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Tetrahydropyridinopyran-monoclonal antibody CD14 conjugate with anti-tumor activity and preparation method and use thereof

A technology of monoclonal antibody and anti-tumor activity, which is applied in the field of the lead compound of monoclonal antibody drug, tetrahydropyridopyran-monoclonal antibody CD14 conjugate, which can solve the problems of low selectivity and toxicity, and achieve toxic and side effects Minimal, low acute toxicity effects

Inactive Publication Date: 2014-12-31
SHANGHAI NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the selectivity of tetrahydropyridopyran derivative TPP is not high, and it has certain toxicity to normal cells, which limits their application in anticancer drugs to a certain extent.

Method used

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  • Tetrahydropyridinopyran-monoclonal antibody CD14 conjugate with anti-tumor activity and preparation method and use thereof
  • Tetrahydropyridinopyran-monoclonal antibody CD14 conjugate with anti-tumor activity and preparation method and use thereof
  • Tetrahydropyridinopyran-monoclonal antibody CD14 conjugate with anti-tumor activity and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Preparation of Conjugates (IIa)~(IIh)

[0040] For the preparation methods of compounds (Ia)~(Ih), please refer to the patent with publication number: CN102285993A.

[0041] Take 10 mg of compounds (Ia)~(Ih), 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)~(Ⅱh) were obtained.

[0042] The killing effects of the compound of formula (I) and the conjugate of formula (II) on human leukemia K562 cell line were determined by MTT method; The lethal effect, and set up multiple control groups at the same time. The control group included: blank group, CD14+DMSO+DCC, CD14, compound (Ia)~(Ih), CD14+compound (Ia)~(Ih).

Embodiment 2

[0043] Example 2: Conjugates (IIa)~(IIh) and compounds (Ia)~(Ih) inhibit human leukemia K562 cell line, and conjugates (IIa)~(IIh) inhibit ovarian cancer MDR-MB-231 cell line and liver cancer IC of proliferation of SMMC-7721 cell line 50 the test

[0044] 1. Test reagents and equipment

[0045] Experimental drugs and reagents: self-made compounds (Ⅰa)~(Ⅰh) and conjugates (Ⅱa)~(Ⅱh), dissolved in DMSO, added distilled water to the required concentration (DMSO concentration ≤ 1‰), sterilized and stored at 4°C. MTT (tetramethylazolazolium blue) reagent was purchased from Sigma. Human leukemia cells K562 ovarian cancer MDR-MB-231 cell line and liver cancer SMMC-7721 cell line were purchased from Shanghai Chinese Academy of Sciences Cell Bank. 10% SDS reagent (Sino-American Biotechnology product), RPMI-1640 (GiBCo, USA) culture medium containing 20% ​​fetal bovine serum (FBS) was used, and other reagents were commercially available analytically pure. At 37°C, 5% CO 2 Subculture...

example 3

[0058] Example 3 Compounds (Ia)~(Ih) and conjugates (IIa)~(IIh) inhibit the proliferation of mouse normal bone marrow cells IC 50 the test

[0059] 1. Test method (colony counting method)

[0060] The mice were sacrificed by vertebral dislocation, the femur was taken out under aseptic conditions, and the bone marrow cells were washed out with TMEM to make a single cell suspension, and 10 6 Mouse bone marrow cells were planted in 2ml Endo M culture system containing 20% ​​fetal bovine serum, placed in a 6-well plate, and drug treatment groups were set up for compound (Ⅰa)~(Ⅰh), conjugates (Ⅱa)~(Ⅱh) and negative control group (DMSO), at 37°C, 5% CO 2 1. Count after 3 days of culture in saturated humidity, take the aggregation of ≥50 cells as a colony, record the number of colonies in each well, and use EXCEL as a trend line to calculate the IC 50 value.

[0061] 2. Outcome Survey

[0062] The ICs of compounds (Ia)~(Ih) and conjugates (IIa)~(IIh) inhibiting the proliferation...

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Abstract

The invention discloses tetrahydropyridinopyran-monoclonal antibody CD14 conjugates with anti-tumor activity and a preparation method and use thereof. The structure of the conjugate is represented by a formula (II). Under the action of dicyclohexylcarbodiimide (DCC) serving as a condensing agent, an amino acid residue on the carbon terminal of a CD14 monoclonal molecule is bonded with an amino on a pyran ring in a tetrahydropyridinopyran derivative to form a monoclonal antibody conjugate CD14-TPP of the formula (II). CD14-TPP can effectively inhibit the proliferation of a human erythroleukemia cell line K562, an ovarian cancer cell line MDR-MB-231 and a liver cancer cell line SMMC-7721 with an IC50 value much lower than 5-fluorouracil (5Fu) which is a conventional chemotherapy medicine. The conjugate of the formula (II) with low toxic effect on normal bone narrow cells of mouse can be used for preparing medicines for treating leukemia, ovarian cancer and liver cancer.

Description

technical field [0001] The present invention relates to a tetrahydropyridopyran-monoclonal antibody CD14 conjugate with anti-tumor activity and its preparation method and application; specifically, it relates to a kind of compound capable of efficiently inhibiting human leukemia K562 cell line and ovarian cancer MDR-MB-231 cell line Preparation of the conjugate of tetrahydropyridopyran and monoclonal antibody CD14 (code name: CD14-TPP) proliferating from liver cancer SMMC-7721 cell line, and as the lead compound of monoclonal antibody drugs for the treatment of leukemia, ovarian cancer and liver cancer . It belongs to the field of chemical biological medicine. Background technique [0002] Leukemia, ovarian cancer, and liver cancer are three common malignant tumors with high incidence rates. However, there is no ideal and efficient drug for the above-mentioned cancers in the prior art. [0003] Leukemia is a clonal disease of hematopoietic stem cells. Occurs more frequent...

Claims

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Application Information

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