CN104177361B - A kind of ASA type enzyme inhibitors based on plant hormone regulatory gene GH3 and preparation method thereof - Google Patents

A kind of ASA type enzyme inhibitors based on plant hormone regulatory gene GH3 and preparation method thereof Download PDF

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CN104177361B
CN104177361B CN201410422288.1A CN201410422288A CN104177361B CN 104177361 B CN104177361 B CN 104177361B CN 201410422288 A CN201410422288 A CN 201410422288A CN 104177361 B CN104177361 B CN 104177361B
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enzyme inhibitors
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asa
acid
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CN104177361A (en
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杨庆华
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Hefei University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

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Abstract

The invention discloses a kind of ASA type enzyme inhibitors based on plant hormone regulatory gene GH3 and preparation method thereof, wherein the structural formula of enzyme inhibitors is: r is styroyl or naphthyl.Enzyme inhibitors of the present invention is for the IC of GH3-6 50be respectively 16.00 ± 1.80,0.45 ± 0.02 μMs, there is good enzyme inhibition activity, show potential application prospect in fields such as agricultural chemicals.The preparation method of enzyme inhibitors of the present invention is simple, and without the need to special reaction condition, react at normal temperatures and pressures, aftertreatment is easy, and product yield is higher.

Description

A kind of ASA type enzyme inhibitors based on plant hormone regulatory gene GH3 and preparation method thereof
One, technical field
The present invention relates to a kind of enzyme inhibitors and preparation method thereof, specifically a kind of ASA type enzyme inhibitors based on plant hormone regulatory gene GH3 and preparation method thereof.
Two, background technology
Plant hormone is the plant hormone found the earliest, its chemical nature is the small molecule organic compound that a class does not have constitutional features, comprise Whitfield's ointment (SA), jasmonic (JA) and most representative 2-indolylacetic acid (IAA) etc., mainly concentrate on the position that the tender shoots of plant, top, the tip of a root etc. have growth vigor.They to the differentiation of the division and proliferation of cell, tissue and organ, blooming has important physiological regulatory action with the sprouting and dormancy etc. of fruit maturation, seed.Plant hormone has dual regulation effect for the physiology of plant: when lower concentration, and it can promote that tender shoots grows, and the tip of a root is flourishing; The growth of plant tip, root system can be suppressed when high density, even can cause Plant death etc.
At present, be GH3 gene family more thoroughly for the research of plant hormone regulatory gene.In arabidopsis gene group, have been found that 19 gene members at present, respectively called after GH3-1, GH3-2, GH3-3 ... GH3-19 etc.Evidence suggests, the protein of GH3 genes encoding has the polyadenylation effect of catalysis Whitfield's ointment (SA), indolylacetic acid (IAA), jasmonic (JA), thus level in the body that can regulate these plant hormones.In addition, research also finds that they can also catalysis IAA and various amino acid whose ligation, store in vivo with the form of IAA-X (X=Ala, Asp, Glu, Leu etc.) inactive form, thus reach the object regulating IAA and related amino acid level in vivo.Detailed process is shown below:
The polyadenylation process of physiology of IAA is: 2-indolylacetic acid (IAA) is under the effect of Triphosaden (ATP), generate its activated intermediate-adenosine monophosphate ester (IAA-AMP), slough a part tetra-sodium (PPi) simultaneously; Then each seed amino acid and IAA-AMP react, form the complex body (IAA-aa) of indolylacetic acid and amino acid (aa), it is the inactive form storage form of IAA, can regulate the hormonal readiness of IAA in plant materials, thus play an important role to the growth regulating of plant.
Three, summary of the invention
The present invention aims to provide a kind of ASA type enzyme inhibitors based on plant hormone regulatory gene GH3 and preparation method thereof, and technical problem to be solved selects by molecular designing the compound obtaining GH3 gene being had to good enzyme inhibition activity.
The present invention has prepared the various ASA-carboxylic acid mixtures (ASA-ca) of series based on ASA intermediate by molecular designing, and they have the adenosine structure similar with IAA-AMP.
The structural formula that the present invention is based on the ASA type enzyme inhibitors of plant hormone regulatory gene GH3 is:
R is styroyl or naphthyl, lower same.
The preparation method that the present invention is based on the ASA type enzyme inhibitors of plant hormone regulatory gene GH3 is as follows:
1) activation of carboxyl
Under nitrogen protection, be dissolved in organic solvent by carboxylic acid and carboxyl activator, solution is clarified, and confined reaction 1-2h under room temperature, obtains intermediate 1, and the intermediate 1 prepared need not be separated and can be directly used in next step reaction.
Mol ratio between described carboxylic acid and described carboxyl activator is 1:1.1-1.3;
Described carboxylic acid is phenylpropionic acid or naphthoic acid etc.;
Described carboxyl activator is carbonyl dimidazoles (CDI), N-hydroxy-succinamide (NHS), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC.HCl) or dicyclohexylcarbodiimide (DCC) etc.;
Described organic solvent is the methylene dichloride etc. of anhydrous acetonitrile, N, N-diformamide (DMF), methyl-sulphoxide (DMSO) or drying;
The structural formula of described intermediate 1 is:
2) coupling
To step 1) add ASA intermediate in obtained reaction solution, solution turned cloudy, 1 is added in the condition downhill reaction liquid of ice-water bath, 8-diazacyclo [5.4.0] 11 carbon-7-alkene (DBU), solution becomes clarification, react 8-12h under room temperature air tight condition, reaction terminates rear underpressure distillation desolvation, then adds CHCl 3dissolve, then add the citric acid solution washing of mass concentration 3%, separated and collected organic phase, through anhydrous sodium sulfate drying after organic phase washed with water and saturated common salt water washing, underpressure distillation removes CHCl 3, cross silicagel column subsequently (with volume ratio CHCl 3/ MeOH=10-12:1 is as moving phase) be separated obtain intermediate 2;
Mol ratio in reaction solution between intermediate 1, ASA intermediate and DBU is 1:1:1.8-2.5.
The structural formula of described ASA intermediate is:
The structural formula of described intermediate 2 is:
3) Deprotection
Added by intermediate 2 in Deprotection reagent solution, react 1.5-2.5h under room temperature, reaction terminates rear removed under reduced pressure solvent, to obtain target product after acetone recrystallization;
In deprotection reaction process, the addition of Deprotection reagent is greatly excessive, and general Deprotection reagent controls at 150-300:1 with the ratio of the molar weight of intermediate 2.
Described Deprotection reagent solution is the HCOOH aqueous solution of mass concentration 80%, the 5-10% hydrochloric acid soln of mass concentration or trifluoroacetic acid (TFA) etc.
The described detailed process with acetone recrystallization is as follows:
The white solid obtained after removed under reduced pressure solvent is added in flask, adds acetone, be heated to reflux state and constantly add new acetone, until white solid no longer dissolves, filtered while hot, filtrate leaves standstill crystallization under the condition of ice-water bath, filters, washs and namely obtain target product after drying.
Reaction scheme of the present invention is shown below:
The ASA intermediate that the present invention uses has the molecular structure similar with IAA-AMP mixture, and adenosine structure wherein can by the exquisite specificity identification of the enzyme of GH3 genes encoding institute.
[enzyme inhibition activity mensuration]
After 1HNMR, ultimate analysis determination product purity, inventors tested a large prepared target product to GH3-6 inhibition of enzyme activity effect.Concrete test procedure is as follows:
1) enzymic catalytic reaction: add Tris-HCl (pH8.0), MgCl in the centrifuge tube of 2mL successively 2, ATP, IAA, aspartic acid, enzyme inhibitors and GH3-6, the cumulative volume controlling centrifugal liquid in pipe is 1mL, and in centrifuge tube, the concentration of Tris-HCl (pH8.0) is 100mM, MgCl 2the concentration that concentration be the concentration of 5mM, ATP is 500 μMs, the concentration of IAA is 100 μMs, the concentration of aspartic acid is 1mM, GH3-6 be 14 μ g/mL, under the condition of 30 DEG C, cultivate 10min;
2) color reaction: add 50 μ L21mM ammonium molybdate reagent, 200 μ L steps 1 in the centrifuge tube of 2mL successively) obtain enzymic catalytic reaction liquid, 50 μ L0.5M2-mercaptoethanols, 20 μ LEikonogen reagent (Sodium Pyrosulfite, 10.4M1-amino-beta naphthal-4-sulfonic acid containing 21mM S-WAT, 0.77M), after equilibrate at room temperature reaction 30min, measure absorbancy under its 580nm condition.
Enzyme inhibitors of the present invention is for the IC of GH3-6 50be respectively 16.00 ± 1.80,0.45 ± 0.02 μMs, there is good enzyme inhibition activity, show potential application prospect in fields such as agricultural chemicals.The preparation method of enzyme inhibitors of the present invention is simple, and without the need to special reaction condition, react at normal temperatures and pressures, aftertreatment is easy, and product yield is higher.
Four, embodiment
Embodiment 1:
1) activation of carboxyl
Under nitrogen protection; phenylpropionic acid (0.6g is added in the round-bottomed flask of 200mL; 4.0mmol) and CDI (0.72g; 4.45mmol); then in flask, inject the dry acetonitrile of about 50mL with syringe needle, nitrogen protection is about 20min, room temperature reaction 1-2h under air tight condition; obtain intermediate 1, the intermediate 1 prepared need not be separated and can be directly used in next step reaction.
2) coupling
To step 1) add ASA intermediate (1.4g in obtained reaction solution, 3.64mmol), solution turned cloudy, 1mLDBU (about 6.58mmol) is added in the condition downhill reaction liquid of ice-water bath, solution becomes clarification, react 8-12h under room temperature air tight condition, the reaction of thin-layer chromatography (TLC) detection display terminates rear underpressure distillation desolvation, obtains white solid.150mLCHCl is added in the white solid obtained 3dissolve, then add the citric acid solution washing of 150mL mass concentration 3%, separated and collected organic phase, repeats this process 2-3 time, merges organic phase; Through anhydrous sodium sulfate drying after organic phase washed with water and saturated common salt water washing, underpressure distillation removes organic solvent, crosses silicagel column subsequently (with volume ratio CHCl 3/ MeOH=10:1 is as moving phase) be separated obtain intermediate 2 (1.69g, yield 81.8%).
3) Deprotection
By intermediate 2 (0.78g, 1.52mmol) join in the HCOOH aqueous solution of 20mL mass concentration 80%, reaction solution is transparent, react under room temperature to TLC detection reaction and terminate, removed under reduced pressure solvent obtains white solid, to obtain target product (0.54g, yield 75.9%) after acetone recrystallization;
The described detailed process with acetone recrystallization is as follows:
The white solid obtained after removed under reduced pressure solvent is added in flask, adds acetone, be heated to reflux state and constantly add new acetone, until white solid no longer dissolves, filtered while hot, filtrate leaves standstill crystallization under the condition of ice-water bath, filters, washs and namely obtain target product after drying.
The structural formula of described target product is:
The inhibition of enzyme activity measure of merit step of enzyme inhibitors to GH3-6 prepared by the present embodiment is as follows:
1) enzymic catalytic reaction: add Tris-HCl (pH8.0), MgCl in the centrifuge tube of 2mL successively 2, ATP, IAA, aspartic acid, enzyme inhibitors and GH3-6, the cumulative volume controlling centrifugal liquid in pipe is 1mL, and in centrifuge tube, the concentration of Tris-HCl (pH8.0) is 100mM, MgCl 2the concentration that concentration be the concentration of 5mM, ATP is 500 μMs, the concentration of IAA is 100 μMs, the concentration of aspartic acid is 1mM, GH3-6 be 14 μ g/mL, under the condition of 30 DEG C, cultivate 10min;
2) color reaction: successively add 50 μ L21mM ammonium molybdate reagent, 200 μ L steps 1 in the centrifuge tube of 2mL) the enzymic catalytic reaction liquid, 50 μ L0.5M2-mercaptoethanols, the 20 μ LEikonogen reagent (Sodium Pyrosulfite, 10.4M1-amino-beta naphthal-4-sulfonic acid containing 21mM S-WAT, 0.77M) that obtain, after equilibrate at room temperature reaction 30min, measure absorbancy under its 580nm condition.
Through measuring, the enzyme inhibitors prepared of the present embodiment is for the IC of GH3-6 50be 16.00 ± 1.80 μMs, show good enzyme inhibition activity.
Embodiment 2:
1) activation of carboxyl
Under nitrogen protection; naphthoic acid (0.50g is added in the round-bottomed flask of 200mL; 2.90mmol) and CDI (0.56g; 3.43mmol); then in flask, inject the dry acetonitrile of about 50mL with syringe needle, nitrogen protection is about 20min, room temperature reaction 1-2h under air tight condition; obtain intermediate 1, the intermediate 1 prepared need not be separated and can be directly used in next step reaction.
2) coupling
To step 1) add ASA intermediate (1.02g in obtained reaction solution, 2.64mmol), solution turned cloudy, 0.68mLDBU (about 4.47mmol) is added in the condition downhill reaction liquid of ice-water bath, solution becomes clarification, react 8-12h under room temperature air tight condition, the reaction of thin-layer chromatography (TLC) detection display terminates rear underpressure distillation desolvation, obtains white solid.150mLCHCl is added in the white solid obtained 3dissolve, then add the citric acid solution washing of 150mL mass concentration 3%, separated and collected organic phase, repeats this process 2-3 time, merges organic phase; Through anhydrous sodium sulfate drying after organic phase washed with water and saturated common salt water washing, underpressure distillation removes organic solvent, crosses silicagel column subsequently (with volume ratio CHCl 3/ MeOH=12:1 is as moving phase) be separated obtain intermediate 2 (1.07g, yield 75.4%).
3) Deprotection
By intermediate 2 (1.07g, 1.98mmol) join in the HCOOH aqueous solution of 30mL mass concentration 80%, reaction solution is transparent, react under room temperature to TLC detection reaction and terminate, reaction terminates rear removed under reduced pressure solvent and obtains white solid, to obtain target product (0.82g, yield 82.5%) after acetone recrystallization;
The described detailed process with acetone recrystallization is as follows:
The white solid obtained after removed under reduced pressure solvent is added in flask, adds acetone, be heated to reflux state and constantly add new acetone, until white solid all dissolves, filtered while hot, filtrate leaves standstill crystallization under the condition of ice-water bath, filters, washs and namely obtain target product after drying.
The structural formula of described target product is:
The inhibition of enzyme activity measure of merit step of enzyme inhibitors to GH3-6 prepared by the present embodiment is as follows:
1) enzymic catalytic reaction: add Tris-HCl (pH8.0), MgCl in the centrifuge tube of 2mL successively 2, ATP, IAA, aspartic acid, enzyme inhibitors and GH3-6, the cumulative volume controlling centrifugal liquid in pipe is 1mL, and in centrifuge tube, the concentration of Tris-HCl (pH8.0) is 100mM, MgCl 2the concentration that concentration be the concentration of 5mM, ATP is 500 μMs, the concentration of IAA is 100 μMs, the concentration of aspartic acid is 1mM, GH3-6 be 14 μ g/mL, under the condition of 30 DEG C, cultivate 10min;
2) color reaction: successively add 50 μ L21mM ammonium molybdate reagent, 200 μ L steps 1 in the centrifuge tube of 2mL) the enzymic catalytic reaction liquid, 50 μ L0.5M2-mercaptoethanols, the 20 μ LEikonogen reagent (Sodium Pyrosulfite, 10.4M1-amino-beta naphthal-4-sulfonic acid containing 21mM S-WAT, 0.77M) that obtain, after equilibrate at room temperature reaction 30min, measure absorbancy under its 580nm condition.
Through measuring, the enzyme inhibitors prepared of the present embodiment is for the IC of GH3-6 50be 0.45 ± 0.02 μM, show good enzyme inhibition activity.

Claims (7)

1., based on an ASA type enzyme inhibitors of plant hormone regulatory gene GH3, it is characterized in that its structural formula is:
Wherein R is styroyl or naphthyl.
2. a preparation method for the ASA type enzyme inhibitors based on plant hormone regulatory gene GH3 according to claim 1, is characterized in that comprising the following steps:
1) activation of carboxyl
Under nitrogen protection, be dissolved in organic solvent by carboxylic acid and carboxyl activator, confined reaction 1-2h under room temperature, obtains intermediate 1;
Mol ratio between described carboxylic acid and described carboxyl activator is 1:1.1-1.3;
The structural formula of described intermediate 1 is:
R is styroyl or naphthyl;
2) coupling
To step 1) add ASA intermediate in obtained reaction solution, in the condition downhill reaction liquid of ice-water bath, add 1,8-diazacyclo [5.4.0] 11 carbon-7-alkene, react 8-12h under room temperature air tight condition, after separation and purification, obtain intermediate 2;
Mol ratio in reaction solution between intermediate 1, ASA intermediate and 1,8-diazacyclo [5.4.0] 11 carbon-7-alkene is: 1:1:1.8-2.5;
The structural formula of described ASA intermediate is:
The structural formula of described intermediate 2 is:
R is styroyl or naphthyl;
3) Deprotection
Added by intermediate 2 in Deprotection reagent solution, react 1.5-2.5h under room temperature, reaction terminates rear removed under reduced pressure solvent, to obtain target product after acetone recrystallization.
3. preparation method according to claim 2, is characterized in that:
Step 1) described in carboxylic acid be phenylpropionic acid or naphthoic acid; Described carboxyl activator is carbonyl dimidazoles.
4. preparation method according to claim 2, is characterized in that:
Step 1) described in organic solvent be the methylene dichloride of anhydrous acetonitrile, DMF, methyl-sulphoxide or drying.
5. preparation method according to claim 2, is characterized in that:
Step 2) described in the detailed process of separation and purification as follows:
By reaction solution underpressure distillation desolvation after reaction terminates, then add CHCl 3dissolve, then add the citric acid solution washing of mass concentration 3%, separated and collected organic phase, through anhydrous sodium sulfate drying after organic phase washed with water and saturated common salt water washing, underpressure distillation removes CHCl 3, cross silicagel column separation subsequently and obtain intermediate 2.
6. preparation method according to claim 2, is characterized in that:
Step 3) described in Deprotection reagent solution be the HCOOH aqueous solution of mass concentration 80%, the 5-10% hydrochloric acid soln of mass concentration or trifluoroacetic acid.
7. preparation method according to claim 2, is characterized in that:
Step 3) described in as follows with the detailed process of acetone recrystallization:
The white solid obtained after removed under reduced pressure solvent is added in flask, adds acetone, be heated to reflux state and constantly add new acetone, until white solid no longer dissolves, filtered while hot, filtrate leaves standstill crystallization under the condition of ice-water bath, filters, washs and namely obtain target product after drying.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5824657A (en) * 1997-03-18 1998-10-20 Cubist Pharmaceuticals, Inc. Aminoacyl sulfamides for the treatment of hyperproliferative disorders

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8461128B2 (en) * 2005-04-15 2013-06-11 Sloan-Kettering Institute For Cancer Research Anti-microbial agents and uses thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5824657A (en) * 1997-03-18 1998-10-20 Cubist Pharmaceuticals, Inc. Aminoacyl sulfamides for the treatment of hyperproliferative disorders

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
The synthesis of nucleoside sulfamates related to nucleocidin;Shuman DA et al.;《Journal of the American Chemical Society》;19700603;第92卷(第11期);第3434-3440页 *
孙涛等.植物GH3基因家族研究进展.《生物工程学报》.2008,第24卷(第11期),第1860-1866页. *

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