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Vinyl sulfonamide connector and application thereof

A technology of vinylsulfonamide and amide, applied in the field of selective modification of cysteine, can solve problems such as poor stability, and achieve the effect of good stability and high selectivity

Inactive Publication Date: 2018-09-14
SHANGHAI TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In recent years, studies have shown that the ADC obtained by coupling maleimide as a linker has poor stability in vivo

Method used

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  • Vinyl sulfonamide connector and application thereof
  • Vinyl sulfonamide connector and application thereof
  • Vinyl sulfonamide connector and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Preparation of vinylsulfonamide linkers 1-3 as figure 1 Shown:

[0073] Compound 1

[0074]

[0075] Dissolve N-methylaniline (0.536g, 5mmol) in dichloromethane (30mL), add triethylamine (1.518g, 15mmol) under ice-cooling, and slowly add 2-chloroethanesulfonyl chloride dropwise after fully cooling (0.978g, 6mmol), react in ice bath for 1h. After diluting the reaction solution with 100mL water, extract with dichloromethane (3*20mL), combine the organic phases, dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation under reduced pressure to obtain a crude product, add 3mL CH 2 Cl 2 and 1.5g 60-100 mesh silica gel, mix well and spin dry. The crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain white solid 1 (0.855 g, 4.34 mmol, 86.8%). 1 H NMR (500MHz, Chloroform-d) δ7.43-7.25(m, 5H), 6.47(dd, J=16.6, 9.9Hz, 1H), 6.21(d, J=16.6Hz, 1H), 6.03(d, J=10.0Hz, 1H), 3.26(s, 3H). 13 C NMR (12...

Embodiment 2

[0095] Selective modification of vinylsulfonamide linkers 1, 2, 3 with the polypeptide LFMSCRTWKHYEQ, such as figure 2 Shown:

[0096] The polypeptide LFMSCRTWKHYEQ (Gill Biochemical) was dissolved in PBS (pH=7.4) buffer solution (product number Cat.NO.SH30256.0) to prepare a 1 mM solution, and the vinylsulfonamide linker was dissolved in acetonitrile to prepare a 6 mM solution. Add 200uL of polypeptide LFMSCRTWKHYEQ solution to three different wells of a microwell plate (330uL LABTIDE 96Round Well), then add 100uL of 3 different ethylenesulfonamide linker solutions, and react at room temperature on a microplate shaker for 2 Hours later, use HPLC (model Waters 1525 and SHIMADZU LC-30AD, the stationary phase is a C-18 silica gel column, and the mobile phase is CH 3 CN / H 2 O=10~100%, 0~10 minutes) analysis, judge product peak with HRMS-ESI, as image 3 shown.

[0097] The polypeptide LFMSARTWKHYEQ (Gill Biochemical) was dissolved in PBS (pH=7.4) buffer solution (product num...

Embodiment 3

[0099] like Figure 4 As shown, the conjugate of vinylsulfonamide linker 2 and polypeptide LFMSCRTWKHYEQ is further coupled with fluorescent substance fluorescein 7, coumarin 9; drug molecule camptothecin 8 and hydrophilic substance PEG 10:

[0100] Dissolve the polypeptide LFMSCRTWKHYEQ (Gill Biochemical) in PBS (pH=7.4) buffer solution (product number Cat.NO.SH30256.0) to make a 1 mM solution, and dissolve the vinylsulfonamide linker 2 in CH 3 CN is made into a 6mM solution, the azide reagent fluorescent substance fluorescein 7 and coumarin 9, the drug molecule camptothecin 8 and the hydrophilic substance PEG polymer 10 (molecular weight 2000) are dissolved in DMSO to make a 10mM solution, L -Sodium ascorbate dissolved in H 2 200mM solution in O, copper sulfate CuSO 4 Soluble in H 2 O to make a 100mM solution, and TBTA was dissolved in a 1:4DMSO-tert-butanol solution to make a 10mM solution.

[0101] Add 100uL of polypeptide LFMSCRTWKHYEQ solution and 50uL of ethylenesul...

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Abstract

The invention provides a vinyl sulfonamide connector and application thereof. The structural formula of the vinyl sulfonamide connector is as shown in formula I, wherein X is selected from C or N; R is selected from one of or optional combination of hydrogen, amide, nitryl, hydroxyl, alkyl hydroxyl, aromatic hydroxyl, amino, alkyl amino, aromatic amino, sulfydryl, alkyl sulfydryl, aromatic sulfydryl, carboxylic acid, alkyl carboxylic acid, aromatic carboxylic acid, alkynyl, alkyl alkynyl, aromatic alkynyl, azide, alkyl azide, aromatic azide, carbonyl, alkyl carbonyl, aromatic carbonyl, aldehyde group, alkyl aldehyde group and aromatic aldehyde group; R1 is selected from one of or optional combination of hydrogen, linear, branched or cyclic alkane, acid, aldehyde group, linear carbonyl, benzyl or other aromatic benzyl and phenyl or other aromatic groups. The vinyl sulfonamide connector is high in selectivity and good in product stability.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals and biotechnology, and in particular relates to the selective modification of cysteine ​​in polypeptides and proteins by using vinylsulfonamide compounds. The selective modification method involved in the present invention has good specificity, and can be used for preparing targeted tracer diagnostic reagents, tumor targeted therapy drugs, including antibody drug conjugates and the like. Background technique [0002] Chemoselective modification of polypeptides or proteins is of great importance in the fields of chemical biology and biomedical research. The selective modification of natural amino acid residues in proteins is a very cost-effective strategy. Cysteine ​​has attracted much attention due to its relatively low natural abundance in proteins and the high nucleophilicity of its sulfhydryl residues. Maleimide and α-halogenated carbonyl compounds are commonly used reagents for the selectiv...

Claims

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Application Information

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IPC IPC(8): C07K1/107C07K16/00C07C311/11A61K47/68A61K47/54A61K49/00
CPCA61K47/54A61K47/6809A61K47/6845A61K49/0058C07C311/11C07K1/1077C07K16/00
Inventor 姜标陈红莉黄容
Owner SHANGHAI TECH UNIV
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