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N-substituted-tetrahydropyridylindole-monoclonal antibody CD14 conjugates, and preparation method and application thereof

A technology of tetrahydropyridine indole and tetrahydropyridine indole, applied in the field of chemical and biological medicine

Inactive Publication Date: 2013-01-30
SHANGHAI NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

To a certain extent, the application of this type of compound in the treatment of leukemia drugs is limited

Method used

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  • N-substituted-tetrahydropyridylindole-monoclonal antibody CD14 conjugates, and preparation method and application thereof
  • N-substituted-tetrahydropyridylindole-monoclonal antibody CD14 conjugates, and preparation method and application thereof
  • N-substituted-tetrahydropyridylindole-monoclonal antibody CD14 conjugates, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: the preparation method of conjugate (IIa)~(IIr)

[0049] For the preparation methods of compounds (Ia)~(Ij), please refer to related patents: patent application number: 201110224878.x, publication number: CN102276581A.

[0050] For the preparation methods of compounds (Ik)~(Ir), see Example 2~Example 9 of this patent specification.

[0051] Take 10 mg of compounds (Ia)~(Ir), dissolve them in 0.1 mL DMSO respectively, add 0.1 mL of DCC solution with a concentration of 0.1 mol / L, and 0.1 mL of CD14 with a concentration of 2 μg / mL to the above solutions, and then use Physiological saline was used to dilute the above mixed solution to 1 mL. After reacting at 37°C for 30 minutes, the conjugates (Ⅱa)~(Ⅱr) were obtained.

[0052] The killing effects of the conjugates (Ⅱa)~(Ⅱr) on leukemia K562 cells were measured by MTT method, and multiple groups of control groups were established at the same time. The control group included: blank group, CD14+DMSO+DCC, CD14,...

Embodiment 2

[0053] Example 2: Preparation method of 3-[N-(2-tetrahydrofurylmethyl)-1,2,3,6-tetrahydropyridin-4-yl]indole (Ik):

[0054] Add 0.005mol indole, 5mL methanol and 5mL sodium methoxide solution (30wt%CH 3 OH solution), under the condition of ice-water bath, stir and add the mixed solution of 0.01mol N-(2-tetrahydrofurylmethyl)-4-piperidone and 5mL methanol. After the dropwise addition, the mixture was stirred at room temperature for 20 min, and then heated to reflux at 63° C. for 5 h, a yellow solid was precipitated, and the reaction progress was tracked by thin-layer chromatography (TLC). After the reaction, the solid was washed with absolute ethanol and recrystallized with ethyl acetate to obtain 3-[N-(2-tetrahydrofuranmethyl)-1,2,3,6-tetrahydropyridin-4-yl]ind Indole (Ik).

[0055] Yield 54%; yellow solid; mp162-164℃; 1 H NMR (400MHz, DMSO-d 6 )δ11.08(s,1H),7.78(d,J=7.9Hz,1H),7.51-6.84(m,4H),6.08(d,J=3.4Hz,1H),4.13-3.86(m,1H ),3.85-3.50(m,2H),3.15(m,2H),2.68(m,2H);2.56-2...

Embodiment 3

[0056] Example 3: Preparation method of 3-[N-phenethyl-1,2,3,6-tetrahydropyridin-4-yl]indole (Il):

[0057] Add 0.005mol indole, 5mL methanol and 5mL sodium methoxide solution (30wt%CH 3 OH solution), and add a mixture of 0.01mol N-phenethyl-4-piperidone and 5mL methanol with stirring under ice-water bath conditions. After the dropwise addition, the mixture was stirred at room temperature for 20 min, and then heated to reflux at 63° C. for 6 h, a yellow solid was precipitated, and the reaction progress was tracked by thin layer chromatography (TLC). After the reaction, the solid was washed with absolute ethanol and recrystallized with ethyl acetate to obtain 3-(N-phenethyl-1,2,3,6-tetrahydropyridin-4-yl)indole (Il) .

[0058] Yield 64%; yellow solid; mp172-174℃; 1 H NMR (400MHz, DMSO-d 6 )δ11.18(s,1H),7.79(d,J=6.9Hz,1H),7.58-6.78(m,9H),6.13(d,J=2.4Hz,1H),3.53-3.46(m,4H ),3.25(m,2H),2.63(t,J=6.0Hz,2H);2.49(s,2H);IR(KBr):3072,2918,2876,1640,1613,1570,1485,1452,1436 ,1370,1...

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Abstract

The invention discloses N-substituted-tetrahydropyridylindole-monoclonal antibody CD14 conjugates, and a preparation method and application thereof, belonging to the field of chemical biomedicine. The structure of the conjugates is disclosed as Formula (II): under the action of a condensing agent DCC, the amino acid residue at the C terminal in the CD14 monoclonal antibody molecule is combined with sec-amino group on the indole ring in N-substituted-tetrahydropyridylindole compounds (I) to obtain the monoclonal antibody CD14 conjugates with General Formula (II). The conjugates disclosed as Formula (II) can efficiently inhibit leukaemia K562 cell proliferation, and the IC50 value for inhibiting leukaemia K562 cell proliferation is obviously lower than that of the conventional chemotherapeutic drug 5-fluorouracil (5Fu); and the conjugates disclosed as Formula (II) have low toxicity for mouse normal marrow cells, and can be used for preparing drugs for treating leukaemia.

Description

technical field [0001] The present invention relates to a kind of N-substituted tetrahydropyridine indole-monoclonal antibody CD14 conjugate (abbreviated as CD14-TPI), the preparation method of the conjugate and the application as the lead compound of the medicine for treating leukemia. Belonging to the field of chemical biopharmaceuticals, Background technique [0002] Leukemia is one of the diseases with the highest mortality rate in the world today, and it has caused extremely serious harm to human health. According to the epidemiological statistics released by China, the incidence of leukemia in various regions of my country ranks sixth among all kinds of tumors. At present, there are at least 4 million leukemia patients, and about 40,000 new cases are added every year. In recent years, due to the pollution caused by interior decoration, the number of patients with blood diseases has increased dramatically. Leukemia is a kind of malignant disease of hematopoietic cells...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61K31/437A61K31/4375A61K47/48A61P35/02A61K47/68
Inventor 孙传文肖笛李静薛思佳李兴玉
Owner SHANGHAI NORMAL UNIVERSITY
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