Oligonucleotide-disulfide and synthesis method thereof
  • Oligonucleotide-disulfide and synthesis method thereof
  • Oligonucleotide-disulfide and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0196] Example 1. Synthesis of oligonucleotide-disulfide P1

[0197]

[0198] 1-Propanethiol S2-1 (20 mmol / L tetrahydrofuran solution) was added to an aqueous solution of 1 nanomolar oligonucleotide-thiol compound S1-1 (1 mmol / L, 1 equiv, 1 μL). , 50 equiv, 2.5 μL) and 1,1,3,3-tetramethylguanidine (TMG, 4 mmol / L tetrahydrofuran solution, 10 equiv, 2.5 μL), the mixture was mixed well by vortexing After reaction at 25°C for 10 minutes. After the reaction was completed, 10% of the total volume of 5 mol / L sodium chloride solution and 3 times the volume of absolute ethanol were added to the reaction solution. High-speed refrigerated centrifugation (4° C., 12,000 rpm, 15 minutes), the supernatant was discarded, and the precipitate was oligonucleotide-disulfide P1. The remaining precipitate was dissolved in deionized water to prepare an aqueous solution of oligonucleotide-disulfide P1 with a concentration of 1 mmol / L. Detected by liquid chromatography-mass spectrometry, the mol...

Embodiment 2

[0200] Example 2. Synthesis of oligonucleotide-disulfide P4

[0201]

[0202] 3-Methoxythiophenol S2-4 (80 mmol / L) was added to an aqueous solution of 1 nanomolar oligonucleotide-thiol compound S1-1 (1 mmol / L, 1 equiv, 1 μL). L tetrahydrofuran solution, 200 equiv, 2.5 μL) and 1,1,3,3-tetramethylguanidine (TMG, 4 mmol / L tetrahydrofuran solution, 10 equiv, 2.5 μL), the mixture was vortexed After thorough mixing, the reaction was carried out at 25°C for 1 hour. After the reaction was completed, 10% of the total volume of 5 mol / L sodium chloride solution and 3 times the volume of absolute ethanol were added to the reaction solution. High-speed refrigerated centrifugation (4° C., 12,000 rpm, 15 minutes), the supernatant was discarded, and the precipitate was oligonucleotide-disulfide P4. The remaining precipitate was dissolved in deionized water to prepare an oligonucleotide-disulfide P4 aqueous solution with a concentration of 1 mmol / L. Detected by liquid chromatography-mass...

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Abstract

The invention provides oligonucleotide-disulfide and a synthesis method thereof, and belongs to the field of gene coding compound library construction. The oligonucleotide-disulfide disclosed by the invention is shown as a formula I in the specification. According to the synthesis method of the oligonucleotide-disulfide, an oligonucleotide-thiol compound 1 and a thiol compound 2 react in a solvent under the alkaline condition, and the oligonucleotide-disulfide shown in the formula I is obtained. The method for synthesizing the oligonucleotide-disulfide is good in universality and simple to operate, and the disulfide can be efficiently synthesized on the oligonucleotide. Meanwhile, the method provided by the invention has small damage to DNA, and the DNA integrity is good in the reaction process. According to the present invention, the chemical reaction types for synthesizing the coding compound library on the DNA are enriched, the new disulfide skeleton is constructed for the synthesis of the DNA coding compound library, the rapid, practical and effective way is provided for the synthesis of the diverse disulfides, and the good application prospects are provided in the lead drug development.

Description

technical field [0001] The invention belongs to the field of gene-encoded compound library construction, in particular to an oligonucleotide-disulfide and a synthesis method thereof. Background technique [0002] Currently, gene-encoded libraries (DELs) have become a common method for discovering new protein ligands (1. Goodnow, R.A.; Dumelin, C.E.; Keefe, A.D. DNA-encoded chemistry: Enabling thedeeper sampling of chemical space. Nat. Rev. .Drug Discov.2016.2.Neri, D.; Lerner, R.A. DNA-Encoded Chemical Libraries: A Selection System Based on EndowingOrganic Compounds with Amplifiable Information.Annu.Rev.Biochem.2018,87,479–502.). Compared with traditional chemistry, through high-throughput screening, DELs have great advantages in cost, output, and construction of a larger chemical space. Several newly discovered inhibitors have been reported for the treatment of many classes of related protein targets (Zimmermann, G.; Neri, D. DNA-encoded chemical libraries: Foundations and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/00C07H21/00C07H21/04C40B40/08
CPCC07H21/04C07H21/00C07H1/00C40B40/08Y02P20/55
Inventor 胡允金薛丽俊刘伟杰马杭柯杨珂新
Owner 康龙化成(宁波)科技发展有限公司
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