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Polyethylene glycol benzothiazole derivative and preparation method and application thereof

A polyethylene glycol and benzothiazole technology, applied in the field of polyethylene glycol benzothiazole derivatives and its preparation, can solve the problems of PEG-MAL instability and large difference in biological activity

Inactive Publication Date: 2013-04-03
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because the interferon molecule contains multiple amino groups, the biological activities of different amino-modified isomeric compounds are quite different.
At present, PEG maleimide derivatives (Polyethylene glycol maleimide, PEG-MAL) are mainly used to modify thiol-containing proteins or polypeptide drugs, but because PEG-MAL is unstable in aqueous solution, an excessive amount of PEG-MAL is required Participate in the modification of protein or polypeptide drugs

Method used

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  • Polyethylene glycol benzothiazole derivative and preparation method and application thereof
  • Polyethylene glycol benzothiazole derivative and preparation method and application thereof
  • Polyethylene glycol benzothiazole derivative and preparation method and application thereof

Examples

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example

[0028] Reagents and Instruments

[0029] Reagents: dichloromethane (DCM), tetrahydrofuran (THF), diethyl ether (DEE), all of which are of analytical grade except those used for determination; N-methylmorpholine (4-methylmorpholine, NMP) , Isobutyl chloroformate (isobutyl chloroformate, ClCOOBu i ), tert-Butylcarbonyl glycine (Boc-gly), dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (4-dimethylaminopyridine, DMAP), crystal violet And phosphate etc. come from Sinopharm Chemical Reagent Company; 2-cyano-6-aminobenzothiazole (2-cyano-6-amidebenzothiazole, CBT-NH 2), cysteine ​​(Cysteine, Cys), homocysteine ​​(Homocysteine, Hcy), newborn bovine serum (fetal bovine serum, FBS), thiazolyl blue (MTT) were derived from Sigma-Aldrich; bovine serum albumin (Solarbio); RPMI1640 culture fluid (GbicoBR1); Polypeptide CT20 (CTFFYGGSRGKRNNFKTEEY) comes from Shanghai Qiangyao Biological Company; N-terminal cysteine ​​interferon a-2b (N-Cys-IFN, purified in this laboratory); Ethylen...

Embodiment 1

[0031] Example 1. Preparation of MePEG 5k -CONH-CBT

[0032] Get monomethoxy terminal carboxyl polyethylene glycol 5000 10g (MePEG 5k -COOH, 2.0mmol) was dissolved in DCM 50ml solution, filled with N at 0°C 2 Under the condition of stirring for 10min, add ClCOOBu i 0.410g (3mmol), NMP 0.40g (4mmol), the above mixture was stirred and reacted for 20min; 2 0.7g (4mmol) of THF 50ml solution, reacted under the above conditions for 2h, then moved to room temperature to continue the reaction for 24h; vacuum rotation to remove the organic solvent, dissolved the residue in brine, filtered off the insoluble matter, extracted with DCM, concentrated the organic phase, and precipitated with anhydrous ether Concentrate the solution and wash the precipitate several times to get MePEG after removing the ether 5k -CONH-CBT 9.5g.

[0033]

Embodiment 2

[0034] Example 2. Preparation of CBT-NHCO-PEG 5k -CONH-CBT

[0035] Get two carboxyl polyethylene glycol 5000 10g (HOOC-PEG 5k -COOH, 2.0mmol) was dissolved in DCM 50ml solution, filled with N at 0°C 2 Under the condition of stirring for 10min, add ClCOOBu i 0.820g (6mmol), NMP 0.80g (8mmol), the above mixture was stirred and reacted for 20min; 2 1.4g (8mmol) THF 50ml solution, after reacting for 2h under the above conditions, move to room temperature and continue to react for 24h; under vacuum condition, rotary evaporation removes organic solvent, dissolves residue in brine, filters out insoluble matter, extracts with DCM, concentrates organic phase, no Precipitate the concentrated solution with water and ether and wash the precipitate several times to obtain CBT-NHCO-PEG after removing the ether 5k -CONH-CBT 9.75g.

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Abstract

The invention belongs to the technical field of polymer synthetic chemistry and relates to a polyethylene glycol benzothiazole derivative with the following structural formula shown in the specification and a preparation method and application thereof. In the polyethylene glycol benzothiazole derivative, one or two 2-cyanobenzothiazole groups are contained at the terminal of polyethylene glycol. According to the invention, the N-terminal cysteine protein and polypeptide medicine can be modified by the terminal cyanobenzothiazole polyethylene glycol, and the two can efficiently conduct an irreversible coupling reaction at normal temperature in physiological conditions. Through the invention, other high molecular benzothiazole derivatives such as polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer and polylysine can be prepared at the same time.

Description

technical field [0001] The invention belongs to the technical field of polymer synthesis chemistry, and in particular relates to a polyethylene glycol benzothiazole derivative and its preparation method and application. Background technique [0002] The prior art discloses that protein and polypeptide drugs, compared with long-acting synthetic drugs, have the characteristics of specific action, high efficiency, less side effects, and less dosage, and play an important role in human disease data. However, protein and polypeptide drugs also have the following problems when they are administered, such as: immunogenicity, susceptibility to degradation by proteolytic enzymes, short half-life in vivo, and large toxic and side effects, which limit their clinical application; and Due to the short plasma half-life of certain drugs, in order to obtain a more significant clinical effect, the dosage and frequency of administration have to be increased, resulting in serious side effects ...

Claims

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Application Information

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IPC IPC(8): C08G65/48C07K1/107
Inventor 孙彦华朱孔黎梁建英刘彩云卢建忠
Owner FUDAN UNIV
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