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A kind of azo bond-linked podophyllotoxin derivative and its preparation method

A technology for podophyllotoxin and derivatives, applied in the field of drug synthesis, can solve problems such as poor water solubility, limited clinical therapeutic effect of etoposide and teniposide, and multidrug resistance

Active Publication Date: 2021-04-20
LANZHOU INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the problems of poor water solubility and multidrug resistance, the clinical therapeutic effects of etoposide and teniposide are greatly limited.

Method used

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  • A kind of azo bond-linked podophyllotoxin derivative and its preparation method
  • A kind of azo bond-linked podophyllotoxin derivative and its preparation method
  • A kind of azo bond-linked podophyllotoxin derivative and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: 4´- O -Nor-4 β - Preparation of p-diaminoazobenzene-4-deoxypodophyllotoxin (GL331-azo)

[0046] (1) Intermediate 4´- O -Nor-4 β -Synthesis of bromo-4-deoxypodophyllotoxin: Dissolve norepipodophyllotoxin (1.0 g, 2.4 mmol) in 25 mL of dry dichloromethane, cool to 0°C in an ice bath, pass through dry bromide Hydrogen gas for 45min, followed by N 2 Remove excess hydrogen bromide, and concentrate under reduced pressure to obtain the target compound (1.1 g);

[0047] (2) 4´- O -Nor-4 β -Synthesis of p-diaminoazobenzene-4-deoxypodophyllotoxin (GL331-azo): take the intermediate 4´ obtained in step (1)- O -Nor-4 β -Bromo-4-deoxypodophyllotoxin (462 mg, 1 mmol) was dissolved in 10 mL of dry dichloromethane, anhydrous potassium carbonate (414 mg, 3 mmol) was added under nitrogen protection and stirred for 5 min, then p-diamine Azobenzene (254 mg, 1.2 mmol) was stirred at room temperature for 4 h, filtered, concentrated under reduced pressure, and separated by c...

Embodiment 2

[0048] Example 2: 4´- O -Nor-4 β - Preparation of p-diaminoazobenzene-4-deoxypodophyllotoxin (GL331-azo)

[0049] (1) Intermediate 4´- O -Nor-4 β -Synthesis of bromo-4-deoxypodophyllotoxin: same as Example 1;

[0050] (2) 4´- O -Nor-4 β -Synthesis of p-diaminoazobenzene-4-deoxypodophyllotoxin (GL331-azo): take the intermediate 4´- obtained in step (1) O -Nor-4 β -Bromo-4-deoxypodophyllotoxin (462 mg, 1 mmol) was dissolved in 10 mL of dry dichloromethane, triethylamine (0.42 mL, 3 mmol) was added under nitrogen protection and stirred for 5 min, then p-diamino Azobenzene (254 mg, 1.2 mmol) was stirred at room temperature for 4 h, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain the target compound GL331-azo (350 mg), with a yield of 59.2%.

Embodiment 3

[0051] Example 3: Preparation of polyethylene glycol-modified azo-linked podophyllotoxin derivatives (PEG-azo-GL331)

[0052] (1) Intermediate 4´- O -Nor-4 β -Synthesis of bromo-4-deoxypodophyllotoxin: Dissolve norepipodophyllotoxin (1.0 g, 2.4 mmol) in 25 mL of dry dichloromethane, cool to 0°C in an ice bath, pass through dry bromide Hydrogen gas for 45min, followed by N 2 Remove excess hydrogen bromide, and concentrate under reduced pressure to obtain the target compound (1.1 g);

[0053] (2) 4´- O -Nor-4 β-Synthesis of p-diaminoazobenzene-4-deoxypodophyllotoxin (GL331-azo): take the intermediate 4´ obtained in step (1)- O -Nor-4 β -Bromo-4-deoxypodophyllotoxin (462 mg, 1 mmol) was dissolved in 10 mL of dry dichloromethane, anhydrous potassium carbonate (414 mg, 3 mmol) was added under nitrogen protection and stirred for 5 min, then p-diamine Azobenzene (254 mg, 1.2 mmol), stirred at room temperature for 4 hours, filtered, concentrated under reduced pressure, and sepa...

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Abstract

The invention discloses an azo bond-linked podophyllotoxin derivative, the structural formula of which is shown in the following formula. The azo bond-linked podophyllotoxin derivative of the present invention has excellent anti-tumor activity and can effectively improve the The water solubility of the compound; in addition, this kind of podophyllotoxin derivatives linked by azo bonds can remain stable in other parts of the body, and only in situ release anti- GL‑331 active molecule with excellent tumor activity.

Description

technical field [0001] The invention relates to a podophyllotoxin derivative, in particular to an azo bond-linked podophyllotoxin derivative and a preparation method thereof, belonging to the technical field of drug synthesis. Background technique [0002] Podophyllotoxin is a lignan compound with excellent anti-tumor activity isolated from the rhizomes of Podophyllotoxin and Star Anise, and its derivatives etoposide and teniposide are obtained through structural modification with podophyllotoxin as the parent It has been widely used clinically in the treatment of small cell lung cancer, testicular cancer, lymphoma, Kaposi's sarcoma and other cancers. However, due to the problems of poor water solubility and multidrug resistance, the clinical therapeutic effects of etoposide and teniposide are greatly limited. In order to improve this situation, researchers have synthesized a large number of podophyllotoxin derivatives in order to discover podophyllotoxin derivatives with b...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04C08G65/333C08G65/334A61P35/00
CPCA61P35/00C07D493/04C08G65/33313C08G65/3346
Inventor 师彦平哈伟赵晓博
Owner LANZHOU INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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