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Podophyllotoxin-indirubin ramification, preparation method and medical application thereof

A technology of podophyllotoxin and indirubin, which can be used in drug combination, antitumor drugs, organic chemistry, etc., can solve the problems that restrict the clinical application of podophyllotoxin in antitumor.

Inactive Publication Date: 2018-07-20
ZUNYI MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because podophyllotoxin can produce serious adverse reactions, such as gastrointestinal discomfort, liver and kidney toxicity, etc., this restricts the anti-tumor clinical application of podophyllotoxin

Method used

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  • Podophyllotoxin-indirubin ramification, preparation method and medical application thereof
  • Podophyllotoxin-indirubin ramification, preparation method and medical application thereof
  • Podophyllotoxin-indirubin ramification, preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Indirubin-N 1 - Preparation of Acetate-4-podophyllotoxin (I-1)

[0033] Podophyllotoxin (0.12g, 0.28mmol) was added to anhydrous dichloromethane (5mL), then triethylamine (0.2mL, 1.4mmol) was added, the above reaction solution was cooled to 0°C, and bromo Acetyl chloride (2.5eq). After dropping, the reaction solution was raised to 30°C for 1-2 hours. The reaction was quenched with ammonium chloride solution, extracted three times with dichloromethane, the organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain intermediate III-1. The above crude product, indirubin (1 g), cesium carbonate (2.5 eq) and catalytic amount of potassium iodide were added into anhydrous DMF, and stirred at 25° C. for 0.5-1 hour. Quench the reaction with brine, extract three times with dichloromethane, combine the organic layers, wash with saturated brine, dry over anhydrous magnesium sulfate, filter to...

Embodiment 2

[0035] Example 2: Indirubin-N 1 - Preparation of propionate-4-podophyllotoxin (I-2)

[0036] Bromopropionyl chloride is replaced by bromoacetyl chloride, according to the method described in Example 1, the rest of the required raw materials and reagents are the same as in Example 1, to obtain purple solid indirubin-N 1 -Propionate-4-podophyllotoxin (I-2), yield 70%.

[0037] 1 H NMR (400MHz, DMSO-d6) δ11.03(s, 1H), 8.79(d, J=7.2Hz, 1H), 7.65(d, J=7.2Hz, 1H), 7.58(t, J=6.4Hz ,1H),7.40(d,J=7.6Hz,1H),7.30(t,J=6.8Hz,1H),7.07(s,2H),7.01(t,J=6.8Hz,1H),6.75(s ,1H),6.50(s,2H),5.89(s,2H),5.74(s,1H),5.66(s,1H),4.36(t,J=7.2Hz,1H),4.25(s,2H) ,4.03(d,J=5.6Hz,2H),3.66(s,6H),3.61(d,J=7.2Hz,2H),3.54(s,3H),2.64-2.73(m,2H); 13C NMR(100MHz,DMSO-d6)δ188.98,177.69,171.17,169.40,153.10,152.87,147.80,146.64,141.07,139.22,138.76,137.65,136.45,132.70,129.47,127.05,124.88,122.32,121.91,121.18,119.50 ,113.92,109.31,109.05,108.22,106.04,105.58,101.60,72.83,70.81,60.27,56.28,55.36,44.07,43.76,35.76,...

Embodiment 3

[0038] Example 3: Indirubin-N 1 - Preparation of butyrate-4-podophyllotoxin (I-3)

[0039] Bromobutyryl chloride is replaced by bromoacetyl chloride, according to the method described in Example 1, the rest of the required raw materials and reagents are the same as in Example 1, to obtain a purple solid indirubin-N 1 -Butyrate-4-podophyllotoxin (I-3), yield 60%.

[0040] 1 H NMR (400MHz, DMSO-d6) δ11.03(s, 1H), 8.80(d, J=8.0Hz, 1H), 7.65(d, J=6.8Hz, 1H), 7.57(t, J=6.8Hz ,1H),7.38(d,J=7.6Hz,1H),7.29(t,J=6.8Hz,1H),7.08(s,2H),7.01(t,J=7.2Hz,1H),6.85(s ,1H),6.50(s,3H),5.95(s,2H),5.67(s,1H),4.39(t,J=7.6Hz,1H),4.29(d,J=14.0Hz,2H),3.81 (s,2H),3.65(s,6H),3.58(s,3H),3.55(d,J=9.2Hz,1H),2.93(s,1H),2.26-2.40(m,2H),1.86( s,2H); 13 C NMR(100MHz,DMSO-d6)δ188.98,177.72,172.67,169.56,153.11,152.86,147.82,146.72,141.55,139.12,138.81,137.67,136.47,132.63,129.59,127.28,124.91,122.25,121.89,121.20,119.48 ,113.88,109.27,108.87,108.26,106.11,105.80,101.64,72.53,70.99,60.34,56.26,44.24,43.77,3...

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Abstract

The invention relates to the field of medical chemistry, in particular to podophyllotoxin-indirubin ramification (I), a preparation method and medical application thereof. The pharmacology experimentproves that the podophyllotoxin-indirubin ramification has an effect of antitumor cell proliferation in vitro and can be applied to clinical precaution or tumor disease treatment.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of podophyllotoxin-indirubin derivatives (I), their preparation methods and their use in drugs for preventing or treating tumors. Background technique [0002] Podophyllotoxin (podophyllotoxin) is a kind of aryl naphthalactone lignans isolated from Podophyllum chinensis of the genus Podophyllum of the Berberaceae family. This type of plant is mainly distributed in the western part of my country and is used in the folk for the treatment of snake bites. And carbuncle furuncle swollen poison embolism. Studies have shown that podophyllotoxin has a variety of pharmacological activities, such as anti-tumor, anti-virus, insecticidal, etc., and its mechanism of action is mainly to inhibit tubulin and free radicals. Because podophyllotoxin can produce serious adverse reactions, such as gastrointestinal discomfort, liver and kidney toxicity, etc., this restricts the clinical appl...

Claims

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Application Information

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IPC IPC(8): C07D493/04A61P35/00
CPCC07D493/04
Inventor 王京张磊龙丽文
Owner ZUNYI MEDICAL UNIVERSITY