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Bifunctional small molecule compound capable of activating enzyme catalytic reaction, and applications thereof

A small molecule compound and catalytic reaction technology, applied in organic chemistry, fermentation, etc., can solve problems such as unsatisfactory catalytic effect, achieve the effect of improving catalytic activity and stereoselectivity, and enhancing activation efficiency

Active Publication Date: 2019-08-16
QINGDAO INST OF BIOENERGY & BIOPROCESS TECH CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Scientists have also tried to use site-directed mutagenesis to introduce such amino acid residues into the active site of P450, but the catalytic effect is not satisfactory

Method used

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  • Bifunctional small molecule compound capable of activating enzyme catalytic reaction, and applications thereof
  • Bifunctional small molecule compound capable of activating enzyme catalytic reaction, and applications thereof
  • Bifunctional small molecule compound capable of activating enzyme catalytic reaction, and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0065] Preparation Examples of Small Molecular Compounds

[0066] 1) Synthesis of imidazolyl carboxylic acids with different chain lengths

[0067] Taking the preparation of ImC6 as an example,

[0068]

[0069] Tomko R.; Overberger, C.G.J. Polym. Sci. Pol. Chem., 1985, 23, 265–277.

[0070] Hack, S.; B.; G.; Pabel, J.; Wanner, K.T. Eur. J. Med. Chem. 2011, 46, 1483–4984.

[0071] Groves, J.T.; Neumann, R.J. Am. Chem. Soc. 1989, 111, 2900-2909.

[0072] General method 1 (taking 6-imidazolyl caproic acid as an example):

[0073] Add imidazole (1.4g, 20.0mmol) into a flask containing 15mL of toluene, slowly add sodium hydride (0.5g, 20.0mmol) while stirring, reflux at 120°C for 3h, cool to room temperature, slowly add ethyl bromohexanoate ( 2.3g, 10.0mmol) of toluene solution, reflux overnight, TLC detection of reaction progress.

[0074] After the reaction, cool to room temperature, concentrate toluene with a rotary evaporator and spin dry, add an appropriate amount...

Embodiment 1

[0131] BMP utilization (Im-C6-Phe) catalysis epoxidation reaction

[0132] The reaction system is as follows: 4mM (10% MeOH solubilization), 0.5μM enzyme BMP (PatrickC.Cirino, Frances H.Arnold.Advanced Synthesis & Catalysis, 2010,344(9):932-937.), 0.5mM Small molecules, 20mMH 2 o 2 Add to PBS (100mM) with pH 8.0 in a final volume of 1mL, react in a water bath at 25°C for 30min, add 125μL of 4-(4-nitrobenzyl)pyridine (0.4g) in absolute ethanol (10mL), 80 ℃ water bath for 30 min, then ice bath for 10 min, add 1 mL of acetone / triethylamine mixed solution (1:1). The 570nm absorption was measured with a UV spectrophotometer (Shimadzu Spectrophotometer UV-1800), and the catalytic reaction without adding small molecule compounds was used as a control (Table 1). The result of the reaction is as follows:

[0133] Table 1

[0134]

[0135]

[0136] Depend on figure 1 and Table 1 can be seen join the pair The epoxidation reaction has a slight promoting effect.

Embodiment 2

[0138] F87A uses catalytic The epoxidation reaction:

[0139] The reaction system is as follows: 4mM (10% MeOH solubilization), 0.5 μM enzyme F87A (PatrickC.Cirino, Frances H.Arnold. Advanced Synthesis & Catalysis, 2010,344(9):932-937.), 0.5mM Small molecules, 20mMH 2 o 2 Add to PBS (100mM) with pH 8.0 in a final volume of 1mL, and react in a water bath at 25°C for 30min, then add 125μL of 4-(4-nitrobenzyl)pyridine (0.4g) in absolute ethanol (10mL), 80°C water bath for 30 min, then ice bath for 10 min, add 1 mL of acetone / triethylamine mixed solution (1:1). The 570nm absorption was measured with an ultraviolet spectrophotometer (Shimadzu Spectrophotometer UV-1800), and the catalytic reaction without small molecule compounds was used as a control (Table 2). The result of the reaction is as follows:

[0140] Table 2

[0141]

[0142] Depend on figure 2 and Table 2 can be seen join the pair The epoxidation reaction is greatly promoted.

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Abstract

The present invention relates to a catalytic reaction, particularly to a bifunctional small molecule compound capable of activating an enzyme catalytic reaction, and applications thereof, wherein thebifunctional small molecule compound is C5-10 carboxylic acid, C5-10 fluorocarboxylic acid, aromatic heterocyclic ring substituted carboxylic acid, heterocyclic ring substituted carboxylic acid, a C5-10 carboxylic acid amide derivative, a C5-10 fluorocarboxylic acid amide derivative, an aromatic heterocyclic ring substituted carboxylic acid amide derivative or a heterocyclic ring substituted carboxylic acid amide derivative substituted with at least a catalytic group, wherein the carboxyl group or the amide derivative is used as an anchoring group. According to the present invention, with themethod, the number of the introduced catalytic groups cannot be limited, and the orientation of the catalytic functional group and the fine adjustment of the distance from the active center can be achieved, such that the H2O2 activation efficiency can be well enhanced, and the catalytic activity and the stereoselectivity can be improved.

Description

technical field [0001] The invention relates to a catalytic reaction, in particular to a bifunctional small molecular compound for activating an enzyme catalytic reaction and its application. Background technique [0002] Cytochrome P450 enzyme has a very important application value, it can catalyze various types of chemical reactions, such as hydroxylation, epoxidation, dealkylation of nitrogen, oxygen, sulfur, nitrogen, sulfur and other heteroatoms A series of reactions such as oxidation, oxidative deamination, dehalogenation and C-C bond breaking. In particular, the selective oxidation of inert C-H bonds has great potential in organic synthesis, and the application of P450 enzymes to develop chiral drug biosynthesis technology has become a research hotspot at home and abroad. [0003] As a member of the P450 enzyme superfamily, cytochrome P450BM3 has been extensively studied and applied due to its ultra-high catalytic efficiency and mature and efficient expression system...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/32C07D403/12C12P17/02C12P11/00C12P7/22C12P7/04
CPCC07D263/32C07D403/12C12P17/02C12P11/00C12P7/22C12P7/04
Inventor 丛志奇陈杰马娜娜陈置丰
Owner QINGDAO INST OF BIOENERGY & BIOPROCESS TECH CHINESE ACADEMY OF SCI
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