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2-cyano phenalenone compound and application thereof in treatment of leukemia

A technology of cyanophenadenone and compounds, applied in the field of 2-cyanophenadenone compounds and their application in the treatment of leukemia, capable of solving problems such as interference and killing tumor cells

Active Publication Date: 2021-05-28
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, designing small molecules to simulate Bim protein, competing for binding to the binding region of Hsp70 protein surface and Bim to generate PPI, so as to interfere with the PPI of Hsp70 / Bim and kill tumor cells has not been reported yet.

Method used

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  • 2-cyano phenalenone compound and application thereof in treatment of leukemia
  • 2-cyano phenalenone compound and application thereof in treatment of leukemia
  • 2-cyano phenalenone compound and application thereof in treatment of leukemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Preparation of 6-cyclohexylsulfanyl-2,3-dicyano-phenadenone (compound 1)

[0051]

[0052] (1) Synthesis of Intermediate A1

[0053] Take 920mg (4.0mmol) of 2,3-dicyanophenadenone and 1162mg (10mmol) of cyclohexanethiol respectively, add 100mL of acetonitrile, react at room temperature for 6h, and remove the solvent by rotary evaporation. The obtained solid was separated by silica gel column chromatography, and the developing solvent was CH 2 Cl 2 :CH 3 OH=100:1 (v / v), the intermediate A1 was obtained as a red solid with a yield of 25%.

[0054] (2) Synthesis of compound 1

[0055] 172 mg (0.5 mmol) of intermediate A1 and 3-amino-1-propanol (10 mmol) were dissolved in 30 mL of acetonitrile, reacted at room temperature for 3 h, and the solvent was removed by rotary evaporation. The obtained solid was separated by silica gel column chromatography, and the developing solvent was CH 2 Cl 2 :CH 3 OH=100:1 (v / v), the compound 1 was obtained as a yellow s...

Embodiment 2

[0057] Embodiment 2: the preparation of compound 2-27

[0058] Similar to Example 1, compound 2-27 was synthesized. Wherein the yield and characterization data of compound 2-27 are as follows:

[0059] Compound 2: Yield 14%. 1 H-NMR (500MHz,D 6 -DMSO): δ8.67(d, J=8.4Hz, 1H), 8.46(t, J=8.4Hz, 1H), 8.02(t, J=8.4Hz, 1H), 7.75(t, J=8.4Hz ,1H),7.68(t,J=8.4Hz,1H),3.73(t,J=6.4Hz,2H),3.62(s,3H),2.61(t,J=6.4Hz,2H),2.84(m ,J=4.4Hz,1H),1.98(d,J=4.4Hz,2H),1.87(d,J=4.4Hz,2H),1.73(d,J=4.4Hz,2H),1.65(t,J =4.4Hz, 2H), 1.43(d, J=4.4Hz, 2H).ESI-MS: (C 24 h 24 N 2o 3 S[M+H] + ): 421.16.

[0060] Compound 3: The yield is 22%. 1 H-NMR (500MHz,D 6 -DMSO): δ8.67(d, J=8.4Hz, 1H), 8.46(t, J=8.4Hz, 1H), 8.02(t, J=8.4Hz, 1H), 7.75(t, J=8.4Hz ,1H),7.68(t,J=8.4Hz,1H),3.73(t,J=6.4Hz,2H),3.55(t,J=4.2Hz,4H),2.61(t,J=6.4Hz,2H ), 2.84(m, J=4.4Hz, 1H), 2.47(t, J=4.2Hz, 4H), 1.98(d, J=4.4Hz, 2H), 1.87(d, J=4.4Hz, 2H), 1.73(d, J=4.4Hz, 2H), 1.65(t, J=4.4Hz, 2H), 1.43(d, J=4.4Hz, 2H); 13 C-NMR (125...

Embodiment 3

[0085] Embodiment 3: the preparation of compound 28

[0086]

[0087] 42 mg (0.1 mmol) of compound 2 was dissolved in 20 mL of methanol, and 2 mL of 10 mM NaOH aqueous solution was added dropwise at 0°C with stirring, and reacted at room temperature for 12 h. 50 mL of deionized water was added to the reaction solution, and the pH was adjusted to 2 with 1M hydrochloric acid to generate a yellow solid. After suction filtration, the resulting solid was rinsed three times with methanol (5 mL) at 0° C. to obtain compound 28 as a yellow solid with a yield of 91%.

[0088] Compound 28 1 H NMR measurement result and mass spectrometry result are as follows: 1 H-NMR (500MHz,D 6 -DMSO): δ8.64(d, J=8.0Hz, 1H), 8.46(t, J=8.0Hz, 1H), 8.00(t, J=8.0Hz, 1H), 7.72(t, J=8.0Hz ,1H),7.64(t,J=8.0Hz,1H),6.46(s,1H),4.37(t,J=6.4Hz,2H),2.85(m,J=4.0Hz,1H),2.76(t ,J=6.4Hz,2H),2.01(d,J=4.0Hz,2H),1.87(d,J=4.0Hz,2H),1.74(m,J=4.0Hz,2H),1.68(d,J =4.0Hz, 2H), 1.44(d, J=4.0Hz, 2H); ESI-MS (C 23 h 23 ...

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Abstract

The invention provides a 2-cyano phenalenone compound and application thereof, which belong to the technical field of medical chemistry. The compound is obtained by carrying out compound modification on the 6-site and the 3-site of 2, 3-dicyanophenalenone (namely, respectively introducing R1 and R2). The 2-cyano phenalenone compound disclosed by the invention can be combined with Hsp70 protein in vitro, in cells and in an animal model, and competitively dissociates an Hsp70 / Bim protein dimer, so that the apoptosis of chronic granulocytic leukemia cells is induced, and the effects of inhibiting the growth of the chronic granulocytic leukemia cells and killing the chronic granulocytic leukemia cells are achieved; the compound is an apoptosis inducer with very high activity, and can be used for preparing a potential medicine for treating or preventing chronic granulocytic leukemia.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a class of 2-cyanophenadenone compounds, in particular to 6-cyclohexylthio-2-cyanophenadenones and derivatives thereof, specifically to the use of these compounds in Dissociation of heat shock protein Hsp70 and Bim protein dimer in vitro, in living cells and in vivo can specifically induce apoptosis of chronic myelogenous leukemia cells, and can be used as a therapeutic drug for chronic myelogenous leukemia. Background technique [0002] Chronic myeloid leukemia (CML) is a malignant myeloproliferative disease characterized by the formation of fusion gene BCR-ABL. It is characterized by the production of a large number of immature white blood cells, which accumulate in the bone marrow and inhibit the normal hematopoiesis of the bone marrow; and can spread throughout the body through the blood, leading to anemia, easy bleeding, infection and organ infiltration in patients...

Claims

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Application Information

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IPC IPC(8): C07C323/63C07D295/13C07D213/38C07D307/52C07C319/20A61K31/277A61K31/5375A61K31/495A61K31/5377A61K31/4409A61K31/341A61P35/02
CPCC07C323/63C07D295/13C07D213/38C07D307/52A61K31/4409A61K31/341A61P35/02C07C2601/14C07C2601/08
Inventor 张志超王紫千宋婷
Owner DALIAN UNIV OF TECH
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