Application of imidazoquinazoline derivatives and salts thereof in preparation of PIM1 enzyme inhibitor, PIM1 enzyme inhibitor and application of PIM1 enzyme inhibitor

A technology of azoquinazolines and derivatives, which is applied in the fields of medicinal chemistry and pharmacotherapeutics, and can solve the problems of easy recurrence, poor chemotherapy sensitivity of myeloma, and difficult clinical treatment of myeloma.

Active Publication Date: 2020-04-24
XUZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Refractory / relapsed myeloma has extremely poor sensitivity to chemotherapy and is prone to relapse, which is a difficult problem in the clinical treatment of myeloma

Method used

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  • Application of imidazoquinazoline derivatives and salts thereof in preparation of PIM1 enzyme inhibitor, PIM1 enzyme inhibitor and application of PIM1 enzyme inhibitor
  • Application of imidazoquinazoline derivatives and salts thereof in preparation of PIM1 enzyme inhibitor, PIM1 enzyme inhibitor and application of PIM1 enzyme inhibitor
  • Application of imidazoquinazoline derivatives and salts thereof in preparation of PIM1 enzyme inhibitor, PIM1 enzyme inhibitor and application of PIM1 enzyme inhibitor

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Compounds 1-10 provided by the present invention having the structure represented by formula I were subjected to cell viability experiments.

[0055] Experimental principle: using the commercialized CCK8 kit, the reagent contains WST-8, which is decomposed under the action of the electron carrier 1-methoxy-5-methylphenazinium dimethyl sulfate (1-Methoxy PMS). The dehydrogenase in the cell is reduced to a highly water-soluble yellow formazan product (Formazan dye). The amount of formazan produced is directly proportional to the number of living cells. Therefore, this property can be used directly for cell proliferation and toxicity assays.

[0056] Experimental steps:

[0057] 1. Plating: Experimental group: Inoculate U266 or RPMI-8226 myeloma cells in the logarithmic growth phase in a 96-well plate, inoculate 100 μL of U266 or RPMI-8226 cell suspension in each well, and the number of cells is 1×10 4 / well; the blank control group (Control) only added 100 μL of RPMI-1...

Embodiment 2

[0065] The compounds 1-10 provided by the present invention having the structure represented by formula I were subjected to cell apoptosis detection research.

[0066] Experimental principle: In normal cells, phosphatidylserine (PS) is only distributed on the inner side of the lipid bilayer of the cell membrane, but in the early stage of apoptosis, the phosphatidylserine (PS) in the cell membrane is turned from the inner side of the lipid membrane to the outer side. Annexin V is Ca with a molecular weight of 35-36kD 2+ Phosphatidylserine-dependent phospholipid-binding protein has a high affinity with phosphatidylserine, so it can bind to the cell membrane of early apoptosis cells through the phosphatidylserine exposed on the outside of the cell. Therefore, Annexin V is used as one of the sensitive indicators for detecting early apoptosis of cells.

[0067] Experimental steps:

[0068] 1. Plating: Take RPMI-8226 cells grown in the logarithmic phase, with 1×10 6 Inoculate a s...

Embodiment 3

[0075] Compounds 1-10 provided by the present invention were studied by western blot experiment.

[0076] Experimental principle: stain the cells or biological tissue samples treated by gel electrophoresis with specific antibodies. Information about the expression of specific proteins in the analyzed cells or tissues can be obtained by analyzing the location and depth of staining.

[0077] Experimental steps:

[0078] 1. Prepare polyacrylamide gel electrophoresis (SDS-PAGE) gel, plate and collect cell suspension (cell suspension treated with compounds 1-10 respectively), wash twice with PBS 1000rpm, centrifuge for 5min, according to RPMI-8226 cell Add different volumes of RIPA (radioimmunoprecipitation) lysate, lysate at least 30 μL, lyse on ice for 2 min, vortex for 1 min, alternately for 40 min, centrifuge at 4 °C, 5000 rpm for 15 min, collect the supernatant, add etc. Volume 2×SDS loading buffer, boiled for 10min, and stored at -20°C; the blank control group (Control) onl...

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Abstract

The invention belongs to the technical field of medicinal chemistry and pharmacotherapeutics, and particularly relates to application of imidazoquinazoline derivatives and salts thereof in the preparation of a PIM1 enzyme inhibitor, the PIM1 enzyme inhibitor and an application of the PIM1 enzyme inhibitor. The imidazoquinazoline derivatives have obvious inhibitory activity on PIM1 enzyme, can be applied to the preparation of the PIM1 enzyme inhibitor, and further can be applied to the preparation of a multiple myeloma cell proliferation inhibitor and an anti-multiple myeloma drug.

Description

technical field [0001] The invention relates to the technical fields of medicinal chemistry and pharmacotherapeutics, in particular to the application of imidazoquinazoline derivatives and salts thereof for preparing PIM1 enzyme inhibitors, PIM1 enzyme inhibitors and applications thereof. Background technique [0002] Multiple myeloma (Multiple Myeloma) is a type of plasma cell clonal disease, mainly in middle-aged and elderly people, which can lead to hypercalcemia, anemia, renal function damage, bone destruction and other symptoms, and it is still difficult to cure. According to relevant statistics, myeloma accounts for about 1% of all cancers and 10% of hematological malignancies. Although there have been some achievements in the treatment of myeloma, the current situation of myeloma treatment and its prognosis have been greatly improved through reasonable comprehensive treatment. But there are still many obstacles to fully treating myeloma. For example, myeloma patient...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61P35/00
CPCA61K31/519A61P35/00
Inventor 姚若斯高剑
Owner XUZHOU MEDICAL UNIV
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