CN110272362A - Have both the PAEs molecule preparation method of low estrogen activity and high fluorescent - Google Patents
Have both the PAEs molecule preparation method of low estrogen activity and high fluorescent Download PDFInfo
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- CN110272362A CN110272362A CN201910599483.4A CN201910599483A CN110272362A CN 110272362 A CN110272362 A CN 110272362A CN 201910599483 A CN201910599483 A CN 201910599483A CN 110272362 A CN110272362 A CN 110272362A
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- C07—ORGANIC CHEMISTRY
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- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
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- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
- C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
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- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
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Abstract
The present invention provides a kind of PAEs molecule preparation methods for having both low estrogen activity and high fluorescent, belong to phthalic acid ester MOLECULE DESIGN technical field.This method includes building Pharmacophore Model, molecular modification is carried out to target PAEs molecule using hydrophobic grouping, screen PAEs molecule derivant of the estrogenic activity lower than the estrogenic activity of target PAEs molecule, screen the PAEs molecule derivant that photoluminescence spectrum intensity is higher than the photoluminescence spectrum intensity of target PAEs molecule, screening meets the PAEs molecule derivant of functional character constraint, it screens while meeting bioconcentration threshold value, migration threshold value, toxicity threshold and persistence threshold value PAEs molecule derivant, obtain the PAEs molecule for having both low estrogen activity and high fluorescent.The present invention realizes PAEs low estrogen activity and has high fluorescent MOLECULE DESIGN and highly sensitive detection, provides completely new thinking to design the plasticizer substitute of low estrogen activity high sensitivity.
Description
Technical field
The present invention relates to phthalic acid ester MOLECULE DESIGN technical fields, and in particular to one kind have both low estrogen activity and
The PAEs molecule preparation method of high fluorescent.
Background technique
Phthalic acid ester (Phthalate acid esters, PAEs) is used as plasticizer and softening agent, is widely used
In toy, packaging material for food, medical blood bag and sebific duct, vinyl flooring and wallpaper, detergent, lubricating oil, personal-care supplies
In (such as nail polish, hair spray, perfumed soap and shampoo) number product, belong to the environmental contaminants of key monitoring, wherein adjacent
Rutgers (Dimethyl phthalate, DMP), dibutyl phthalate (Dibutyl phthalate,
DBP), this 3 kinds of PAEs of di-n-octyl phthalate (Di-n-octylphthalate, DNOP) are classified as by the U.S. and China
Environment Priority controls pollutant.Currently, it is commonly found that the presence of PAEs, has become in atmosphere, water body, soil, animal and human body
For global organic pollutant, referred to as the 2nd global " PCB pollutant ".PAEs have apparent teratogenesis, it is carcinogenic,
Mutagenesis, at the same still a kind of typical incretion interferent (Endocrine Disrupting Chemicals,
EDCs)。
Incretion interferent EDCs has the function of quasi- estrogen, can control the generation, release of natural hormone, fortune in body
Defeated, metabolism, elimination, combination and Function are the exogenous materials of generation interference effect during body development.As one kind
Incretion interferent, PAEs have significant quasi-waverider vehicle, can liver organization to the mankind and other organisms, reproduction hair
It educates and central nervous system generates harm.Since molecular structure has larger impact, the different PAEs of structure to estrogen effect
Estrogenic activity has differences, therefore estrogenic activity can be reduced from the point of view of molecular modification.Meanwhile studies have shown that
PAEs molecule after in conjunction with bovine serum albumin can have fluorescent effect, design low estrogen activity, high fluorescence spectrum accordingly
Intensity and the small plasticizer substitute of environmental hazard.
Summary of the invention
The purpose of the present invention is to provide a kind of PAEs molecule preparation sides for having both low estrogen activity and high fluorescent
Method, to solve technical problem present in above-mentioned background technique.
To achieve the goals above, this invention takes following technical solutions:
On the one hand, a kind of PAEs molecule preparation side having both low estrogen activity and high fluorescent provided by the invention
Method includes the following steps:
Step S110: according to the estrogenic activity of target PAEs molecule, pharmacophore corresponding to target PAEs molecule is constructed
Model；
Step S120: according to Pharmacophore Model corresponding to target PAEs molecule, using hydrophobic grouping to target PAEs points
Son carries out molecular modification, obtains PAEs molecule derivant；
Step S130: screening estrogenic activity is lower than the PAEs molecule derivant of the estrogenic activity of target PAEs molecule,
As level-one PAEs molecule derivant；
Step S140: screening photoluminescence spectrum intensity is higher than the level-one PAEs molecule of the photoluminescence spectrum intensity of target PAEs molecule
Derivative, as second level PAEs molecule derivant；
Step S150: screening meets the second level PAEs molecule derivant of functional character constraint, spreads out as three-level PAEs molecule
Biology；Wherein, the functional character constraint includes that edge energy and positive frequency are worth；
Step S160: it screens while meeting bioconcentration threshold value, migration threshold value, toxicity threshold and persistence threshold value
Three-level PAEs molecule derivant obtains the PAEs molecule for having both low estrogen activity and high fluorescent.
Preferably, the step S120 is specifically included:
The selection of target PAEs molecule is determined in conjunction with constructed Pharmacophore Model according to target PAEs molecular structure
Phenyl ring is upper to be set to decorating site, using hydrophobic grouping to disubstituted reaction is carried out at the decorating site, to target PAEs points
Son carries out molecular modification；Wherein, the hydrophobic grouping includes sulfydryl, methyl, ethyl and methoxyl group；
Using the B3LYP method in density functional theory, the ground state of the target PAEs molecule derivant after optimization modification is several
What structure, wherein base group is 6-31G, obtains PAEs molecule derivant.
Preferably, in step S140, for target PAEs molecule, PAEs molecule and ox blood are simulated using molecular docking method
The combination of albumin BSA, the photoluminescence spectrum intensity of the target PAEs molecule in conjunction with after.
Preferably, the bioconcentration threshold value is the logarithm of living being concentration ratio, and the migration threshold value is vapour pressure
Negative logarithm, the toxicity threshold be biology half lethal concentration, the persistence threshold value be half-life period logarithm.
Preferably, the target PAEs molecule is repefral DMP molecule.
Preferably, the target PAEs molecule is dibutyl phthalate DBP molecule.
Preferably, the target PAEs molecule is di-n-octyl phthalate DNOP molecule.
On the other hand, the present invention provide it is a kind of using method as described above preparation have both low estrogen activity and Gao Ying
The DMP molecule of luminous intensity, molecular structural formula are one of following structural:
On the other hand, the present invention provide it is a kind of using method as described above preparation have both low estrogen activity and Gao Ying
The DBP molecule of luminous intensity, molecular structural formula are one of following structural:
On the other hand, the present invention provide it is a kind of using method as described above preparation have both low estrogen activity and Gao Ying
The DNOP molecule of luminous intensity, molecular structural formula are one of following structural:
That the invention has the advantages that: this method is easy to operate, it is quick, easy to accomplish to calculate, not only can be with theoretical validation PAEs
The feasibility of molecular modification and detection scheme, and can more deeply probe into the four big characteristics of PAEs (toxicity, is held at migration
Long property, bioconcentration), functional characteristic (stability, insulating properties) and the mechanism for making PAEs have Fluorescence Characteristic grinds
Study carefully, to realize PAEs low estrogen activity and there is high fluorescent MOLECULE DESIGN and highly sensitive detection to provide direct method.
In addition, the low estrogen activity provided by the invention based on Pharmacophore Model has both the molecular design method research and development week of high fluorescent
Phase is short, at low cost, can save a large amount of human and material resources and financial resources, for the plasticizer for designing low estrogen activity high sensitivity
Substitute provides completely new thinking.
The additional aspect of the present invention and advantage will be set forth in part in the description, these will become from the following description
Obviously, or practice through the invention is recognized.
Detailed description of the invention
In order to illustrate the technical solution of the embodiments of the present invention more clearly, required use in being described below to embodiment
Attached drawing be briefly described, it should be apparent that, drawings in the following description are only some embodiments of the invention, for this
For the those of ordinary skill of field, without creative efforts, it can also be obtained according to these attached drawings others
Attached drawing.
Fig. 1 is the PAEs molecule preparation method that low estrogen activity and high fluorescent are had both described in the embodiment of the present invention
Flow chart.
Fig. 2 is the PAEs molecule preparation side that low estrogen activity and high fluorescent are had both described in the embodiment of the present invention 4
Method flow chart.
Specific embodiment
It is exemplary below with reference to the embodiment of attached drawing description, for explaining only the invention, and cannot explain
For limitation of the present invention.
Those skilled in the art of the present technique are appreciated that unless expressly stated, singular " one " used herein, " one
It is a ", " described " and "the" may also comprise plural form.It is to be further understood that being arranged used in specification of the invention
Diction " comprising " refer to that there are the feature, integer, step, operation, element and/or modules, but it is not excluded that in the presence of or addition
Other one or more features, integer, step, operation, element, module and/or their group.
Those skilled in the art of the present technique are appreciated that unless otherwise defined, all terms used herein (including technology art
Language and scientific term) there is meaning identical with the general understanding of those of ordinary skill in fields of the present invention.Should also
Understand, those terms such as defined in the general dictionary, which should be understood that, to be had and the meaning in the context of the prior art
The consistent meaning of justice, and unless defined as here, it will not be explained in an idealized or overly formal meaning.
In order to facilitate understanding of embodiments of the present invention, further by taking specific embodiment as an example below in conjunction with attached drawing to be solved
Explanation is released, and embodiment does not constitute the restriction to the embodiment of the present invention.
Those of ordinary skill in the art are it should be understood that attached drawing is the schematic diagram of one embodiment, the portion in attached drawing
Part or device are not necessarily implemented necessary to the present invention.
Embodiment 1
As shown in Figure 1, the embodiment of the present invention 1 provides a kind of DMP molecule for having both low estrogen activity and high fluorescent
Preparation method includes the following steps:
Step S110: according to the estrogenic activity of target DMP molecule, pharmacophore mould corresponding to target DMP molecule is constructed
Type；
Step S120: according to Pharmacophore Model corresponding to target DMP molecule, using hydrophobic grouping to target DMP molecule
Molecular modification is carried out, DMP molecule derivant is obtained；
Step S130: screening estrogenic activity is made lower than the DMP molecule derivant of the estrogenic activity of target DMP molecule
For level-one DMP molecule derivant；
Step S140: the level-one DMP molecule for the photoluminescence spectrum intensity that screening photoluminescence spectrum intensity is higher than target DMP molecule spreads out
Biology, as second level DMP molecule derivant；
Step S150: screening meets the second level DMP molecule derivant of functional character constraint, derivative as three-level DMP molecule
Object；Wherein, the functional character constraint includes that edge energy and positive frequency are worth；
Step S160: it screens while meeting bioconcentration threshold value, migration threshold value, toxicity threshold and persistence threshold value
Three-level DMP molecule derivant obtains the DMP molecule for having both low estrogen activity and high fluorescent.
The step S120 is specifically included:
The selection benzene of target DMP molecule is determined in conjunction with constructed Pharmacophore Model according to target DMP molecular structure
Ring is upper to be set to decorating site, using hydrophobic grouping to carrying out disubstituted reaction at the decorating site, to target DMP molecule into
Row molecular modification；Wherein, the hydrophobic grouping includes sulfydryl, methyl, ethyl and methoxyl group；
Using the B3LYP method in density functional theory, the ground state geometry of the target DMP molecule derivant after optimization modification
Structure, wherein base group is 6-31G, obtains totally 6 kinds of DMP molecule derivant, structural formula is as follows:
In step S140, for target DMP molecule, DMP molecule and bovine serum albumin BSA are simulated using molecular docking method
Combination, the photoluminescence spectrum intensity of the target DMP molecule in conjunction with after.
The bioconcentration threshold value is the logarithm of living being concentration ratio, and the migration threshold value is negative pair of vapour pressure
Number, the toxicity threshold are the half lethal concentration of biology, and the persistence threshold value is the logarithm of half-life period.
In the embodiment of the present invention 1, using DMP points for having both low estrogen activity and high fluorescent of above method preparation
Son, molecular structural formula are one of following structural:
Embodiment 2
As shown in Figure 1, the embodiment of the present invention 2 provides a kind of DBP molecule for having both low estrogen activity and high fluorescent
Preparation method includes the following steps:
Step S110: according to the estrogenic activity of target DBP molecule, pharmacophore mould corresponding to target DBP molecule is constructed
Type；
Step S120: according to Pharmacophore Model corresponding to target DBP molecule, using hydrophobic grouping to target DBP molecule
Molecular modification is carried out, DBP molecule derivant is obtained；
Step S130: screening estrogenic activity is made lower than the DBP molecule derivant of the estrogenic activity of target DBP molecule
For level-one DBP molecule derivant；
Step S140: the level-one DBP molecule for the photoluminescence spectrum intensity that screening photoluminescence spectrum intensity is higher than target DBP molecule spreads out
Biology, as second level DBP molecule derivant；
Step S150: screening meets the second level DBP molecule derivant of functional character constraint, derivative as three-level DBP molecule
Object；Wherein, the functional character constraint includes that edge energy and positive frequency are worth；
Step S160: it screens while meeting bioconcentration threshold value, migration threshold value, toxicity threshold and persistence threshold value
Three-level DBP molecule derivant obtains the DBP molecule for having both low estrogen activity and high fluorescent.
The step S120 is specifically included:
The selection benzene of target DBP molecule is determined in conjunction with constructed Pharmacophore Model according to target DBP molecular structure
Ring is upper to be set to decorating site, using hydrophobic grouping to carrying out disubstituted reaction at the decorating site, to target DBP molecule into
Row molecular modification；Wherein, the hydrophobic grouping includes sulfydryl, methyl, ethyl and methoxyl group；
Using the B3LYP method in density functional theory, the ground state of the target PAEs molecule derivant after optimization modification is several
What structure, wherein base group is 6-31G, obtains totally 6 kinds of DBP molecule derivant, structural formula is as follows:
In step S140, for target DBP molecule, DBP molecule and bovine serum albumin BSA are simulated using molecular docking method
Combination, the photoluminescence spectrum intensity of the target DBP molecule in conjunction with after.
The bioconcentration threshold value is the logarithm of living being concentration ratio, and the migration threshold value is negative pair of vapour pressure
Number, the toxicity threshold are the half lethal concentration of biology, and the persistence threshold value is the logarithm of half-life period.
In the embodiment of the present invention 2, low estrogen activity and high fluorescent are had both using method as described above preparation
DBP molecular structural formula be one of following structural:
Embodiment 3
As shown in Figure 1, the embodiment of the present invention 3 provides a kind of DNOP molecule for having both low estrogen activity and high fluorescent
Preparation method includes the following steps:
Step S110: according to the estrogenic activity of target DNOP molecule, pharmacophore corresponding to target DNOP molecule is constructed
Model；
Step S120: according to Pharmacophore Model corresponding to target DNOP molecule, using hydrophobic grouping to target DNOP points
Son carries out molecular modification, obtains DNOP molecule derivant；
Step S130: screening estrogenic activity is lower than the DNOP molecule derivant of the estrogenic activity of target DNOP molecule,
As level-one DNOP molecule derivant；
Step S140: screening photoluminescence spectrum intensity is higher than the level-one DNOP molecule of the photoluminescence spectrum intensity of target DNOP molecule
Derivative, as second level DNOP molecule derivant；
Step S150: screening meets the second level DNOP molecule derivant of functional character constraint, spreads out as three-level DNOP molecule
Biology；Wherein, the functional character constraint includes that edge energy and positive frequency are worth；
Step S160: it screens while meeting bioconcentration threshold value, migration threshold value, toxicity threshold and persistence threshold value
Three-level DNOP molecule derivant obtains the DNOP molecule for having both low estrogen activity and high fluorescent.
The step S120 is specifically included:
The selection of target DNOP molecule is determined in conjunction with constructed Pharmacophore Model according to target DNOP molecular structure
Phenyl ring is upper to be set to decorating site, using hydrophobic grouping to disubstituted reaction is carried out at the decorating site, to target DNOP points
Son carries out molecular modification；Wherein, the hydrophobic grouping includes sulfydryl, methyl, ethyl and methoxyl group.
Using the B3LYP method in density functional theory, the ground state of the target DNOP molecule derivant after optimization modification is several
What structure, wherein base group is 6-31G, obtains totally 6 kinds of DNOP molecule derivant, structural formula difference is as follows:
In step S140, for target DNOP molecule, DNOP molecule and bovine serum albumin are simulated using molecular docking method
The combination of BSA, the photoluminescence spectrum intensity of the target DNOP molecule in conjunction with after.
The bioconcentration threshold value is the logarithm of living being concentration ratio, and the migration threshold value is negative pair of vapour pressure
Number, the toxicity threshold are the half lethal concentration of biology, and the persistence threshold value is the logarithm of half-life period.
In the embodiment of the present invention 3, low estrogen activity and high fluorescent are had both using method as described above preparation
DNOP molecular structural formula be one of following structural:
Embodiment 4
The embodiment of the present invention 4 devises a kind of MOLECULE DESIGN side PAEs for having both low estrogen activity and high fluorescent
Method, for obtain target PAEs (DMP, DBP, DNOP) molecule is corresponding, meet it is specified require target PAEs (DMP, DBP,
DNOP the structural formula of) molecule derivant, three kinds of PAEs (DMP, DBP, DNOP) molecules is as follows:
In specific practical application, this method specifically comprises the following steps.
Step A. according to the estrogenic activity of target PAEs (DMP, DBP, DNOP) molecule, estrogenic activity data quoted from
Estimation Program Interface (EPI) Suite database, estrogenic activity index half effective concentration
(EC50) it indicates, medium effective concentration (EC50) refers to that drug generates 50% ceiling effect to corresponding symptom in effect experiment
When concentration；Using Accelrys company, the U.S. exploitation 4.0 software of Discovery Studio (DS,
Www.accelrys.com Pharmacophore Model corresponding to target PAEs (DMP, DBP, DNOP) molecule) is constructed.
According to the estrogenic activity of target PAEs molecule, 3D-QSAR pharmacophore mould corresponding to target PAEs molecule is constructed
Type, wherein 3D-QSAR (Three-dimensional quantitative structure-activity
Relationship, three-dimensional quantitative structure activity relationship) it is the side for introducing molecule three-dimensional structure information and carrying out Quantitative Structure-Activity Relationship Study
Method.
Step B. is according to target PAEs (DMP, DBP, DNOP) molecular structure, in conjunction with constructed Pharmacophore Model, really
Surely the specific site modified for PAEs (DMP, DBP, DNOP) molecule, selection specify each hydrophobic grouping for target PAEs
(DMP, DBP, DNOP) molecule carries out molecular modification, obtains PAEs to be detected (DMP, DBP, DNOP) molecule derivant total 18
Kind.
In practical application, constructed Pharmacophore Model is combined by PAEs (DMP, DBP, DNOP) molecular structure, really
Surely it chooses position on phenyl ring to modify PAEs (DMP, DBP, DNOP) molecule, choosing 4 kinds of specified hydrophobic groupings is modification
Group, including sulfydryl (Sulfhydryl ,-SH), methyl (Methyl ,-CH3), ethyl (Ethyl ,-CH2CH3) and methoxyl group
(Methoxy ,-OCH3), to disubstituted reaction is carried out at above-mentioned site, to obtain each PAEs to be detected (DMP, DBP, DNOP)
Molecule derivant.
Then optimize the ground state geometry of each PAEs to be detected (DMP, DBP, DNOP) molecule derivant, update each to be checked
PAEs (DMP, DBP, DNOP) molecule derivant is surveyed, and enters step C；Wherein, in practical application, using in density functional theory
B3LYP method, optimize the ground state geometry of each PAEs (DMP, DBP, DNOP) molecule derivant to be detected, wherein base group is
6-31G(d)。
The corresponding estrogenic activity of each PAEs (DMP, DBP, DNOP) molecule derivant difference to be detected of step C. acquisition,
Estrogenic activity numerical value change corresponding to relative target PAEs molecule；Then screening obtains wherein estrogenic activity numerical value and is lower than in advance
If each PAEs molecule derivant to be detected of threshold value, subsequently into step D.
Step D. be directed to target PAEs molecule, the combination of simulated target PAEs molecule and bovine serum albumin (BSA), obtain and
Target PAEs molecular fluorescence spectroscopy intensity after BSA combination, subsequently into step E；
In practical application, using the Dock-Ligands (Libdock) in 4.0 software package of Discovery Studio
Module, the combination of PAEs (DMP, DBP, DNOP) molecule and bovine serum albumin (BSA) is simulated by molecular docking method, and is obtained
Target PAEs (DMP, DBP, DNOP) molecular fluorescence spectroscopy intensity in conjunction with after, bovine serum albumin structure are originated from Protein Data
Bank (http://www.rcsb.org/pdb), and PDB ID is 3V03.
Step E. obtains the corresponding photoluminescence spectrum intensity of each PAEs molecule derivant difference to be detected, relative target PAEs
The variation of fluorescence spectrum peak intensity corresponding to molecule；Then screening obtains wherein fluorescence spectrum enhancing and low estrogen is active each to be checked
PAEs molecule derivant is surveyed, as each target PAEs molecule derivant.
Step F. is lower than each to be checked of preset threshold and high fluorescent for obtained estrogenic activity numerical value is screened in step E
PAEs molecule derivant is surveyed, as each primary PAEs molecule derivant.
It is directed to each primary PAEs molecule derivant respectively, calculates and obtains energy gap corresponding to primary PAEs molecule derivant
Value, positive frequency are worth, as functional character corresponding to primary PAEs molecule derivant；Then screening obtains while meeting default energy
Gap value, default positive frequency are worth each primary PAEs molecule derivant of threshold value, as each target PAEs molecule derivant, subsequently into
Step G.
Screening in step F is obtained while being met default edge energy threshold value, each primary of default positive frequency value threshold value by step G.
PAEs molecule derivant, as each middle rank PAEs molecule derivant.
Bioconcentration, migration, toxicity and persistence number corresponding to each middle rank PAEs molecule derivant are obtained respectively
According to, wherein bioconcentration parameter is logBCF value (logarithm of living being concentration ratio), and migration parameter is pPL value (vapour pressure
Negative logarithm), toxicity parameter be LC50 value (to the half lethal concentration of fish), persistent parameters be logt1/2 value (half-life period
Logarithm).
Then screening obtain meet default bioconcentration threshold value, default migration threshold value simultaneously, preset toxicity threshold and
The advanced PAEs molecule derivant of default persistence threshold value.
I.e. finishing screen selects 12 kinds of low estrogen activity and the PAEs molecule with high fluorescent, as follows:
Its functional characteristic (stability, insulating properties), which is not affected by, to be significantly affected, at the same have lower persistence, migration,
The PAEs molecule derivant of toxicity and bioconcentration.
In conclusion the method that the embodiment of the present invention proposes utilizes 3D-QSAR Pharmacophore Model and molecular docking technology
(Dock-Ligands) combine density functional theory (DFT) have studied a series of design and rational of PAEs molecules, performance transformation and
Screening process, not only can be with theoretical validation PAEs molecular modification and the feasibility of detection scheme, but also can more deeply probe into
The big characteristic of the four of PAEs (toxicity, migration, persistence, bioconcentration), functional characteristic (stability, insulating properties) and make
PAEs has the mechanism study of Fluorescence Characteristic, to realize PAEs low estrogen activity and having high fluorescent MOLECULE DESIGN
And highly sensitive detection provides direct method, meanwhile, it is provided to design the plasticizer substitute of low estrogen activity high sensitivity
Completely new thinking.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
In the technical scope disclosed by the present invention, any changes or substitutions that can be easily thought of by anyone skilled in the art,
It should be covered by the protection scope of the present invention.Therefore, protection scope of the present invention should be with scope of protection of the claims
Subject to.
Claims (10)
1. a kind of PAEs molecule preparation method for having both low estrogen activity and high fluorescent, which is characterized in that including as follows
Step:
Step S110: according to the estrogenic activity of target PAEs molecule, Pharmacophore Model corresponding to target PAEs molecule is constructed；
Step S120: according to Pharmacophore Model corresponding to target PAEs molecule, using hydrophobic grouping to target PAEs molecule into
Row molecular modification obtains PAEs molecule derivant；
Step S130: screening estrogenic activity is lower than the PAEs molecule derivant of the estrogenic activity of target PAEs molecule, as
Level-one PAEs molecule derivant；
Step S140: the level-one PAEs molecule that screening photoluminescence spectrum intensity is higher than the photoluminescence spectrum intensity of target PAEs molecule is derivative
Object, as second level PAEs molecule derivant；
Step S150: screening meets the second level PAEs molecule derivant of functional character constraint, as three-level PAEs molecule derivant；
Wherein, the functional character constraint includes that edge energy and positive frequency are worth；
Step S160: it screens while meeting bioconcentration threshold value, migration threshold value, the three-level of toxicity threshold and persistence threshold value
PAEs molecule derivant obtains the PAEs molecule for having both low estrogen activity and high fluorescent.
2. the PAEs molecule preparation method according to claim 1 for having both low estrogen activity and high fluorescent, special
Sign is that the step S120 is specifically included:
The selection phenyl ring of target PAEs molecule is determined in conjunction with constructed Pharmacophore Model according to target PAEs molecular structure
It is upper to be set to decorating site, using hydrophobic grouping to carrying out disubstituted reaction at the decorating site, to target PAEs molecule into
Row molecular modification；Wherein, the hydrophobic grouping includes sulfydryl, methyl, ethyl and methoxyl group；
Using the B3LYP method in density functional theory, the ground state geometry knot of the target PAEs molecule derivant after optimization modification
Structure, wherein base group is 6-31G, obtains PAEs molecule derivant.
3. the PAEs molecule preparation method according to claim 1 for having both low estrogen activity and high fluorescent, special
Sign is, in step S140, for target PAEs molecule, simulates PAEs molecule and bovine serum albumin using molecular docking method
The combination of BSA, the photoluminescence spectrum intensity of the target PAEs molecule in conjunction with after.
4. the PAEs molecule preparation method according to claim 1 for having both low estrogen activity and high fluorescent, special
Sign is: the bioconcentration threshold value is the logarithm of living being concentration ratio, and the migration threshold value is the negative logarithm of vapour pressure,
The toxicity threshold is the half lethal concentration of biology, and the persistence threshold value is the logarithm of half-life period.
5. the PAEs molecule preparation side according to claim 1-4 for having both low estrogen activity and high fluorescent
Method, it is characterised in that: the target PAEs molecule is repefral DMP molecule.
6. the PAEs molecule preparation side according to claim 1-4 for having both low estrogen activity and high fluorescent
Method, it is characterised in that: the target PAEs molecule is dibutyl phthalate DBP molecule.
7. the PAEs molecule preparation side according to claim 1-4 for having both low estrogen activity and high fluorescent
Method, it is characterised in that: the target PAEs molecule is di-n-octyl phthalate DNOP molecule.
8. a kind of PAEs points for having both low estrogen activity and high fluorescent using method as claimed in claim 5 preparation
Son, which is characterized in that its molecular structural formula is one of following structural:
9. a kind of utilize PAEs points for having both low estrogen activity and high fluorescent prepared method as claimed in claim 6
Son, which is characterized in that its molecular structural formula is one of following structural:
10. a kind of utilize the PAEs for having both low estrogen activity and high fluorescent prepared the method for claim 7
Molecule, which is characterized in that its molecular structural formula is one of following structural:
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101059520A (en) * | 2007-05-29 | 2007-10-24 | 南京大学 | Organic ER affinity quick screening and forecast method based on receptor binding mode |
| CN106526054A (en) * | 2016-11-24 | 2017-03-22 | 复旦大学 | Method for rapid analysis of phthalate metabolites, bisphenol A and estrogen in urine |
| CN109839371A (en) * | 2019-03-28 | 2019-06-04 | 南京源恒环境研究所有限公司 | A kind of high Raman spectrum PBDEs molecule derivant detection screening technique |
| CN109932348A (en) * | 2019-03-28 | 2019-06-25 | 南京源恒环境研究所有限公司 | A kind of PAEs molecule sensitivity detection screening technique based on disubstituted modification |
-
2019
- 2019-07-04 CN CN201910599483.4A patent/CN110272362A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101059520A (en) * | 2007-05-29 | 2007-10-24 | 南京大学 | Organic ER affinity quick screening and forecast method based on receptor binding mode |
| CN106526054A (en) * | 2016-11-24 | 2017-03-22 | 复旦大学 | Method for rapid analysis of phthalate metabolites, bisphenol A and estrogen in urine |
| CN109839371A (en) * | 2019-03-28 | 2019-06-04 | 南京源恒环境研究所有限公司 | A kind of high Raman spectrum PBDEs molecule derivant detection screening technique |
| CN109932348A (en) * | 2019-03-28 | 2019-06-25 | 南京源恒环境研究所有限公司 | A kind of PAEs molecule sensitivity detection screening technique based on disubstituted modification |
Non-Patent Citations (3)
| Title |
|---|
| CHU, ZHENHUA 等: "Designing modified polybrominated diphenyl ether BDE-47, BDE-99, Designing modified polybrominated diphenyl ether BDE-47, BDE-99,BDE-100, BDE-183, and BDE-209 molecules with decreased estrogenic activities using 3D-QSAR, pharmacophore models coupled", 《JOURNAL OF HAZARDOUS MATERIALS》 * |
| 邱尤丽 等: "一种环境友好型的PAEs荧光光谱衍生分子修饰方法", 《光谱学与光谱分析》 * |
| 邱尤丽 等: "基于药效团模型设计的PAEs分子拉曼特征振动光谱衍生增强研究", 《光谱学与光谱分析》 * |
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