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A kind of polypeptide prodrug modified by Evans blue and its preparation and application

A technology of Evans Blue and peptides, which is applied to medical preparations with no active ingredients, medical preparations containing active ingredients, peptides, etc., can solve the problems of low curative effect, large side effects, high price, etc., and achieve stable blood circulation , reduce toxic side effects, strong cytotoxic effect

Active Publication Date: 2022-04-19
SHANGHAI THERANOSTICS BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ADCs still have limitations: first, many cancers do not have specific antigens, and it is difficult to find suitable antibodies, resulting in limited application of ADCs to cancers; second, some ADCs still have the characteristics of low curative effect, high price, and large side effects
At present, research on monomethyl auristatin or Mertansine (DM1) at home and abroad is mainly focused on antibody-drug conjugates, and there is no monomethyl auristatin or Mertansine (Mertansine, DM1). DM1) Amphiphilic small molecule prodrugs were reported

Method used

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  • A kind of polypeptide prodrug modified by Evans blue and its preparation and application
  • A kind of polypeptide prodrug modified by Evans blue and its preparation and application
  • A kind of polypeptide prodrug modified by Evans blue and its preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1: the preparation of EB-VcMMAE

[0069] Synthesize EB-SH according to the following synthetic route:

[0070]

[0071] Specific steps include:

[0072] Drop into 3,3'-dimethylbenzidine (4.18g, 2eq.) and N-Boc-γ-aminobutyric acid (2g, 1eq) respectively in a 500mL flask containing 250 acetonitrile, and add 2-(7 -benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 7.47g, 2eq) and N,N-diisopropylethylamine (DIPEA, 6.3g, 5eq). Under stirring at room temperature, after 24 hours of reaction, the solvent was spin-dried, and the residue was purified through a silica gel column to obtain the brown intermediate BT. In an ice bath, 15 mL of ice-cold 2.0M HCl was added dropwise to 40 mL of BT (3.98 g, 10.0 mmol) in acetonitrile. Stir for 15min, then add 20mL NaNO 2 (2.07g, 30.0mmol) ice-water solution was slowly added dropwise to the flask, after the dropwise stirring was continued for 30min to generate a yellow diazonium salt solution, w...

Embodiment 2

[0074] Embodiment 2: Preparation of EB1-VcMMAE

[0075]Synthesize EB-SH according to the following synthetic route:

[0076]

[0077] Specific steps include:

[0078] In a 20mL reaction bottle, add 10mg (1eq) of EB-NH prepared according to the method of Example 1 2 , 3,3'-thiodipropionic acid (7.8mg, 10eq), benzotriazol-1-oxytri(pyrrolidino)phosphonium hexafluorophosphate (PyBOP, 19mg, 2eq), DIPEA (23.8, 10eq) In 5mL DMF, reacted for 24 hours, then purified by preparative HPLC using acetonitrile and 0.1% trifluoroacetic acid aqueous solution (gradient: 5-95% acetonitrile), the purified solution was directly added excess tris(2-carboxyacetate) phosphine hydrochloride (TECP), reacted for 4 hours, then purified by preparative HPLC using acetonitrile and 0.1% aqueous trifluoroacetic acid (gradient: 5-95% acetonitrile), and freeze-dried to obtain EB1-SH. LC-MS confirmed the structure as image 3 , ESI-MS m / z: calculated 630.09, found 629.17 (M-H).

[0079] In a 20 mL reacti...

Embodiment 3

[0080] Embodiment 3: Preparation of EB-DM1

[0081] In a 20 mL reaction vial, DM1 (5.3 mg, 7.2 μmol) was weighed and dissolved in 2 mL DMF, then EB-Mal (2.5 mg, 3.6 μmol, 2 mL PBS) was added. The reaction solution was shielded from light with aluminum foil and stirred overnight at room temperature, and then purified by preparative HPLC using acetonitrile and 0.1% aqueous trifluoroacetic acid (gradient: 5-95% acetonitrile) to obtain EB-DM1. The collected purified product was lyophilized and stored at -20°C for later use. Yield: 2.7 mg (52% yield). ESI-MS m / z: calculated value 1431.40, measured value 1430.57 (M-H) ( Figure 5 ).

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Abstract

The present invention provides a polypeptide drug prodrug, which is a prodrug formed by monomethylauristat or maytansine and Evans blue, and its structural formula is as formula (I); wherein, R 1 for or ‑CH 2 One of ‑; R 2 It is one of the new structures of monomethyl auristatin or metan, a polypeptide drug; m and n are the number of repeating units, and both are integers of 0-4. The polypeptide drug prodrugs of the present invention have excellent tumor cell uptake both in vivo and in vitro, and some prodrugs also show significant cancer cell inhibitory effect. The present invention also provides the preparation method of the prodrug and the application of the prodrug in the preparation of cancer treatment drugs.

Description

technical field [0001] The invention belongs to the technical field of nanomedicine and drug controlled release, and in particular relates to a prodrug formed by Evans blue and monomethyl auristatin or maytansine, its preparation method and its application in the preparation of anticancer drugs . Background technique [0002] Cancer is one of the leading causes of morbidity and death worldwide. According to the World Health Organization, there were about 14 million new cases worldwide in 2012, and the number of new cases is expected to increase by about 70% in the next two decades. Cancer caused 8.8 million deaths worldwide in 2015, with approximately 70% of cancer deaths occurring in low- and middle-income countries. Currently, chemotherapy is one of the main treatments for cancer. Traditional chemotherapeutic drugs, such as camptothecin, paclitaxel, doxorubicin, etc., often face ineffective curative effect, and have adverse and serious side effects. In recent years, be...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/03C07K7/02C07D498/18A61K38/07A61K38/08A61K31/537A61K47/54A61P35/00
CPCA61K47/54A61P35/00A61K31/537C07D498/18C07K5/021C07K7/02A61K38/00
Inventor 陈小元张福武
Owner SHANGHAI THERANOSTICS BIOTECH CO LTD
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