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Tumor microtubulin HIF-1alpha double target inhibitor and preparation method thereof

A technology of tubulin and HIF-1, which is applied in the field of malignant tumors and can solve problems such as poor efficacy of blood vessel blocking agents

Inactive Publication Date: 2017-07-07
NANHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The purpose of the present invention is to provide a tumor tubulin HIF-1α dual-target inhibitor and its preparation method, aiming at solving the problem of poor effect of using blood vessel blocking agents alone in clinical medicine, and the tumor blood vessels still remain after blockade. survivable problem

Method used

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  • Tumor microtubulin HIF-1alpha double target inhibitor and preparation method thereof
  • Tumor microtubulin HIF-1alpha double target inhibitor and preparation method thereof
  • Tumor microtubulin HIF-1alpha double target inhibitor and preparation method thereof

Examples

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preparation example Construction

[0021] Such as figure 1 As shown, the preparation method of the tumor tubulin HIF-1α dual-target inhibitor provided in the embodiment of the present invention includes the following steps:

[0022] S101: Add 3', 4', 5'-trimethoxy-7-hydroxyflavone or 2', 3', 4'-trimethoxy-7-hydroxyflavone or 4', 5 ', 6'-trimethoxy-7-hydroxyflavone (3.31g, 0.01mol), anhydrous potassium carbonate (5.52g, 0.04mol) and acetone (100ml), heated and stirred to reflux, then added dropwise 1,2- Dibromoethane or 1,3-dibromopropane or 1,4-dibromobutane (0.04mol) was heated and condensed to reflux at 60°C, the solution became clear and then cloudy. TCL (thin-layer chromatography) detects the reaction process, and column chromatography purifies, and the eluent is: methanol: dichloromethane=1:50;

[0023] S102: add benzimidazole derivative (0.015mol) in 250mL there-necked flask, make it dissolve in 100mL acetone, add potassium carbonate (5.52g, 0.04mol), after stirring for 10min, add the flavone derivative...

Embodiment 1

[0027] Example 1: 7-(2-bromoethoxy)-2-(3,4,5-trimethylphenyl)-4H-benzopyran-4-one

[0028] In a 250mL round bottom flask, add 3', 4', 5'-trimethoxy-7-hydroxyflavone (3.31g, 0.01mol), anhydrous potassium carbonate (5.52g, 0.04mol) and acetone (30ml) successively, Heat and stir to reflux, then add 1,2-dibromoethane (0.04mol) dropwise, heat and condense to reflux at 60°C, the solution becomes clear and then turbid. TCL (thin-layer chromatography) detects the reaction process, and purifies by column chromatography, the eluent is: methanol:dichloromethane=1:50. Yellow powder, the yield is 80%. 1 H NMR (400MHz, cdcl 3 )δ7.72(d, J=8.5Hz, 1H), 7.14(s, 2H), 6.78(d, J=2.1Hz, 1H), 6.76(d, J=2.2Hz, 1H), 6.75–6.73( m, 2H), 4.40 (t, J = 6.2Hz, 2H), 3.92 (d, J = 10.7Hz, 9H), 3.68 (t, J = 6.2Hz, 2H).

[0029]

Embodiment 2

[0030] Example 2: 7-(2-(1H-benzo[d]imidazol-1-yl)ethoxy)-2-(3,4,5-trimethoxyphenyl)-4H-benzopyran -4-one

[0031] Add benzimidazole (0.0015mol) in 100mL three-necked flask, make it dissolve in 30mL acetone, add potassium carbonate (0.552g, 0.004mol), after stirring for 10min, add the pale yellow solid 7-(2- Bromoethoxy)-2-(3,4,5-trimethylphenyl)-4H-benzopyran-4-one (0.001mol), tetrabutylammonium bromide (TBAB) (0.03g, 0.0001mol), heated to 60°C and stirred for reaction, (TCL detection reaction process), extracted with ethyl acetate, washed the organic layer with saturated brine, then dried with anhydrous sodium sulfate, evaporated the solvent to dryness under reduced pressure and separated it with a silica gel column. The target compound was obtained, and the eluent was: methanol:dichloromethane=1:50. Yellow powder, yield 51%. 1 H NMR (400MHz, cdcl 3 )δ8.03(s, 1H), 7.82(d, J=7.0Hz, 1H), 7.68(d, J=8.6Hz, 1H), 7.47(d, J=7.3Hz, 1H), 7.32(dq, J=7.2, 6.0Hz, 2H), 7.11(s, 2H), 6...

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Abstract

The invention discloses a tumor microtubulin HIF-1alpha double target inhibitor and a preparation method thereof. A synthesized compound inhibits capacity of glycolysis of tumor cells while blocks tumor vessels. As a vascular disrupting agent takes microtubulin and colchicines binding site as a target spot and inhibition of glycolysis takes a hypoxia-inducible factor 1alpha as a target, serial 3',4',5'-trimethoxyl-7-hydroxyl flavone derivatives or 2',3',4'-trimethoxyl-7-hydroxyl flavone derivatives or 4',5',6'-trimethoxyl-7-hydroxyl flavone derivatives are designed and synthesized by taking a flavone natural compound as a nuclear parent and modifying a tumor blood blocking agent. Compounds which act on the microtubulin and inhibit the hypoxia-inducible factor 1alpha at the same are screened by means of in vitro antineoplastic activity and the inhibiting level of a target protein. A candidate drug which acts on a tumor vessel and inhibits glycolysis at the same is selected. A novel potential candidate drug is provided for treating tumor.

Description

technical field [0001] The invention belongs to the technical field of malignant tumors, in particular to a dual-target inhibitor of tumor tubulin and HIF-1α and a preparation method thereof. Background technique [0002] Tumor is a common and frequently occurring disease, among which malignant tumors are currently the most serious hazard to human health. Blood vessels provide sufficient oxygen and nutrients for tumor growth and survival, and eliminate metabolic waste products. Therefore, tumor vascular targeting therapy has become an effective tumor treatment strategy. Research Progress of Tumor Vascular Inhibitors In the early 1970s, Folkman first proposed that tumor angiogenesis plays an important role in the growth and spread of tumors. Further studies such as Bergers have also shown that: tumor cells need the support of new blood vessels and functional blood vessels in the process of proliferation and metastasis; moreover, a large number of studies in recent years hav...

Claims

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Application Information

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IPC IPC(8): C07D405/12A61P35/00
CPCC07D405/12
Inventor 邓湘萍唐国涛王哲曹轩熊淑娟熊润德刘娟邹柳
Owner NANHUA UNIV
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