Sulfur-substituted podophyllum derivative and synthetic method and application thereof

A podophyllotoxin and reaction technology, applied in the field of podophyllin derivatives, can solve problems such as toxic side effects and poor bioavailability, and achieve the effects of reducing toxic side effects, improving anti-tumor activity, and improving anti-tumor efficacy.

Inactive Publication Date: 2012-10-31
HUBEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the disadvantages of strong toxic side effects and poor bioavailability, their clinical use is

Method used

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  • Sulfur-substituted podophyllum derivative and synthetic method and application thereof
  • Sulfur-substituted podophyllum derivative and synthetic method and application thereof
  • Sulfur-substituted podophyllum derivative and synthetic method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1 Synthesis and purification of 4-S-(1,2,4-triazole-3)-4-deoxypodophyllotoxin (compound (1))

[0036] (1) Synthesis of 4-(1,2,4-triazole-3)-4-deoxypodophyllotoxin: take 414mg (1mmol) of podophyllotoxin, 101mg (1mmol) of triazole, and vacuum-dry for 1h , using 15ml of trifluoroacetic acid as a solvent in an ice bath, stirring in vacuum (600 rpm) at 4°C for 1 h, using chloroform acetone as a developer, and detecting the end point of the reaction. Concentrate under reduced pressure to nearly dryness, dissolve in ethyl acetate, and wash three times with 10 ml of deionized water, collect the ethyl acetate layer, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product.

[0037] (2) Separation and purification of 4-(1,2,4-triazole-3)-4-deoxypodophyllotoxin:

[0038] Separation and purification using silica gel column chromatography and gel column chromatography:

[0039] (A) Use a normal phase silica gel column (normal phase silica gel: China Q...

Embodiment 2

[0042] Example 2 Synthesis and purification of 4-S-(1,3,4-thiadiazole-2)-4-deoxypodophyllotoxin (compound (2))

[0043] (1) Synthesis of 4-S-(1,3,4-thiadiazole-2)-4-deoxypodophyllotoxin: get 414mg (1mmol) of podophyllotoxin, 118mg (1mmol) of triazole, vacuum Dry for 1 hour, use 15 ml of trifluoroacetic acid as a solvent under ice bath conditions, stir in vacuum (600 rpm) at 4°C for 1.5 hours, use chloroform acetone as a developer, and detect the end point of the reaction. Concentrate under reduced pressure to nearly dryness, dissolve in ethyl acetate, and wash three times with 10 ml of deionized water, collect the ethyl acetate layer, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product.

[0044] (2) Separation and purification of 4-S-(1,3,4-thiadiazole-2)-4-deoxypodophyllotoxin:

[0045] Separation and purification using silica gel column chromatography and gel column chromatography:

[0046] (A) Use a normal phase silica gel column (normal phase s...

Embodiment 3

[0049] Example 3 Synthesis and purification of 4-S-(1,2,4-triazole-3)-4-deoxy-4'-desmethyl epipodophyllotoxin (compound (3))

[0050] (1) Synthesis of 4-S-(1,2,4-triazole-3)-4-deoxy-4'-demethyl epipodophyllotoxin: get 400mg (1mmol) of podophyllotoxin, 101mg ( 1mmol) of triazole, vacuum-dried for 1h, under ice-bath conditions, with 15ml of trifluoroacetic acid as solvent, stirred in vacuum (800 rpm) at -4°C for 3h, using chloroform acetone as developer, and detected the end point of the reaction. Concentrate under reduced pressure to nearly dryness, dissolve in ethyl acetate, and wash three times with 10 ml of deionized water, collect the ethyl acetate layer, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product.

[0051] (2) Isolation and purification of 4-S-(1,2,4-triazole-3)-4-deoxy-4'-desmethyl epipodophyllotoxin:

[0052] Separation and purification using silica gel column chromatography and gel column chromatography:

[0053] (A) Use a normal ph...

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Abstract

The invention discloses a sulfur-substituted podophyllum derivative, and a synthetic method and application thereof. Through sulfur substitution reaction, 2-mercapto-1,3,4-thiadiazole or 3-mercapto-1,2,4-triazole is respectively introduced into a C-4 site of podophyllotoxin or 4'-demethyl-epipodophyllotoxin so as to obtain the sulfur-substituted podophyllum derivative represented by a formula (V). Cell apoptosis test results of in-vitro BGC823, HepG2 and A549 tumor cell strains show that sulfur-substituted podophyllum derivative has good anti-tumor activity, high safety and low toxicity and can be prepared into clinical anticancer medicines.

Description

technical field [0001] The present invention relates to sulfur-substituted podophyllin derivatives, in particular to sulfur-substituted podophyllin derivatives obtained by substituting the 4-position of the C ring of podophyllotoxin or 4'-desmethyl epipodophyllotoxin and a preparation method thereof. The invention also relates to the use of the sulfur-substituted podophyllum derivatives in the preparation of antitumor drugs, which belongs to the field of podophyllum derivatives. Background technique [0002] The structural formulas of Podophyllotoxin and 4'-Demethylepipodophyllotoxin are figure 1 Shown in the formulas (I) and (II), they are the natural antitumor activity extracts from podophyllum plants (for example: Berberidaceae plant Taoerqi, mountain lotus leaf, star anise lotus, etc.) active lead compound. However, their clinical use is limited due to their strong toxic side effects and poor bioavailability. Therefore, the research on drug development after structural...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61K31/433A61K31/4196A61P35/00
Inventor 汤亚杰白佳珂
Owner HUBEI UNIV OF TECH
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