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Synthetic method and application of o-phenol sulfimine compound of on-dna

A technology of phenol sulfimide and synthesis method, which is applied in the field of biomedicine and can solve the problems of limited diversity of molecular chemical structures and limited reaction types, etc.

Active Publication Date: 2022-05-17
SHENZHEN INNOVATION CENT OF SMALL MOLECULE DRUG DISCOVERY CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In the on-DNA reaction of constructing a DNA-encoded compound library, DNA must be stable in a certain aqueous phase, pH, temperature, metal ion concentration, and inorganic salt concentration, which limits the available resources for constructing a DNA-encoded compound library. Reaction types, resulting in limited diversity of molecular chemical structures of compound libraries. In addition, in addition to considering compatibility with DNA chemistry, yield is also a key consideration for those skilled in the art

Method used

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  • Synthetic method and application of o-phenol sulfimine compound of on-dna
  • Synthetic method and application of o-phenol sulfimine compound of on-dna
  • Synthetic method and application of o-phenol sulfimine compound of on-dna

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preparation example Construction

[0058] A method for synthesizing an on-DNA o-phenol sulfimine compound, comprising:

[0059] S01, providing a substrate and a thio reagent, the structural formula of the substrate is DNA-Ar-O-NH-R 1 , the thio reagent is an N-alkylthio substituted isoindole-1,3-dione compound; wherein, DNA is a nucleotide chain, Ar is selected from a benzene ring, an aromatic ring or a heterocycle, and R 1 One selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl;

[0060] S02, reacting the substrate and the thio reagent in a solvent system containing an inorganic buffer to obtain on-DNA ortho-phenol sulfimine compounds.

[0061] In step S01, the structural formula of the substrate is DNA-Ar-O-NH-R 1 , wherein, DNA is a single-stranded or double-stranded nucleotide chain obtained by polymerizing artificially modified and / or unmodified nucleotide monomers, and the DNA can pass through carboxyl groups, amine groups, C-C bonds or C-N bonds, etc. A variety of ...

Embodiment 1

[0091] 1. Synthesis of On-DNA N-phenoxyamide compound (3)

[0092] The synthetic route is as follows:

[0093]

[0094] Concrete synthetic steps are as follows:

[0095] Compound (1) was dissolved in borate buffer (0.1 M, pH = 9.4) to prepare a solution of compound (1) with a final concentration of 1.0 mM, using DMTMM as a condensing agent, and carboxylic acid derivatives (2 ) reaction to obtain the corresponding On-DNA compound (3), after the completion of the reaction, use ethanol precipitation treatment (specifically: add 5 M sodium chloride solution with 10% of the total reaction volume, 2.5 times the volume of -20 ° C storage without Water ethanol, stand at -20°C for 1 h, centrifuge at 13,300 rpm for 15 min at 4°C), after HPLC purification and MS detection, the target product - On-DNA compound (3), freeze-dried and directly used in the next step reaction.

[0096] 2. Synthesis of On-DNA o-phenol sulfimine compound (6) or (7)

[0097] The synthetic route is as follo...

Embodiment 2

[0108] In this example, the compound (6b) synthesized in Example 1 was taken as a representative, and the effects of reaction temperature, reaction time, organic solvent, and inorganic buffer on the reaction yield were explored according to the method steps of Example 1.

[0109] The synthetic route is as follows:

[0110]

[0111] Table 2 shows the test results. As shown in the results, the reaction temperature, reaction time, organic solvent, and inorganic buffer all have different degrees of influence on the reaction yield.

[0112] Wherein, the reaction temperature of embodiment 1,6,7 is room temperature, and the reaction time is 16h, all adopts PBS damping fluid, and its difference is only to have adopted different organic solvent, and the organic solvent of embodiment 1 is DMSO, and its product Rate is 71%, greater than embodiment 6 and 7, shows to adopt the solvent system that is made up of PBS damping fluid and DMSO, and its productive rate can guarantee at higher l...

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Abstract

The invention belongs to the technical field of biomedicine, and specifically relates to a method for synthesizing on-DNA ortho-phenol sulfimine compounds. The synthesis method comprises: providing a substrate and a thio reagent, and the structural formula of the substrate is DNA-Ar- O‑NH‑R 1 , the thio reagent is an N-alkylthio-substituted isoindole-1,3-diketone compound; wherein, DNA is a nucleotide chain, Ar is selected from a benzene ring, an aromatic ring or a heterocycle, and R 1 One selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, heteroaryl; the substrate and the thio reagent are carried out in a solvent system containing an inorganic buffer reaction to obtain on-DNA ortho-phenol sulfimine compounds. The synthesis method has mild conditions, good biocompatibility, little damage to DNA, good substrate universality, high yield, low cost and convenient operation, and is suitable for the construction of a DNA-encoded compound library.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a synthesis method and application of on-DNA ortho-phenol sulfimine compounds. Background technique [0002] DNA-Encoded Library (DEL) technology is an emerging small molecule drug screening technology, which combines DNA technology with combinatorial chemistry to efficiently construct a compound library with a capacity of 100 million. Moreover, in the screening During the process, DEL can simultaneously screen multiple conditions or the same target. Compared with traditional high-throughput screening, DEL has great advantages in terms of compound library capacity, library construction difficulty, and screening time and cost. [0003] In the on-DNA reaction of constructing a DNA-encoded compound library, DNA must be stable in a certain aqueous phase, pH, temperature, metal ion concentration, and inorganic salt concentration, which limits the available resources f...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H21/04C07H1/00C40B40/06C40B50/10
CPCC07H21/04C07H1/00C40B40/06C40B50/10Y02P20/55
Inventor 熊峰傅天成徐林林
Owner SHENZHEN INNOVATION CENT OF SMALL MOLECULE DRUG DISCOVERY CO LTD
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