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Anti-tumor compound and preparation method and application thereof

A compound and anti-tumor technology, applied in anti-tumor drugs, medical preparations containing active ingredients, organic chemistry, etc., can solve the problems of unseen small molecular compounds and limited drug application, and achieve good effect, high yield, Effects in simple steps

Active Publication Date: 2016-05-04
SHANGHAI TENTH PEOPLES HOSPITAL +1
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

However, there are still the following deficiencies: firstly, the single-drug effective rate of these drugs in relapsed / refractory patients is only 25% to 50%; secondly, although the disease-free survival time is prolonged, most patients will eventually relapse, and Significant drug resistance; third, some serious side effects such as neuritis limit the application of drugs
[0005] At present, there is no small molecule compound 7-((4-(pyridine-4-methylene)phenyl)carbamoyl) tricyclic [3.2.2.0 2,4 ]Related reports about non-8-ene-6-carboxylic acid

Method used

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  • Anti-tumor compound and preparation method and application thereof
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  • Anti-tumor compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0037] The preparation of embodiment 1TI17

[0038] The synthetic reaction formula is as follows:

[0039]

[0040] The specific preparation method is:

[0041] Compound 1 was prepared according to the method of patent US2006 / 160803.

[0042] Compound 1 (1.84g, 10mmol) and compound 3 (1.90g, 10mmol) were dissolved in DMF (20mL) and stirred at room temperature for 12 hours. The solvent was evaporated to dryness under reduced pressure, and the residue was recrystallized from ethyl acetate / n-hexane (2:1) to obtain the target compound 2 (2.62 g, yield 70.0%) as a white solid. LC-MS:375[M+1] + ,749[2M+1] + ; 1 HNMR (400MHz, DMSO-d 6 )δ11.60(brs,1H),9.75(s,1H),8.38(d,J=6.0Hz,2H),7.41(d,J=8.4Hz,2H),7.15(d,J=5.6Hz, 2H), 7.08(d, J=8.8Hz, 2H), 5.75(t, J=6.8Hz, 1H), 5.62(t, J=6.8Hz, 1H), 3.84(s, 2H), 3.11(dd, J 1 =2.0Hz,J 2 =10.4Hz,1H),2.92-2.97(m,2H),2.88(dd,J 1 =2.0Hz,J 2 =10.4Hz,1H),0.92-2.93(m,2H),0.01-0.03(m,2H).

Embodiment 2TI17

[0043] Example 2 Molecular docking of TI17 and TRIP13

[0044] 1. Method

[0045] The C. elegans TRIP13 crystal structure (PDB number: 4XGU) was downloaded from the protein crystal structure database PDB, and used as a template to obtain the three-dimensional structure of human TRIP13 protein by homology modeling (Schrodinger2010). Then the compound small molecule TI17 was docked onto TRIP13 (Glide5.6, docking accuracy: XP).

[0046] 2. Results

[0047] see results figure 1 .

[0048] Conclusion: TI17 is well docked with TRIP13 protein, and it is a compound targeting TRIP13 gene.

Embodiment 3TI17

[0049] TRIP13 protein inhibitory activity of embodiment 3TI17

[0050] 1. Experimental materials

[0051] (1) Main reagents: TI17 (synthesized according to the method of Example 1); TRIP13 protein (synthesized by Shanghai Institute of Materia Medica, Chinese Academy of Sciences).

[0052] (2) Main instrument: Bruker AvanceⅢ-600 nuclear magnetic resonance wave spectrum instrument.

[0053] 2. Experimental method

[0054] (1) Sample preparation: the sample was dissolved in phosphate buffer (20mMNaPO 4 , 100 mM NaCl, 2% DMSO), DMSO was used as an internal reference.

[0055] (2) NMR tube positioning.

[0056] (3) On-machine operation: the sampling temperature is 25°C.

[0057] 3. Experimental results

[0058] figure 2 In 200μM TI17 solution alone, NMR Pop is red, when the molar ratio of TI17 and TRIP13 protein is 40:1, Pop is green, when the molar ratio is 20:1, Pop is blue-green, and the molar ratio is 10: At 1 o'clock, Pope is blue. This figure shows that the binding ...

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Abstract

The invention provides an anti-tumor compound, and the structural formula of the anti-tumor compound is as followed (please see the structural formula in the description). The invention further provides a preparation method of the compound, and the method has the advantages of being simple in step and high in yield. According to the compound, proliferation of tumor cells can be inhibited through targeted thyroid hormone receptor interaction 13 genes or proteins, the purpose of preventing and treating tumors is achieved, and experiments prove that the compound can be used for preventing and treating the tumors such as multiple myeloma and lymphoma. Due to the fact that the compound is a small-molecule targeted compound, compared with an untargeted drug, the compound is better in effect and fewer in side effect and has the good application prospect in the cancer field.

Description

technical field [0001] The present invention relates to the technical field of pharmaceutical compounds, in particular to the small molecule compound 7-((4-(pyridine-4-methylene)benzene Base) carbamoyl) tricyclo[3.2.2.0 2,4 ]non-8-ene-6-carboxylic acid (7-((4-(pyridin-4-ylmethyl)phenyl)carbamoyl)tricyclo[3.2.2.0 2,4 ]non-8-ene-6-carboxylic acid, TI17) and the application of TI17 in the preparation of drugs targeting the TRIP13 gene or protein, especially the application of TI17 in the preparation of anti-tumor drugs targeting the TRIP13 gene or protein. Background technique [0002] Multiple myeloma is a malignant monoclonal plasma cell disease common in middle-aged and elderly people, accounting for about 10% of hematological malignancies, ranking second in hematological malignancies, and its median survival time is 5-6 years. The main methods of traditional treatment of multiple myeloma are chemotherapy and hematopoietic stem cell transplantation, and its clinical effica...

Claims

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Application Information

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IPC IPC(8): C07D213/40A61K31/4409A61P35/00
CPCC07D213/40
Inventor 施菊妹朱维良杨洸徐志建陶怡李波吴慧群张勇
Owner SHANGHAI TENTH PEOPLES HOSPITAL
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