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Isatin compounds as well as preparation method and application thereof

A compound, isatin technology, applied in the field of isatin compounds and their preparations, can solve the problems of large neurotoxicity, limited medicines, poor water solubility and high cytotoxicity, etc., and achieves great application potential, reduced in vitro cytotoxicity, and good HIV latency. The effect of the activation ability

Inactive Publication Date: 2019-08-30
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the inventors found that the chemical structure of JQ1 is similar to that of benzodiazepine sedative-hypnotics, and there are side effects such as greater neurotoxicity, poor water solubility, and high cytotoxicity, which limit the possibility of making it into a drug

Method used

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  • Isatin compounds as well as preparation method and application thereof
  • Isatin compounds as well as preparation method and application thereof
  • Isatin compounds as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1 Compound preparation

[0045] The synthetic route of compound sees following reaction formula:

[0046]

[0047] Reaction conditions: (a) potassium carbonate, DMF, room temperature; (b) sodium carbonate; tetrakis(triphenylphosphine)palladium; 1,4-dioxane and water; 95°C; (c) cesium carbonate, DMSO, 100℃; (d) palladium carbon / H 2 ; methanol, room temperature; (e) pyridine, DCM, 0 °C to room temperature.

[0048] In compound 5, R is selected from ethyl, propyl, cyclopropyl, thienyl, substituted and unsubstituted phenyl; further, the compound 5 includes the following structure: wherein YHP-1 is the compound of formula (I).

[0049]

[0050] Concrete reaction process is as follows:

[0051] (1) Preparation of intermediate 6-bromo-1-methylindoline-2,3-dione (1)

[0052] Dissolve 1.15g (5mmol) 6-bromoisatin in 10mL DMF, add 1.03g (7.5mmol) potassium carbonate under stirring, then add 0.804g (6.25mmol) dimethyl sulfate dropwise, react at room temperature ...

Embodiment 2

[0081] Example 2 Detection of inhibitory activity of compounds on BRD4 protein

[0082] The inhibitory activity of compounds on BRD4 was tested by Homogeneous Time-Resolved Fluorescence (HTRF). The specific method is as follows:

[0083] Experimental principle: HTRF combines the advantages of fluorescence resonance energy transfer FRET and time-resolved fluorescence TRF, and integrates the homogeneous experimental method of FRET and the low background characteristics of TRF. It has the advantages of simple operation, high sensitivity and large test throughput. , The experimental data is stable and reliable.

[0084] (1) Compounds were diluted with DMSO.

[0085] (2) Use the Diluent Buffer in the kit to dilute BRD4 (BD2, BD2) and Biotin-labeled histone H4 peptides, and prepare the reaction solution.

[0086] (3) Use Dtection Buffer in the kit to dilute Anti-GST-TB 2+ Cryptate and SA-XL-665, and configure the detection solution.

[0087] (4) Take a 384-well plate and arra...

Embodiment 3

[0094] Example 3: EC of YHP-1 in J-Lat HIV-1 latent infection cell line 50

[0095] Experiment principle: EC 50 is the half-maximum effect concentration, which refers to the concentration of the compound when the compound reaches the 50% maximum effect of activating HIV latent activity, and the unit is μM.

[0096] Experimental procedure: take well-grown J-Lat cells and spread them in 96-well transparent plates, and the amount of cells used is 2×10 per well. 5 Add different concentrations of the test compound respectively, the final concentrations are 320, 160, 80, 40, 20, 10, 5, 0 μM respectively, JQ1 is used as the positive control, the untreated group is the negative control, and each concentration is at least 3 Duplicate wells, each experiment was repeated 3 times. After culturing in a 5% CO2 incubator for 24 hours, the cells were collected by centrifugation, the supernatant was discarded, washed once with PBS, the supernatant was discarded, and then resuspended with PB...

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Abstract

The invention provides isatin compounds as well as a preparation method and an application thereof. The compounds have the structure shown in a formula (I) and have good BRD4 protein inhibition activity, have huge application potential in the antitumor and anti-virus aspects and can be applied to preparation of BRD4 inhibitor drugs; meanwhile, the compounds have good HIV latent virus activation capability, have greatly reduced in-vitro cytotoxicity as compared with known HIV latent activators JQ1, are safer to use and have good tolerance.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to isatins compounds and their preparation methods and applications. Background technique [0002] The information disclosed in this background section is only intended to increase the understanding of the general background of the present invention, and is not necessarily taken as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to those skilled in the art. [0003] BRD4, bromodomain protein 4, is a member of the BET bromodomain family. The BET family comprises four proteins, namely BRD2, BRD3, BRD4 and BRDT. Each member contains two highly conserved bromodomains, such as BRD4(BD1), BRD4(BD2). BRD4 acts on the core part of the positive transcription elongation factor composed of cyclin kinase 9 and cyclin T1, and participates in the transcriptional regulation of HIV, EBV, HPV and other viruses. In recent years, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/38A61K31/404A61P31/18
CPCA61P31/18C07D209/38
Inventor 李荀于海鹏郑永唐黄旭升
Owner SHANDONG UNIV
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