Application of podophyllotoxin isatin derivative to anti-leukemia drug and preparation method for podophyllotoxin isatin derivative

A technology for podophyllotoxin and derivatives, applied in the field of podophyllotoxin isatin derivatives and their synthesis, can solve problems such as multidrug resistance, bone marrow suppression and the like

Active Publication Date: 2016-01-20
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although great progress has been made in the structural modification and transformation of podophyllotoxins, there are still some defects in the clinically used podophyllotoxins, such as multidrug resistance, bone marrow suppression, etc.

Method used

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  • Application of podophyllotoxin isatin derivative to anti-leukemia drug and preparation method for podophyllotoxin isatin derivative
  • Application of podophyllotoxin isatin derivative to anti-leukemia drug and preparation method for podophyllotoxin isatin derivative
  • Application of podophyllotoxin isatin derivative to anti-leukemia drug and preparation method for podophyllotoxin isatin derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of 4-α-[2-chloro-acetate]-podophyllotoxin (b)

[0035] Add podophyllotoxin (a) (2.4mmol), triethylamine (9.6mmol) and dichloromethane (20ml) into a 50ml round-bottomed flask, stir, add chloroacetyl chloride (6mmol) dropwise under ice-cooling, dropwise, The reaction solution was raised to room temperature and stirred for reaction. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution, extracted three times with dichloromethane, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and column chromatography gave light yellow solid 4-α-[2-chloro-acetic acid Esters]-podophyllotoxin (b) 0.95g, yield 81%.

[0036] 1 HNMR (400MHz, CDCl 3 )δ6.77(s,1H),6.55(s,1H),6.37(s,2H),5.99(d, J =4.8Hz,2H),5.96(d, J =8.4Hz,1H),4.61(d, J =2.6Hz,1H),4.38-4.42(m,1H),4.13-4.24(m,3H),3.80(s,3H),3.75(s,6H),2.84-2.97(m,2H); 13 CNMR (100MHz, CDCl 3 )δ 173.41, 167.94, 152.65, 148.41, 147.70, 137....

Embodiment 2

[0038] Preparation of 4-α-[2-(1H-indol-2,3-dione-1-yl)-acetate]-podophyllotoxin (I-1)

[0039] Add chloroacetate podophyllotoxin (0.2mmol), potassium carbonate (0.2mmol), isatin (0.19mmol) and N,N-dimethylformamide (2ml) in a 10ml round bottom flask, and heat the oil bath to The reaction was stirred at 80°C. After completion of the reaction, water (20ml) was added to quench the reaction, extracted three times with dichloromethane, the organic layer was washed with saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and column chromatography gave an orange-red solid 4 -α-[2-(1H-indol-2,3-dione-1-yl)-acetate]-podophyllotoxin (I-1) 0.087g, yield 73%.

[0040] 1 HNMR (400MHz, CDCl 3 )δ7.63~7.69(m,2H),7.21(t, J =7.0Hz,1H),6.84(d, J =6.6Hz,1H),6.59(s,1H),6.52(s,1H),6.33(s,2H),5.99(d, J =9.6Hz,2H),5.94(d, J =8.1Hz,1H),4.70(d, J =17.2Hz,1H),4.59(s,1H),4.53(d, J =17.1Hz,1H),4.33~4.36(m,1H),4.16(t...

Embodiment 3

[0042] Preparation of 4-α-[2-(4-chloro-1H-indol-2,3-dione-1-yl)-acetate]-podophyllotoxin (I-2)

[0043] Replace isatin with 4-chloroisatin, according to the method described in Example 2, all the other required raw materials and reagents are the same as in Example 2, to obtain orange-red solid 4-α-[2-(4-chloro-1H-indole -2,3-Diketone-1-yl)-acetate]-podophyllotoxin (I-2), yield 70%.

[0044] 1 HNMR (400MHz, CDCl 3 )δ7.55(t, J =8.0Hz,1H),7.15(d, J =8.2Hz,1H),6.75(d, J =7.9Hz,1H),6.55(s,1H),6.52(s,1H),6.32(s,2H),5.99(dd, J =6.1,1.1Hz,2H),5.93(d, J =8.6Hz,1H),4.72(d, J =17.8Hz,1H),4.59(d, J =3.9Hz,1H),4.52(d, J =17.8Hz,1H),4.32~4.36(m,1H),4.16(t, J =9.6Hz,1H),3.80(s,3H),3.72(s,6H),2.86~2.95(m,2H);HRMScalcdforC 32 h 27 ClNO 11 [M+H] + 636.1267, found 636.1271; 13 CNMR (100MHz, CDCl 3 )δ178.85,173.23,167.23,157.19,152.66,150.94,148.49,147.72,138.69,137.10,134.60,134.45,132.53,126.78,126.21,114.88,109.86,107.88,106.49,101.81,70.99,60.77,56.13,45.40,43.57 ,41.54,38.43...

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Abstract

The invention discloses a podophyllotoxin isatin derivative as shown in a formula (I) which is described in the specification. The invention also discloses a preparation method for the derivative and application of the derivative to preparation of an anti-leukemia drug.

Description

technical field [0001] The invention relates to isatin derivatives of podophyllotoxin and a synthesis method thereof, and the preparation of anti-leukemia drugs. Background technique [0002] Podophyllotoxin is a kind of natural product with lignin structure, which is mainly isolated from the roots and stems of plants of the genus Podophyllum in the family Berberaceae, and has antitumor and other activities. Although podophyllotoxin has strong anti-tumor activity, due to its strong toxic and side effects, podophyllotoxin is mainly used for external use in clinical treatment of diseases such as condyloma acuminatum. Since the 1950s, people began to modify the structure of podophyllotoxin, obtained a large number of structural analogs, and found some derivatives with lower toxicity and side effects while maintaining strong anti-tumor activity. For example, the antineoplastic drugs etoposide and teniposide are currently used clinically, and some podophyllotoxin derivatives are...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/404C07D493/04A61P35/02
Inventor 张磊王京
Owner ZUNYI MEDICAL UNIVERSITY
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