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Small molecular PAD4 inhibitor as well as preparation method and application thereof

A small molecule, inhibitor technology, applied in chemical instruments and methods, active ingredients of boron compounds, drug combinations, etc., can solve problems such as unsatisfactory activity, poor bioavailability, and lack of oral activity

Active Publication Date: 2021-04-20
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Based on the small molecule substrate N-benzoyl-L-arginineamide (BAA) of PAD4, researchers have developed a variety of potent and irreversible haloacetamidine PAD4 inhibitors, but there are still lack of oral activity and biological Problems of poor utilization and unsatisfactory activity

Method used

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  • Small molecular PAD4 inhibitor as well as preparation method and application thereof
  • Small molecular PAD4 inhibitor as well as preparation method and application thereof
  • Small molecular PAD4 inhibitor as well as preparation method and application thereof

Examples

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preparation example Construction

[0079] In the present invention, when R 1 for R 2 for When, the preparation method of described small molecule PAD4 inhibitor comprises the following steps:

[0080] Dissolve the first reaction raw material in tetrahydrofuran, mix the resulting mixture with 1-hydroxybenzotriazole and dicyclohexylcarbodiimide, and perform the first activation, then mix the resulting activation system with benzylamine, and use N- Methylmorpholine adjusts the pH value of the obtained mixed solution to 8-9, performs the first condensation reaction, and obtains the first intermediate product;

[0081] Dissolving the first intermediate product in ethyl acetate, mixing the resulting mixture with HCl in ethyl acetate, and then performing a first hydrolysis reaction to obtain a second intermediate product;

[0082] Dissolving the second reaction raw material in tetrahydrofuran, mixing the resulting mixture with 1-hydroxybenzotriazole and dicyclohexylcarbodiimide, and then performing the second ...

Embodiment 1

[0131] The synthesis of embodiment 1 (3-boronobenzoic acid)-Orn (Cl)-NBzl (ZD-E-2)

[0132] (1) Synthesis of Boc-Orn(Z)-NBzl

[0133] Weight loss method Accurately weigh 3.660g (10mmol) Boc-Orn(Z)-OH and place it in an eggplant bottle, dissolve it with 100mL anhydrous THF until it is colorless, clear and transparent, add a stirrer; under ice bath stirring, add 1.620g (12mmol) 1-hydroxybenzotriazole (HOBt) and 2.472g (12mmol) dicyclohexylcarbodiimide (DCC), after activating 10min, white solid is separated out; Add 1.6mL benzylamine dropwise in eggplant bottle, And use N-methylmorpholine (NMM) to adjust the pH to 8; remove the ice bath, stir and react at room temperature (25°C) for 8h, and use TLC (by volume, the developing agent is CH 2 Cl 2 :CH 3 OH=30:1,R f =0.35) detect the reaction process, observe the disappearance of the raw material point, and judge that the reaction is complete. After the reaction, use a vacuum circulating water pump to filter under reduced pressur...

Embodiment 2

[0142] The synthesis of embodiment 2 (2-boronobenzoic acid)-Orn (Cl)-NBzl (ZD-E-3)

[0143] (1) Synthesis of (2-boronobenzoic acid)-Orn(Z)-NBzl

[0144] The target product was prepared with reference to the method of step (3) in Example 1, except that "3-carboxyphenylboronic acid (3-boronobenzoic acid)" was replaced by "2-carboxyphenylboronic acid (2-boronobenzoic acid)", and finally 1.650 g (65.6%) of the target product (2-boronobenzoic acid)-Orn(Z)-NBzl were obtained as a white solid. ESI-MS(m / z):538.6[M+Cl] - ; 1 H-NMR (300MHz, DMSO-d 6 ): δ(ppm)=8.78(t, J=5.7Hz, 1H), 7.76(dt, J=7.7Hz, 1.9Hz, 1H), 7.57(d, J=7.4Hz, 1H), 7.44(m, 1H),7.41(m,1H),7.38(m,1H),7.30(m,10H),6.88(m,1H),5.01(s,2H),4.28(m,2H),3.97(t,J =6.6Hz, 1H), 3.03(t, J=6.7Hz, 2H), 1.75(m, 2H), 1.50(m, 2H).

[0145] (2) Synthesis of (2-boronobenzoic acid)-Orn-NBzl

[0146] The target product was prepared by referring to the method of step (4) in Example 1, specifically, 1.650g (3.3mmol) (2-boronobenzoic acid)...

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Abstract

The invention provides a molecular PAD4 inhibitor as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. Two functional groups are adopted to modify an amino acid skeleton, one functional group is NBD-Cl with the characteristics of low polarity and strong fluorescence, the NBD-Cl is used for modifying the N end of the amino acid skeleton and can be used for subcellular imaging; in addition, due to the fact that the NBD-Cl is small in relative size and lacks reaction orthogonality, interference on the biochemical reaction of organisms is small; the other one is PBA with tumor targeting, the PBA can be combined with a cell membrane by recognizing a cis-diol unit of glycoprotein, the PBA / cis-diol interacts, and a formed dynamic covalent bond can be regulated and controlled by regulating the pH value or adding competitive molecules, so a controllable self-assembly system is realized. The small-molecule PAD4 inhibitor has good oral activity, has an inhibiting effect on tumor growth and metastasis of mice, and also has a treatment effect on arterial thrombosis of rats.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a small molecule PAD4 inhibitor and its preparation method and application. Background technique [0002] Remarkable progress has been made in the fight against cancer in recent years, but it remains a daunting public health challenge. [0003] Post-translational modifications (PTMs) of histones are hallmarks of epigenetic regulation. Studies have shown that the silencing of tumor suppressor genes by epigenetic modifiers is an early event in the process of tumorigenesis. The approval of anticancer drugs targeting histone deacetylases and DNA methyltransferases over the past few decades has highlighted the important role of epigenetics in human disease and suggested that factors controlling gene expression can act as Novel drug targets. Peptidylarginine deiminase 4 (PAD4) is one such target because it has similar effects on gene expression as histone deacetylases. PAD4 act...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02A61K31/69A61P35/00
CPCY02P20/55
Inventor 王玉记王彦明朱迪卢玉阿依江贾翌江王炜
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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