Arenobufagin derivative as well as preparation method and application thereof

A technology of sandbuad venom and its derivatives, which is applied in the field of medicine and can solve the problems of enhancing the toxicity of compounds and high toxicity

Active Publication Date: 2018-04-24
ANHUI CHINA RESOURCES JINCHAN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although sabugain has excellent anti-tumor activity, its toxicity is relatively high. Therefore, it is necessary to carry out structural modification on this basis to enhance the activity of the compound and reduce toxicity, so as to discover new anti-tumor drugs

Method used

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  • Arenobufagin derivative as well as preparation method and application thereof
  • Arenobufagin derivative as well as preparation method and application thereof
  • Arenobufagin derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1, the preparation of compound 1a

[0064]

[0065] Dissolve sabubaptin (83mg, 0.2mmol) in 10mL of dry dichloromethane, add triethylamine (81mg, 0.8mmol), and then add n-octanoyl chloride (129.6mg, 0.8mmol) dropwise. After the dropwise addition, Stir overnight at room temperature. Purified by column chromatography to obtain 60 mg of white solid 1a with a yield of 55.5%. 1 H NMR: (CDCl 3 ,500MHz) δ: 7.76(d,1H),7.41(s,1H),6.27(d,1H),5.3(s,1H),4.33(d,1H),4.11(d,1H),3.84(s ,1H),2.43(d,1H),2.30(t,2H),2.05-2.09(m,2H),1.86-1.94(m,2H),1.75-1.80(m,5H),1.63-1.73(m ,4H), 1.45(d,1H), 1.33-1.44(m,15H), 1.27(s,3H), 0.86-0.88(m,3H).

Embodiment 2

[0066] Embodiment 2, the preparation of compound 1b

[0067]

[0068] Dissolve sabubaptin (83 mg, 0.2 mmol) in 10 mL of dry dichloromethane, add DMAP (4-dimethylaminopyridine) (24.4 mg, 0.2 mmol), Boc-alanine (tert-butoxycarbonyl -L-alanine) (56.8mg, 0.3mmol), then add EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) (115mg, 0.6mmol), stir at room temperature overnight . Purified by column chromatography to obtain 50 mg of white solid 1b with a yield of 43.2%. 1 H NMR: (CDCl 3,500MHz) δ: 7.76(d,1H),7.41(s,1H),6.27(d,1H),5.13(s,1H),5.04(s,1H),4.34-4.36(m,1H),4.12 -4.16(m,1H),3.85(d,1H),3.42(d,2H),2.54-2.57(m,2H),2.46(d,1H),2.04-2.08(m,3H),1.96-2.00 (m,1H),1.65-1.85(m,7H),1.57-1.62(m,4H),1.40-1.46(m,9H),1.19-1.23(m,3H),0.92-0.96(m,3H) .

Embodiment 3

[0069] Embodiment 3, the preparation of compound 1c

[0070]

[0071] Sabubuadin (83mg, 0.2mmol) was dissolved in 10mL of dry dichloromethane, DMAP (24.4mg, 0.2mmol), Boc-phenylalanine (N-tert-butoxycarbonyl-L- Phenylalanine ) (79.6mg, 0.3mmol), then added EDCI (115mg, 0.6mmol), and stirred at room temperature overnight. Purified by column chromatography to obtain 52 mg of white solid 1c with a yield of 40.2%. 1 H NMR: (CDCl 3 ,500MHz)δ: 7.76(d,1H),7.41(s,1H),7.23-7.31(m,4H),7.15-7.16(m,2H),6.27(d,1H),5.07-5.12(m, 2H),4.58(d,1H),4.31-4.34(m,1H),4.09-4.12(m,1H),3.83-3.86(m,1H),3.06-3.10(m,2H),2.06(s, 1H),2.38(d,1H),2.06-2.08(m,2H),1.82-1.89(m,3H),1.67-1.79(m,6H),1.65-1.66(m,1H),1.31-1.37( m,5H), 1.21-1.23(m,10H), 0.91-0.97(m,3H).

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PUM

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Abstract

The invention discloses an arenobufagin derivative. The arenobufagin derivative is prepared from pharmaceutical salt thereof; the structure is as shown in a general formula (1) (which is shown in thedescription); in the general formula (1), A is selected from a compound I which is shown in the description or a compound II which is shown in the description, and the definitions of all substituent groups in the general formula (1) are as shown in the description. The invention also discloses application of the arenobufagin derivative and the pharmaceutical salt thereof in preparing anti-tumor medicine. The arenobufagin derivative disclosed by the invention has anti-tumor activity, and can be used for preparing anti-tumor, cardiovascular and anti-nervous system medicine.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a class of sabugain derivatives, a preparation method thereof, and an application in medicine. Background technique [0002] Arenobufagin is a bufolide compound extracted from toad venom. Its chemical structure is as follows: [0003] [0004] Studies have shown that sabuad toxin has strong anti-tumor activity, can inhibit the adhesion, migration, invasion and angiogenesis of liver cancer HepG2 cells (Chinese Pharmacology Bulletin, 2011, 27; 19-23), and can also significantly inhibit liver cancer SMMC-7721 mitochondrial apoptosis pathway induces apoptosis of tumor cells (Chinese Medicine Emergency, 2013, 22: 1845-1883). Therefore, it is of great significance to synthesize sandbuad toxin derivatives, study their structure-activity relationship, and find sandbuad toxin derivatives with high efficiency and low toxicity. [0005] At present, there are relatively few studies on ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J19/00C07J41/00C07J43/00C07J31/00A61P9/10A61P25/00A61P35/00
CPCC07J19/00C07J31/006C07J41/0033C07J43/003
Inventor 高波罗川缪震元吴岳林庄春林
Owner ANHUI CHINA RESOURCES JINCHAN PHARMA CO LTD
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