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Double-target inhibitor as well as preparation method and application thereof

A dual-target and inhibitor technology, which can be used in pharmaceutical formulations, medical preparations containing active ingredients, organic active ingredients, etc., can solve the problems of unsatisfactory therapeutic effect of histone deacetylase inhibitors, and achieve good inhibition effect, the effect of enhancing inhibitory activity

Active Publication Date: 2019-05-17
QINGDAO UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to provide a dual-target inhibitor and its preparation method and application. The inhibitor solves the problem of unsatisfactory therapeutic effect of the existing histone deacetylase inhibitors, and can selectively inhibit HDAC6, which is beneficial to tumors. Cells have a better inhibitory effect

Method used

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  • Double-target inhibitor as well as preparation method and application thereof
  • Double-target inhibitor as well as preparation method and application thereof
  • Double-target inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037]

[0038] 4-methoxy-N 1 -Methyl-N 1 -(2-Methyl-quinolyl-4-)-1,3-phenylenediamine (0.293 g, 1 mmol, 1 times the amount) was dissolved in 15 ml of anhydrous dichloromethane, and triethyl Amine (209 μl, 1.5 mmol, 1.5 times the amount) and 4-bromobutyryl chloride (0.278 g, 1.5 mmol, 1.5 times the amount), the mixture was stirred at 25 ° C for 4 hours, and the reaction mixture was directly used on silica gel Separation and purification by column chromatography, the eluent was dichloromethane:methanol=40:1, and 0.221 g of compound C-1 was obtained with a yield of 50%.

[0039] Compound C-1 (0.221 g, 0.5 mmol, 1 times the amount) and potassium thioacetate (0.114 g, 1 mmol, 2 times the amount) were mixed in 10 ml of absolute ethanol, and stirred at 25 ° C for 24 hours , directly separated and purified by silica gel column chromatography, the eluent was dichloromethane:methanol=40:1, and 98.5 mg of compound E-1 was obtained with a yield of 45%.

[0040] The NMR characteriza...

Embodiment 2

[0046]

[0047] The preparation method of Example 2 is basically the same as that of Example 1, except that 4-bromobutyryl chloride is replaced by 5-bromovaleryl chloride.

[0048] The NMR characterization data of compound E-2 are as follows:

[0049] 1 H-NMR(400MHz,DMSO-d6),δ9.02(brs,1H),8.29(m,1H),7.91(m,1H),7.71(m,1H),7.46(m,1H),7.35( s,1H),7.32(d,J=2.0Hz,1H),7.09(dd,J=8.8,2.0Hz,1H),7.02(d,J=8.8,1H),3.81(s,3H),3.53 (t,J=8.8Hz,2H),3.38(s,3H),2.64(s,3H),2.37(t,J=8.8Hz,2H),2.30(s,3H),1.82(m,2H) ,1.72(m,2H).

[0050] 13 C-NMR (101MHz, DMSO-d6), δ194.8, 179.8, 159.1, 149.2, 148.8, 141.6, 138.0, 129.6, 128.6, 127.2, 124.6, 123.7, 119.6, 115.3, 110.1, 106.5, 106.2, 51.33.0, 4 , 35.2, 28.5, 27.2, 24.7, 20.2.

[0051] The mass spectral data of compound E-2 are as follows:

[0052] HRMS: calcd for C 25 h 30 N 3 o 3 S + [M+H] + :452.2002found: 452.2004.

Embodiment 3

[0054]

[0055] The preparation method of Example 3 is basically the same as that of Example 1, except that 4-bromobutyryl chloride is replaced by 6-bromohexanoyl chloride.

[0056] The nuclear magnetic characterization data of compound E-3 are as follows:

[0057] 1 H-NMR(400MHz,DMSO-d6),δ9.02(brs,1H),8.29(m,1H),7.91(m,1H),7.71(m,1H),7.46(m,1H),7.35( s,1H),7.32(d,J=2.0Hz,1H),7.09(dd,J=8.8,2.0Hz,1H),7.02(d,J=8.8,1H),3.95(s,3H),3.50 (t,J=8.6Hz,2H),3.32(s,3H),2.62(s,3H),2.35(t,J=8.6Hz,2H),2.30(s,3H),1.86(m,2H) ,1.69(m,2H),1.29(m,2H).

[0058] 13 C-NMR (101MHz, DMSO-d6), δ194.8, 179.8, 159.1, 149.2, 148.8, 141.6, 138.0, 129.6, 128.6, 127.2, 124.6, 123.7, 119.6, 115.3, 110.1, 106.5, 106.2, 51.3, 38.0, 4 , 30.5, 29.5, 29.2, 25.3, 24.7, 20.0.

[0059] The mass spectral data of compound E-3 are as follows:

[0060] HRMS: calcd for C 26 h 32 N 3 o 3 S + [M+H] + :466.2159found: 466.2160.

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Abstract

The invention discloses a double-target inhibitor as well as a preparation method and application thereof. The double-target inhibitor has a structure shown as a formula (I), wherein R1 is H, an electron-withdrawing group or an electron-donating group; R is alkyl; n is equal to 1 to 5. The double-target inhibitor provided by the invention can be used for selectively inhibiting HDAC6 and IC50 values on HDAC1 and HDAC8 are greater than 20 muM; the double-target inhibitor is used as a prodrug to be subjected to hydrolysis reaction in cells, and tubulin and an HDAC double-target inhibitor can be released; the inhibition activity of histone deacetylase on solid tumors is improved; the double-target inhibitor has a relatively good inhibition effect on tumor cells. The formula (I) is shown in thedescription.

Description

technical field [0001] The invention relates to a histone deacetylase inhibitor, in particular to a dual-target inhibitor and its preparation method and application. Background technique [0002] Histone deacetylases (histone deacetylases, HDACs) are one of the key enzymes that maintain the balance of histone acetylation in nucleosomes, the basic unit of chromosomes. Closely related, involving many processes of promoting gene silencing, the imbalance of histone and non-histone acetylation status is closely related to the occurrence and development of tumors, so histone deacetylase is a popular target in the design of anti-tumor drugs. [0003] Histone deacetylase inhibitors (histone deacetylase inhibitors, HDACi) are a class of compounds that interfere with the function of histone deacetylases. HDACis can inhibit the proliferation of tumor cells, induce tumor cell differentiation and (or) apoptosis by increasing the degree of acetylation of intracellular histones, increasin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/44A61K31/4706A61P35/00A61P35/02
Inventor 栾业鹏牟梓硕苗贺王克威
Owner QINGDAO UNIV
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