Novel protein kinase inhibitor, preparation method and application thereof

A protein kinase inhibitor, a new technology, used in organic chemistry, anti-tumor drugs, drug combinations, etc., can solve the problems of weak effect, underdevelopment, acquired drug resistance and other problems

Active Publication Date: 2021-02-02
XUZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, current research on many therapies is limited by acquired drug resistance
In addition, serine-threonine-protein kinase is critical for the activation of multiple survival signaling pathways, and its catalytic activity is increased in various types of tumors, including renal cancer, where serine-threonine-protein kinase CK2 inhibitors are underdeveloped in RCC
[0003]The CK2 inhibitor Ellagic acid with dicoumarin structure has strong inhibitory activity on CK2, IC50=0.04 μM, crystal structure analysis shows that the coumarin structure of ellagic acid occupies the interior of the cavity, and the 3-hydroxyl passes through and forms a hydrogen bond with K68 in the positive region, which is the key to the inhibitory activity of CK2 kinase. In addition, ellagic acid has a certain inhibitory effect on kidney cancer cells Inhibitory activity, but weak (IC50=38.6±2.3μM, ACHN)

Method used

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  • Novel protein kinase inhibitor, preparation method and application thereof
  • Novel protein kinase inhibitor, preparation method and application thereof
  • Novel protein kinase inhibitor, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] In view of the many types of protein kinase inhibitors prepared in the present invention, the applicant only lists one class of compounds, and other compounds can achieve the following technical effects. The compound of formula I-1 is a class of compounds of formula I, and its structural formula is as follows:

[0038]

[0039] The concrete steps of preparation formula Ⅰ-1 are as follows:

[0040]

[0041] I is a compound of XI, and II is a compound of formula II.

[0042] R 1 Represents hydrogen, halogen, nitro, methoxy, trifluoromethyl, methoxy, methyl;

[0043] R 2 represents a hydrocarbon group;

[0044] R 3 : hydroxyl, hydrogen.

[0045] The specific preparation method is: dissolve II (compound of formula II) (1 equivalent) in thionyl chloride (1.5mL, 20mmol), heat up to 80°C for 4h, concentrate to remove excess thionyl chloride, and dry with toluene , add I(XI compound) (1 equivalent), add triethylamine (1 equivalent), stir at room temperature for 48h,...

Embodiment 2

[0054] CCK8 method was used to determine the inhibitory effect of compounds on renal cancer cell line ACHN, breast cancer cell line MCF7, colorectal cancer cell line HCT116 and liver cancer cell line HepG2. Add 100 μL (about 5000 cells) of tumor cell suspension in logarithmic growth phase to each well of a 96-well plate, and culture the plate in an incubator for 24 hours (37°C, 5% CO 2 ), add 100 μL of the test compound with a concentration of 10 μmol / L to each well, incubate in the incubator for 72 hours or 96 hours, discard the liquid in the well, add 10 μL of CCK-8 solution to each well in the dark and incubate in the incubator for 0.5- After 4 hours, the absorbance was measured with a microplate reader at a wavelength of 450-570 nm, and the inhibitory rate of the test compound against each tumor cell at a single concentration (10 μmol / L) was calculated.

[0055] Table 1 Effect of 10μM compounds on tumor cell proliferation inhibition

[0056]

[0057]

[0058] Known ...

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PUM

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Abstract

The invention belongs to the technical field of medicinal chemistry. The invention discloses a novel protein kinase inhibitor, of which the structural formula is shown as a formula I, wherein, R1 represents hydroxyl, carboxyl, acylamino or hydrogen; R2 represents nitro, amino, acylamino, hydroxyl, sulfydryl, halogen or trifluoromethyl; R3 represents alkoxy or hydroxyl; ring A represents benzopyrone, 1H-benzo[d]imidazole, substituted hydroxyl 1H-benzo[d]imidazole, benzoxazole, 1H-pyrrolo[2, 3-b]pyridine, benzopyrrole, 2, 3-dihydrobenzo[b][1, 4]dioxin, or 1H-indazole; X represents an ester groupor an amide group; and ring B represents a benzene ring, a nitrogen-containing five-membered heterocyclic ring or a nitrogen-containing six-membered heterocyclic ring. According to the invention, a novel protein kinase inhibitor is obtained by utilizing a splicing principle, and an anti-tumor effect is achieved by inhibiting tumor cell proliferation and promoting tumor cell apoptosis.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, and more specifically relates to the preparation of a novel protein kinase inhibitor and its application in the field of antitumor medicine. Background technique [0002] Renal cell carcinoma (RCC) is refractory to conventional therapies including radiation and cytokine therapy. The use of molecularly targeted therapies against mTOR, VEGF and other angiogenic factors has significantly improved the treatment of this disease. However, research into many current therapies is limited by acquired drug resistance. In addition, serine-threonine-protein kinase is critical for the activation of multiple survival signaling pathways, and its catalytic activity is continuously enhanced in various types of tumors, including renal cancer, where serine-threonine-protein kinase The use of CK2 inhibitors in RCC has not been developed. [0003] The CK2 inhibitor ellagic acid (Ellagic acid) with a di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/12C07D311/16A61K31/37A61P35/00
CPCC07D311/12C07D311/16A61P35/00
Inventor 牟杰李龙宝周婷杨瑞聪项睿裴冬生
Owner XUZHOU MEDICAL UNIV
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