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Indirubin derivative and application of indirubin derivative used as dual-target inhibitor of CDK/HDAC

A derivative, indirubin technology, is applied to indirubin derivatives and its application field as a DK/HDAC dual target inhibitor, and achieves the effects of low cost, cheap synthetic raw materials, and obvious anti-tumor activity

Active Publication Date: 2019-12-20
GUIZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Relevant studies have proved that the combination of CDK inhibitors and HDAC inhibitors can effectively treat neuroblastoma, melanoma, and mantle cell lymphoma, etc., but there are few reports on the bifunctional targeting of CDK and HDAC by single chemical inhibitors, so We designed a novel single molecule targeting CDKs and HDACs to avoid more side effects of individual drugs, such as drug-drug interactions or different physicochemical properties

Method used

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  • Indirubin derivative and application of indirubin derivative used as dual-target inhibitor of CDK/HDAC
  • Indirubin derivative and application of indirubin derivative used as dual-target inhibitor of CDK/HDAC
  • Indirubin derivative and application of indirubin derivative used as dual-target inhibitor of CDK/HDAC

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The following synthetic routes to indirubin derivatives were employed:

[0028]

[0029] Among them, the definitions of n, R1, R2, and R3 are shown in Table 1:

[0030] Table 1

[0031]

[0032] Compounds 1-6 13 C-NMR, 1 H-NMR and HR-MS data

[0033] Compound 1: 1 H NMR (400MHz, DMSO-d 6 ): δ11.70(s,1H),10.80(s,1H),10.40(s,1H),8.71(s,1H),8.61(d,J=7.7Hz,1H),8.11(d,J= 7.1Hz, 1H), 7.42(s, 2H), 7.15(t, J=7.5Hz, 1H), 7.05–6.98(m, 2H), 6.90(d, J=7.4Hz, 1H), 4.58(s, 2H), 2.03-1.96(m, 2H), 1.90(s, 2H), 1.66–1.55(m, 2H), 1.47(d, J=6.2Hz, 2H). 13 C NMR (100MHz, DMSO-d 6 ):171.39,169.51,151.61,145.98,144.51,139.18, 133.31,128.68,126.90,123.74,122.87,122.04,121.12,116.69,112.31,109.51, 100.55,76.86,49.12,32.72,28.85,25.53.HR-MS( ESI) m / z calculated C 22 h 21 N 4 o 4 - [M-H] - for 405.1568, found 405.1582.

[0034] Compound 2: 1 H NMR (400MHz, DMSO-d 6):δ11.71(s,1H),10.83(s,1H),10.40(s,1H),8.61(d,J=7.8Hz,2H),8.10(d,J=7.6Hz,1H),7.41 (s,2H),7.14(t,J=7.5Hz,1H...

Embodiment 2

[0041] CDK Inhibitory Activity and HDAC Inhibitory Activity of Indirubin Derivatives as CDK / HDAC Dual Target Inhibitors in Vitro

[0042] HDAC Inhibitory Activity Screening

[0043] Add the solution required for the reaction system into the EP tube (see Table 2 for details), and finally add the nucleated extract and incubate at 37°C for 1 hour, (add the second sample after adding the first sample at an interval of 30 seconds), after the reaction is complete, Take one on ice in 30s, then add 2×trypsin and continue to incubate for 1h. After the reaction is completed, take one on ice in 30s, then take 120ul and add it to a 96-well plate, Ex: 360nm, Em: 460nm to measure fluorescence (note the whole process dark operation). Finally, S-curve fitting was carried out on the inhibition rate % and concentration of different concentrations of compounds, and the IC50 value was calculated.

[0044] Table 2

[0045]

[0046]*Unit: μL; Substrate: (Boc-Lys(acetyl)-AMC; SAHA final concen...

Embodiment 3

[0059] Antitumor activity of indirubin derivatives as CDK / HDAC dual target inhibitors against different tumor cells.

[0060] The anti-proliferation activity of candidate compounds on five human cancer cell lines was evaluated by the tetramethylazolium blue colorimetric method (MTT), which is recognized for large-scale anti-tumor drug screening and cytotoxicity assay. The test compounds were compounds 2 and 4; the negative control group was the no-drug group; the positive control drug was Vorinostat (SAHA), a clinically used antitumor drug.

[0061] Cell lines: human breast cancer cell MCF-7, human liver cancer cell HepG2, human lung cancer cell A549, human colon cancer cell SW480, and cervical cancer cell Hela.

[0062] Cell proliferation inhibition rate=(OD value of negative control group-OD value of drug group)*100% / OD value of negative control group. The IC was calculated by the inhibition rate of the compound concentration series 50 Value (in μM), the results are shown ...

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Abstract

The invention discloses an indirubin derivative and application of the indirubin derivative used as a dual-target inhibitor of CDK / HDAC. The indirubin derivative can effectively inhibit the activity of the CDK / HDAC, and can be used as the dual-target inhibitor of CDK / HDAC; and in addition, according to the indirubin derivative and the application of the indirubin derivative used as the dual-targetinhibitor of CDK / HDAC, synthetic raw materials are cheap, the cost is low, antitumor activity is obvious, and the indirubin derivative can be used for novel high-efficiency and low-toxicity CDK / HDACdual-target inhibitor antitumor drugs.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to an indirubin derivative and its application as a DK / HDAC dual-target inhibitor. Background technique [0002] CDK is cyclin-dependent kinases, which is a group of serine / threonine protein kinases. CDK drives the cell cycle through the chemical action on serine / threonine protein, and cooperates with cyclin cyclin. An important factor in cycle regulation; CDK can combine with cyclin to form a heterodimer, in which CDK is a catalytic subunit, cyclin is a regulatory subunit, and different cyclin-CDK complexes catalyze the phosphorylation of different substrates through CDK activity. To achieve the promotion and transformation of different phases of the cell cycle. It plays an important role in the regulation of cell cycle progression, transcription, and other major biological processes, including neuronal differentiation and metabolism; amplification, overexpression, or...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/40A61K31/404A61P35/00
CPCA61P35/00C07D209/40
Inventor 何彬赵永龙曹灼贤杨芬芬李燕李勇军
Owner GUIZHOU MEDICAL UNIV
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