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Lysine derivative histone deacetylase inhibitor, synthesis and application

A technology of lysine derivatives and deacetylase, which is applied in drug combination, thioether preparation, organic chemistry, etc., can solve the problems of high cost, no anti-tumor activity, and low selectivity, and achieve low cost, Strong selectivity and obvious anti-tumor activity

Active Publication Date: 2018-01-26
GUIZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the currently reported Sirtuins inhibitors are obtained through high-throughput screening and structural optimization, and their selectivity is relatively low and the cost is high.
[0006] Therefore, the Sirtuins inhibitors in the prior art have the problems of low selectivity, high cost, and no antitumor activity.

Method used

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  • Lysine derivative histone deacetylase inhibitor, synthesis and application
  • Lysine derivative histone deacetylase inhibitor, synthesis and application
  • Lysine derivative histone deacetylase inhibitor, synthesis and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] A kind of lysine derivative class histone deacetylase inhibitor: its general formula is:

[0024]

[0025] Its synthesis method is:

[0026] Synthesis scheme 1:

[0027] In the general formula (I), X is S or O or NH; Y is C; Z is S or O; R 1 is benzyloxycarbonyl, fluorenylmethoxycarbonyl; R 2 It is methoxy group and anilino group, and the specific synthetic route is:

[0028]

[0029] R 3 = H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 (CH 2 ) 4 CH 3 , CH 2 (CH 2 ) 6 CH 3 , CH 2 (CH 2 ) 8 CH 3 , CH 2 (CH 2 ) 11 CH 3

[0030]

[0031] Synthesis scheme 2:

[0032] In the general formula (I), X is S or O or NH; Y is NH; Z is S or O; R 1 is benzyloxycarbonyl, fluorenylmethoxycarbonyl; R 2 It is methoxy group and anilino group; the specific synthetic route is:

[0033]

[0034] R 3 = H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 (CH 2 ) 4 CH 3 , CH 2 (CH 2 ) 6 CH 3 , CH 2 (CH 2 ) 8 CH 3 , CH 2 (CH 2 ) 11 CH 3

[0...

experiment example 2

[0139] Concrete synthetic routes of compounds of general formula III

[0140]

[0141] Among them, the definition of R is shown in Table 2.

[0142] 1. The synthetic route of compound 21:

[0143]

[0144] The preparation of compound 21: take compound 4 (2g, 7.6mmol) with 10%Na 2 CO 3 Dissolve 15ml of the solution, add Fmoc-Cl (2.94g, 11.4mmol) dissolved in THF, react overnight at room temperature, adjust pH to 4-5 with 10% citric acid, remove THF under reduced pressure, add CH 2 Cl 2 Extraction, the organic phase was washed with a saturated NaCl solution, and dried under reduced pressure to obtain the product 21 (200mg, yield: 10%);

[0145] 1 H NMR (400MHz, DMSO-d) δ7.85(d, J=7.5Hz, 2H), 7.77~7.61(m, 3H), 7.37(t, J=7.5 Hz, 2H), 7.28(t, J= 7.4Hz, 2H), 4.32~4.14(m, 3H), 4.08(qd, J=8.8, 4.6Hz, 1H), 2.86(dt, J= 24.4, 10.2Hz, 1H), 2.70(ddd, J=15.2 ,9.6,5.6Hz,1H),2.55~2.41(m,2H),2.23(t,J=7.3Hz, 2H),1.68(dd,J=8.4,6.1Hz,2H),1.33(s,9H) .

[0146] 13 C-NMR (100MHz, DMS...

experiment example 3

[0264] activity screening

[0265] The existing Sirtuins subtypes are 1, 2, 3, 5, and 6, and the corresponding substrate polypeptides of 1, 2, and 3 subtypes are H3K9AcWW (200 μM) and its coenzyme NAD (1 mM); the substrate polypeptide of 5 H3K9SuWW ( 200 μM) and its coenzyme NAD (1 mM); the substrate polypeptide of 6 H3K9MyWW (200 μM) and its coenzyme NAD (1 mM).

[0266] 6.1 Sirt1, 2, 3 enzyme reaction

[0267]The substrate polypeptide H3K9AcWW (200 μM) and its coenzyme NAD (1 mM) were reacted with Sirt1, 2, 3 (1 μM) in Tris pH7.4 (20 mM) solution containing DTT (1 mM) at 37°C for 45 min, 10 min, and 30 min, respectively. In the positive group, the drug components to be tested were added during the reaction process, and the drug concentration was 100 μM for preliminary screening. Two negative control groups were set up, one group without adding screening drugs, and one group without adding Sirt1, 2, and 3 proteins. After reacting for 45min, 10min and 30min, all components ...

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Abstract

The invention discloses a lysine derivative histone deacetylase inhibitor. The inhibitor has high selectivity, can be used for Sirtuin mechanism inhibitor antitumor drugs with strong Sirtuin selectivity, high efficiency and low toxicity, has easily available raw materials, and is low in cost.

Description

technical field [0001] The invention relates to a lysine derivative-like histone deacetylase inhibitor and its synthesis and application, in particular to a lysine derivative-like histone deacetylase inhibitor with antitumor activity and its synthesis and application application. Background technique [0002] It has long been recognized that histone acetylation modification is closely related to chromatin structure and gene transcription regulation. In the nucleus, the process of histone acetylation and histone deacetylation is in dynamic equilibrium, and is jointly performed by histone acetyltransferases (HATs) and histone deacetylases (histonedeacetylases, HDACs) with opposite activities. regulation. The catalytic activity of HAT uses acetyl coenzyme A as the acetyl donor to transfer the acetyl group to the ε-amino group of histone lysine side chain, so that the chromatin is in a relatively loose state, which is conducive to transcription factors and RNA polymerization ...

Claims

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Application Information

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IPC IPC(8): C07C319/20C07C323/60C07C323/59A61P35/00
Inventor 何彬李燕王春王芳陈晓雪邹叶芳
Owner GUIZHOU MEDICAL UNIV
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