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Application of scutellarin biotin-labeled probe and related PKM2 kinase inhibitor

A biotin-labeled, scutellarin aglycone technology, which can be used in drug combination, bulk chemical production, organic chemistry, etc., can solve the problem of low activity of inhibiting PKM2

Active Publication Date: 2017-10-20
GUIZHOU MEDICAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Therefore, the purpose of the present invention is to provide the preparation method and application of using scutellarin aglycon as a lead compound to react with WR reagent and Lawson's reagent to form scutellarin aglycon derivatives, which can solve the problem of inhibiting PKM2 activity existing in the prior art. high, and the scutellarin aglycon derivatives prepared by the present invention are water-soluble, and are good for growth inhibition of various tumor cells such as human osteosarcoma Saos-2 cells, and can be applied to the preparation of drugs for preventing or treating tumors

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  • Application of scutellarin biotin-labeled probe and related PKM2 kinase inhibitor
  • Application of scutellarin biotin-labeled probe and related PKM2 kinase inhibitor
  • Application of scutellarin biotin-labeled probe and related PKM2 kinase inhibitor

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preparation example Construction

[0037] Preparation principle of scutellarin biotin-labeled probe: After the hydrogen atoms on the hydroxyl groups of scutellarin aglycone 5, 6, 7, and 4' are protected by dibenzocarbone, scutellarin aglycone is directly or indirectly combined with biotin connected, and finally the protective group was removed under the action of TFA to obtain two different scutellarin biotin-labeled probes. Such as figure 1 and figure 2 shown.

[0038] Preparation principle of scutellarin aglycon derivatives: After the hydrogen atoms on the hydroxyl groups of scutellarin aglycone 5, 6, 7, and 4' are replaced by methyl groups, the oxygen at the 3-position is replaced by Lawson's reagent and WR reagent respectively For intermediates containing sulfur and selenium, finally in BBr 3 Under the action of removing the protecting group methyl, two derivatives different from scutellarin aglycone are obtained. Such as image 3 shown.

Embodiment 1

[0041] Preparation of ketal protected scutellarin aglycone (2):

[0042]

[0043] Take the dried scutellarin aglycone (1) (0.5g, 1.75mmol) and place it in a dry 100mL two-necked bottle, add 10mL DME to dissolve it, add DMAP (0.25g, 1.75mmol), add dichlorodimethoxylate under stirring at room temperature Benzene methane (0.5mL, 1.75mmol) was reacted at 180°C under reflux for 2h, the reaction was complete as monitored by TLC, the solvent was removed by rotary evaporation under reduced pressure, and the residue was separated on silica gel to obtain light brown powdery solid (2), 0.34g, The yield is 62%. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 7.92 (d, J = 8.8Hz, 2H), 7.56-7.53 (m, 4H), 7.46-7.44 (m, 6H), 7.04 (s, 1H ),6.90(d,J=8.8Hz,2H),6.83(s,1H).EI-MS(m / z)[M+H] + 451.11.

[0044] Preparation of scutellarin aglycon-4'-biotin (3):

[0045]

[0046] Take the ketal-protected scutellarin aglycon (2) (0.4g, 0.89mmol) in a 100mL eggplant-shaped bottle, add DMAP (0.054g, 0.44mmol) ...

Embodiment 2

[0066] The scutellarin aglycon derivatives are self-prepared in the present invention, and the preparation method is as follows:

[0067] Preparation of compound SC2:

[0068]

[0069] Take scutellarin aglycone (1g, 3.49mml) and K 2 CO 3 (2.41g, 17.47mml) in 15mL acetone solution, oil bath to reflux, slowly add 1.3mL dropwise, after addition, reflux reaction for 2h, TLC monitors that the reaction is complete, extract with ethyl acetate (300mL×2), and the organic layer is water (300mL×2) washing, anhydrous MgSO 4 After drying, ethyl acetate was recovered under reduced pressure to dryness, and silica gel column chromatography gave light yellow powdery solid SC2 (0.96 g), with a yield of 85%. 1 H-NMR (400MHz, DMSO-d6) δ (ppm): 7.92 (d, J = 8.8Hz, 2H), 6.90 (d, J = 8.8Hz, 2H), 6.83 (s.1H), 6.30 (s. 1H),3.95(s.12H).EI-MS(m / z)[M+H] + 343.34.

[0070] Preparation of compound SC3:

[0071]

[0072] Take compound SC2 (0.5g, 1.46mml) and Lowe's reagent (0.59g, 1.46mml) in 1...

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Abstract

The invention discloses application of a scutellarin biotin-labeled probe and a related PKM2 kinase inhibitor. The PKM2 kinase inhibitor is characterized in that a target of an active group is found by the scutellarin biotin-labeled probe; a scutellarin aglycone derivative is prepared by the found target protein; then, the scutellarin aglycone derivative is applied to a tumor treating medicine preparation.

Description

technical field [0001] The present invention relates to the field of medical technology, in particular to the preparation and use of scutellarin aglycone biotin-labeled probes, scutellarin aglycone and its derivatives that can be used as PKM2 kinase inhibitors, and pharmaceutical compositions containing the compound, It relates to the preparation method of the compound and the application of the compound in the preparation of M2-type pyruvate kinase inhibitors, and relates to the application of the compound in the treatment of diseases such as PKM2 overexpression cancer. Background technique [0002] Targeted therapy is a treatment that uses specific genes or gene expression products that can be expressed by tumor cells but rarely or not expressed by normal cells to form relative or absolute targeting to kill tumor cells to the greatest extent while causing little damage to normal cells method. At present, more and more researchers are turning their attention to natural pro...

Claims

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Application Information

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IPC IPC(8): C07D495/04A61P35/00
CPCY02P20/55C07D495/04
Inventor 何彬尤玲李燕杜宇王春王芳黄文斐
Owner GUIZHOU MEDICAL UNIV
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