Application of N-(thiofuran-2) pyrazolo (1, 5-a) pyridine-3-formanides compounds for preparing antineoplastic

A technology of carboxamides and compounds is applied in the research field of anti-tumor drugs, which can solve the problems of few reports and restricting anti-tumor drugs, etc.

Inactive Publication Date: 2009-09-23
INST OF HEMATOLOGY & BLOOD DISEASES HOSPITAL CHINESE ACADEMY OF MEDICAL SCI & PEKING UNION MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, there are few reports on the research results of specific inhibitors of the new target CDK9
The reason is that, in addition to the relatively new target of CDK9, and the previous research on it focused on AIDS treatment, another important reason is that there is no crystal structure of CDK9, which greatly restricts the use of CDK9 as a target to develop Development of Anticancer Drugs

Method used

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  • Application of N-(thiofuran-2) pyrazolo (1, 5-a) pyridine-3-formanides compounds for preparing antineoplastic
  • Application of N-(thiofuran-2) pyrazolo (1, 5-a) pyridine-3-formanides compounds for preparing antineoplastic
  • Application of N-(thiofuran-2) pyrazolo (1, 5-a) pyridine-3-formanides compounds for preparing antineoplastic

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Embodiment 1: MMT detects the inhibitory effect of compound on tumor cells

[0041] The proliferation inhibitory activity of each compound on tumor cell lines was determined by conventional MTT method. H1299 cells in the logarithmic growth phase were used for preliminary activity experiments, and the cell concentration was adjusted to 1×10 with RPMI1640 culture medium containing 10% serum. 5 / ml, inoculated in a 96-well culture plate, 100 μl per well, and cultured for 24 hours at 37°C and 5% CO2. Add drugs in groups, set three parallel wells for each concentration, add different concentrations of drugs to the treatment group, and add equal volume of PBS to the negative control group, after 48 hours of incubation, add 20 μl of 5 mg / ml MTT to each well, and continue to incubate at 37°C for 4 hours Discard the supernatant, add 150 μl DMSO to each well, shake until the precipitate is completely dissolved, and measure the optical density (OD) value at 570 nm on a microplate...

Embodiment 2

[0050] Example 2: Inhibition experiment of C-21 on the kinase action of CDK9

[0051] In this study, compound C-21 (a specific substituted derivative of N-(thiophene-2)pyrazolo[1,5-a]pyrimidine-3-carboxamide) with the highest inhibitory activity was selected for further molecular mechanism research .

[0052] H1299 cells in the logarithmic growth phase were taken, operated according to the instructions of RIPA cell lysate, and then subjected to ultrasound to obtain fresh cell lysate, which was quantified by BCA kit. Adjust the concentration of cell lysate and CTD protein solution to an appropriate level, add different concentrations of drug C-21, shake and mix (a certain amount of ATP solution can be added at the same time), react at 37°C for 4 hours, and take an appropriate amount for 10% SDS-PAGE electrophoresis. After the electrophoresis is completed, according to the gel area, press 0.65mA / cm 2 Turn on the power, and electrotransfer for 3 hours. After the transfer, the ...

Embodiment 3

[0054] Example 3: Binding mode of compound C-21 and CDK9 crystal structure

[0055] According to the known amino acid sequence of CDK9, on the SGI graphics workstation, the homology modeling (MODELLER / HOMOLOGY) module of the software Insight II was used to carry out the homology modeling of the three-dimensional structure of CDK9. The main steps are as follows: use the primary sequence of CDK9 as a probe, use the BlastP program to search for homologous proteins in the PDB library, and select homologous proteins with high homology and known protein types as templates. Superimposed with homologous proteins, the SCR (structurally conserved region) and LOOP regions were determined. Align the modeled protein and homologous protein sequences, the sequence that can match the SCR region of the homologous protein is the SCR region of the modeled protein, and then assign the spatial coordinates of the SCR region of the modeled protein, and then use the Modeler software package to query ...

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Abstract

The invention searches the novel micromolecule inhibitor pyrazolo (1, 5-a) miazines compounds of cyclin-dependent kinase CDK9 (cyclin-dependent kinase) through the virtual screening of a computer, biometrically measures activity thereof, and validates interaction mechanism. The invention specifically comprises the following steps: the three-dimensional crystal conformation of the cyclin-dependent kinase family member CDK9 is obtained in a way of homology modeling; and micromolecule three-dimensional database is screened with DOCK (molecular docking). The invention uses a MTT tumor cell growth inhibition test to biometrically measures the activity of the selected compounds, researches the selected compounds pyrazolo (1, 5-a) miazines with high activety in a way of molecular mechanism, validates the inhibiting effect of the compounds to the activity of CDK9 kinase, and clarifies the interaction mechanism of the compounds for inhibiting the external activity and the molecule of various malignancies such as lung cancer, osteosarcoma, oophoroma, cervical carcinoma, breast cancer, etc.

Description

technical field [0001] The invention relates to the application of an anti-malignant tumor compound and belongs to the research field of anti-tumor drugs. Specifically, the present invention relates to a kind of N-(thiophene-2)pyrazolo[1,5-a]pyrimidine-3-carboxamide compound and its substitution in inhibiting lung cancer, osteosarcoma, ovarian cancer, cervical cancer , breast cancer and other malignant tumors. Background technique [0002] Malignant tumors are a large class of diseases that seriously threaten human health. The main cause of their formation is the abnormal proliferation of cells caused by mutations at the level of cell genes. The proliferation and division of eukaryotic cells is a precise and complex regulatory process. The proliferation process is completed through the cell cycle, and the orderly progress of the cell cycle has its strict molecular regulation mechanism. With the development of molecular biology, these complex regulatory molecules and their...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519C07D487/04C40B30/06A61P35/00
Inventor 杨纯正高瀛岱熊冬生纪庆秦立苏晔周园刘娟妮周圆张永慈杨铭
Owner INST OF HEMATOLOGY & BLOOD DISEASES HOSPITAL CHINESE ACADEMY OF MEDICAL SCI & PEKING UNION MEDICAL COLLEGE
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