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Histone lysine methyltransferase NSD2 inhibiting small-molecule compound and application thereof

A small molecule compound, lysine methyl technology, applied in the direction of drug combination, organic chemistry, antineoplastic drugs, etc., can solve the problems of no high activity NSD2 small molecule inhibitors, limited research, etc., to achieve good medicinal potential, The preparation method is simple and the energy consumption is small

Inactive Publication Date: 2019-05-10
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the research on histone lysine methyltransferase NSD2 is still very limited, and there are no reports on the treatment of histone lysine methyltransferase NSD2 for diseases, and there is no highly active NSD2 small molecule. Inhibitor

Method used

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  • Histone lysine methyltransferase NSD2 inhibiting small-molecule compound and application thereof
  • Histone lysine methyltransferase NSD2 inhibiting small-molecule compound and application thereof
  • Histone lysine methyltransferase NSD2 inhibiting small-molecule compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Compound 1: Compound N-cyclopropyl-3-(3-(1-methyl-1H-benzo[d][1,2,3]triazole-5)ureido)benzenesulfonamide

[0034] The synthetic route is as follows:

[0035]

[0036] Concrete synthetic steps are as follows:

[0037] At 0°C, N-methyl-4-nitrobenzene-1,2-diamine (A01a) (1.13g, 6.76mmol) was dispersed in 22ml of water, and then 5.6ml of concentrated hydrochloric acid was added to form a strongly acidic mixture An aqueous solution of sodium nitrite (568 mg, 8.23 ​​mmol) dissolved in 10 ml was added dropwise. Keep stirring at 0°C for 4 hours, then slowly rise to room temperature, filter and wash the filter cake with cold water to obtain the off-white compound 5-nitrobenzo(1-methyl)triazole (A01b).

[0038] Then A01b (950mg, 5.3mmol) was dispersed in about 50ml EtOH:H 2In the solvent system of O=2:1, ammonium chloride (570mg, 10.6mmol) was added and the temperature was raised. When the temperature rose to 60°C, iron powder (1190mg, 21.2mmol) was added, and the temperatu...

Embodiment 2

[0043] Compound 2: N-cyclopropyl-3-(3-(1-methyl-1H-benzo[d][1,2,3]triazole-5)ureido)benzamide

[0044] The synthetic route is as follows:

[0045]

[0046] Other specific synthetic steps were the same as the above-mentioned examples, and compound 2 was prepared with a yield of 61.2%.

[0047] The MS (ESI) data of compound 2 are as follows:

[0048] MS(ESI)351.3[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ8.91(s,1H),8.89(s,1H),8.41(d,J=3.6Hz,1H),8.20(s,1H),7.86(s,1H),7.77(d,J=8.8 Hz,1H),7.64(d,J=8.0Hz,1H),7.51(d,J=7.6Hz,1H),7.40(d,J=7.6Hz,1H),7.35(t,J=7.6Hz, 1H),4.28(s,3H),2.91–2.79(m,1H),0.73–0.66(m,2H),0.58-0.57(m,2H).

Embodiment 3

[0050] Compound 3: 1-(1-methyl-1H-benzo[d][1,2,3]triazole-5)-3-(3-(morpholine-4-carbonyl)phenyl)urea

[0051] The synthetic route is as follows:

[0052]

[0053] Other specific synthetic steps were the same as those in the above examples, and compound 3 was prepared with a yield of 68.3%.

[0054] The MS (ESI) data of compound 3 are as follows:

[0055] MS(ESI)381.1[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 )δ8.96(s,1H),8.90(s,1H),8.19(d,J=1.2Hz,1H),7.77(d,J=8.8Hz,1H),7.60(s,1H),7.54– 7.43(m,2H),7.36(t,J=7.6Hz,1H),7.01(d,J=7.6Hz,1H),4.27(s,3H),3.61(s,8H).

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PUM

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Abstract

The invention belongs to the field of chemical medicine and particularly relates to a histone lysine methyltransferase NSD2 inhibiting small-molecule compound. A general formula of the small-moleculecompound is as shown in the specification. According to implementation schemes of the small-molecule compound, the small-molecule compound has a great inhibiting effect on histone lysine methyltransferase NSD2, also has an excellent inhibiting effect on tumor cells, can be made into inhibiting agents and can be applied to preparation of medicines for cancer treatment. The prepared compound is highin bioactivity, high in tumor cell selectivity and remarkable in drug likeness and has a promising market prospect.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis drugs, in particular to a small molecule compound for inhibiting histone lysine methyltransferase NSD2 and its application. Background technique [0002] Histone methylation is mediated by histone methyltransferases (PMTs), which catalyze the transfer of methyl groups from the cofactor S-5'-adenosyl-L-methionine (SAM) to histone lysine transfer on amino acid or arginine residues. According to the different amino acid residues that undergo methylation, histone methyltransferases can be divided into two categories: histone arginine methyltransferases (PRMTs) and histone lysine methyltransferases (PKMTs). Methylation modification on lysine or arginine residues does not change the charge of the residue, but changes the size and hydrophobicity of the protein, thereby affecting the interaction between proteins. [0003] The NSD family of nuclear receptor-binding SET domain proteins is a gro...

Claims

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Application Information

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IPC IPC(8): C07D249/18C07D277/62C07D285/14C07D209/42C07D241/44C07D209/48A61K31/4192A61K31/428A61K31/4035A61K31/404A61K31/433A61K31/472A61K31/498A61P35/00
Inventor 杨胜勇李琳丽
Owner SICHUAN UNIV
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