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Sulfur-substituted podophyllotoxin derivative as well as synthetic method and application thereof

A technology of podophyllotoxin and derivatives, applied in the field of podophyllotoxin derivatives, which can solve the problems of limited application, toxic side effects and poor bioavailability

Active Publication Date: 2014-03-05
HUBEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Podophyllotoxin and 4'-Demethylepipodophyllotoxin, the structure of which is figure 1 Chinese formulas (I) and (II); podophyllotoxin and 4'-desmethyl epipodophyllotoxin are derived from podophyllotoxin plants (such as: Berberidaceae plant Taoerqi, mountain lotus leaf, star anise lotus, etc. The natural active lead compounds with unique anti-tumor activity extracted from ) have limited their clinical application due to the disadvantages of strong toxic side effects and poor bioavailability

Method used

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  • Sulfur-substituted podophyllotoxin derivative as well as synthetic method and application thereof
  • Sulfur-substituted podophyllotoxin derivative as well as synthetic method and application thereof
  • Sulfur-substituted podophyllotoxin derivative as well as synthetic method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 Synthesis and purification of 4-S-(3-amino-1,2,4-triazole-5)-4-deoxy-podophyllotoxin (compound (1))

[0040] (1) Synthesis of 4-S-(3-amino-1,2,4-triazole-5)-4-deoxy-podophyllotoxin: take 414mg (1mmol) of podophyllotoxin, 116mg (1mmol) of 3-Amino-5-mercapto-1,2,4-triazole, vacuum-dried for 1 hour, under ice-bath condition with 15ml trifluoroacetic acid as solvent, stirred in vacuum for 1-3 hours, with chloroform acetone as developing agent, detection reaction end. The reaction system is added to 20-50 times the volume of deionized water, the filter cake is collected by filtration, washed and dried to obtain the crude product.

[0041] (2) Separation and purification of 4-S-(3-amino-1,2,4-triazole-5)-4-deoxy-podophyllotoxin:

[0042] Separation and purification using silica gel column chromatography and gel column chromatography:

[0043] (A) Use a normal phase silica gel column (normal phase silica gel: China Qingdao Ocean Chemical Co., Ltd., HG / T2354-92; se...

Embodiment 2

[0046] Example 2 Synthesis and purification of 4-S-(5-methyl-1,2,4-triazole-3)-4-deoxy-podophyllotoxin (compound (2))

[0047] (1) Synthesis of 4-S-(5-methyl-1,2,4-triazole-3)-4-deoxy-podophyllotoxin: take 414mg (1mmol) of podophyllotoxin, 115mg (1mmol) The 3-mercapto-5-methyl-1,2,4-triazole was vacuum-dried for 1 h, and stirred in vacuum for 1-3 h with 15 ml of trifluoroacetic acid as a solvent in an ice bath, and chloroform-acetone was used as a developer to detect end point of the reaction. The reaction system is added to 20-50 times the volume of deionized water, the filter cake is collected by filtration, washed and dried to obtain the crude product.

[0048] (2) Separation and purification of 4-S-(5-methyl-1,2,4-triazole-3)-4-deoxy-podophyllotoxin:

[0049] Using silica gel column chromatography and gel column chromatography for separation and purification, the method is the same as in Example 1.

[0050] Compound (2) 4-S-(5-methyl-1,2,4-triazole-3)-4-deoxy-podophyllo...

Embodiment 3

[0051] Example 3 Synthesis and purification of 4-S-(2-amino-1,3,4-thiadiazole-5)-4-deoxy-podophyllotoxin (compound (3))

[0052] (1) Synthesis of 4-S-(2-amino-1,3,4-thiadiazole-5)-4-deoxy-podophyllotoxin: take 414mg (1mmol) of podophyllotoxin, 133mg (1mmol) of podophyllotoxin 2-Amino-5-mercapto-1,3,4-thiadiazole, vacuum-dried for 1 hour, under ice-bath condition, use 15ml trifluoroacetic acid as solvent, stir in vacuum for 1-3 hours, use chloroform acetone as developer, detect reaction end. The reaction system is added to 20-50 times the volume of deionized water, the filter cake is collected by filtration, washed and dried to obtain the crude product.

[0053] (2) Separation and purification of 4-S-(2-amino-1,3,4-thiadiazole-5)-4-deoxy-podophyllotoxin:

[0054] Using silica gel column chromatography and gel column chromatography for separation and purification, the method is the same as in Example 1.

[0055] Compound (3) 4-S-(2-amino-1,3,4-thiadiazole-5)-4-deoxy-podophyll...

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Abstract

The invention discloses a sulfur-substituted podophyllotoxin derivative as well as a synthetic method and application thereof. The podophyllotoxin derivative, shown by a formula (V), with significantly improved anti-tumor activity and reduced toxic or side effect is obtained by introducing an aromatic heterocyclic compound with rigidity and a further sulfonamide product of 3-amino-5-mercapto-1,2,4-triazole, 2-amino-5-mercapto-1,3,4-thiadiazole, and 4-methyl benzenesulfonyl chloride or 4-methoxy benzenesulfonyl chloride, serving as substituent groups, into the fourth position of a C ring of podophyllotoxin or 4'-demethylepipodophyllotoxin respectively. An activity inhibition experiment of tumor cells in vitro shows that the anti-tumor activity of the compound shown by the formula (V) is significantly improved as compared with that of podophyllotoxin or 4'-demethylepipodophyllotoxin.

Description

technical field [0001] The present invention relates to podophyllotoxin derivatives and their synthesis methods, especially to sulfur-substituted podophyllotoxin derivatives and their synthesis and purification methods. The present invention further relates to their use in the preparation of antitumor drugs, which belong to podophyllotoxins Derivatives field. Background technique [0002] Podophyllotoxin and 4'-Demethylepipodophyllotoxin, the structure of which is figure 1 Chinese formulas (I) and (II); podophyllotoxin and 4'-desmethyl epipodophyllotoxin are derived from podophyllotoxin plants (such as: Berberidaceae plant Taoerqi, mountain lotus leaf, star anise lotus, etc. ) natural active lead compounds with unique anti-tumor activity, but due to strong toxic side effects and poor bioavailability, their clinical application is limited. Contents of the invention [0003] One of the objectives of the present invention is to provide a class of sulfur-substituted podophyl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04A61P35/00
CPCC07D493/04A61P35/00
Inventor 汤亚杰李建龙赵巍李红梅
Owner HUBEI UNIV OF TECH
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