3,3'-(3,5-difluorobenzylidene)-bis-4-hydroxycoumarin and application thereof

A technology of difluorobenzylidene and hydroxycoumarin, applied in the directions of organic chemistry, drug combination, antitumor drugs, etc., to achieve the effects of low toxicity, good anti-leukemia activity and good safety

Inactive Publication Date: 2018-11-09
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this type of drug is only effective for 15-20% of leukemia patients with Philadelphia chromosome-positive Bcr-Abl fusion gene, and its drug resistance has also brought severe challenges to clinical treatment.

Method used

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  • 3,3'-(3,5-difluorobenzylidene)-bis-4-hydroxycoumarin and application thereof
  • 3,3'-(3,5-difluorobenzylidene)-bis-4-hydroxycoumarin and application thereof
  • 3,3'-(3,5-difluorobenzylidene)-bis-4-hydroxycoumarin and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Example 1: Synthetic route and method of the compound of the present invention

[0018]

[0019] R=H, 3,5-2F, 3,5-2Cl, 3,5-2Br, 3,5-2OCH 3 Or 3,4-2CF 3 .

[0020] resolve resolution:

[0021] Mix 20mmol of 4-hydroxycoumarin and 100mL of absolute ethanol and heat until 4-hydroxycoumarin is dissolved, add 10mmol series of aromatic aldehydes containing different substituents (the compound R=H does not have this step), and heat After refluxing, white solid particles are precipitated. Continue heating. After the reaction is over, cool and filter with suction, and then recrystallize with ethanol to finally obtain pure white granular crystals.

Embodiment 2

[0022] Example 2: Structural identification

[0023] The molecular weight, structure and purity of the synthesized series of 4-hydroxycoumarin compounds were identified by nuclear magnetic resonance spectroscopy (NMR).

[0024] Compound 1:

[0025] 3,3′-benzylidene-bis-4-hydroxycoumarin

[0026] 3,3′-Benzylidene-bis-(4-hydroxycoumarin)

[0027] 1 H NMR(CDCl 3 ,δ,ppm): 11.528(s,1H),11.299(s,1H),7.994-8.080(q,2H),7.606-7.649(m,2H),7.215-7.421(m,9H),6.104(s ,1H).

[0028] Compound 2:

[0029] 3,3′-(3,5-difluorobenzylidene)-bis-4-hydroxycoumarin

[0030] 3,3′-(3,5-Difluorobenzylidene)-bis-(4-hydroxycoumarin)

[0031] 1 H NMR(CDCl 3 ,δ,ppm): 11.666 (s, 1H), 11.323 (s, 1H), 8.033-8.109 (q, 2H), 7.660-7.701 (m, 2H), 7.427-7.462 (t, 4H), 6.731-6.790 (m,3H),6.051(s,1H).

[0032] Compound 3:

[0033] 3,3′-(3,5-Dichlorobenzylidene)-bis-4-hydroxycoumarin

[0034] 3,3′-(3,5-Dichlorobenzylidene)-bis-(4-hydroxycoumarin)

[0035] 1 H NMR(CDCl 3 ,δ,ppm): 11.630 (s, 1H), 11.314 (s, 1H), 8.04-8.114 (m, 2H), 7.6...

Embodiment 3

[0053] Example 3: Inhibition rate of compound 1-6 on the proliferation of human chronic myeloid leukemia cells K562 cells and human umbilical vein endothelial cells HUVECs

[0054] (1) The MTT method was used to detect the inhibitory rate of compound 1-6 on the proliferation of human chronic myeloid leukemia cells K562 cells and human umbilical vein endothelial cells HUVECs. K562 cells and HUVECs were cultured to 80% confluence for passage, with 2.0 ×10 5 Inoculated in 96-well culture plate at a density of pieces / mL, in 5% CO 2 , 37 ℃ incubator overnight. The supernatant was discarded, and the 6 compounds obtained in Example 1 were diluted with RPMI-1640 and MEM containing 2% fetal bovine serum. The above compounds were added to each well to a final concentration of 1, 2, 4, 8, 16, 32, 64, 128, 256μg / ml, set three repeat holes, and set blank holes. MTT method was used to detect cell viability in 24 hours. Cell survival rate=(A administration-A blank) / (A control-A blank). The e...

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PUM

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Abstract

The invention discloses 3,3'-(3,5-difluorobenzylidene)-bis-4-hydroxycoumarin and application thereof. According to the invention, 3,3'-(3,4-dichlorobenzylidene)-bis-4-hydroxycoumarin is prepared and is found to have good in-vitro and in-vivo activity and exert strong inhibitory effect on leukemia tumor cells; and 3,3'-(3,4-dichlorobenzylidene)-bis-4-hydroxycoumarin is low in toxicity and good in safety.

Description

Technical field [0001] The invention relates to the application of 3,3'-(3,5 difluorobenzylidene)-bis-4-hydroxycoumarin for preparing anti-leukemia drugs. Background technique [0002] Leukemia is a malignant clonal disease of hematopoietic stem cells. Clonal leukemia cells are out of control of proliferation, differentiation and apoptosis, and are stagnated at different stages of cell development, inhibiting normal hematopoietic function. In recent years, the prevalence of leukemia in my country is 2.76 per 100,000. In the mortality rate of malignant tumors, leukemia ranks 6th and 8th among men and women, respectively, and ranks 1st among children and adults under 35. Clinically, the first choice drugs for the treatment of leukemia are imatinib and nilotinib, which are tyrosine kinase inhibitors. However, these drugs are only effective for 15-20% of leukemia patients with Philadelphia chromosome-positive Bcr-Abl fusion gene, and their drug resistance also brings severe challen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/56A61P35/02
CPCA61P35/02C07D311/56
Inventor 辛佳佳胡兴斌李明凯尹文
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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