CN105726527B - Purposes of micromolecular compound and combinations thereof - Google Patents
Purposes of micromolecular compound and combinations thereof Download PDFInfo
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- CN105726527B CN105726527B CN201610178193.9A CN201610178193A CN105726527B CN 105726527 B CN105726527 B CN 105726527B CN 201610178193 A CN201610178193 A CN 201610178193A CN 105726527 B CN105726527 B CN 105726527B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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Abstract
Purposes the invention discloses micromolecular compound and combinations thereof, the purposes of the micromolecular compound are specially：Acceptable salt or ester or derivative or their mixture are used to prepare treatment tumour, suppress the material of growth of tumour cell, and/or inducing apoptosis of tumour cell on 2 (4 tert-butyl benzene epoxide) N (2 { [(4 tert-butyl benzene epoxide) acetyl group] amino } ethyl) acetamides or its pharmacy, health care conduct and learning or bromatology, and the composition contains：(1) acceptable salt or ester or derivative or their mixture in compound 2 (4 tert-butyl benzene epoxide) N (2 { [(4 tert-butyl benzene epoxide) acetyl group] amino } ethyl) acetamides or its pharmacy, health care conduct and learning or bromatology；(2) apoptosis medicine is caused；(3) acceptable carrier or excipient in pharmacy, health care conduct and learning or bromatology.
Description
Technical field
The invention belongs to biotechnology and medical domain, and in particular to and one kind is based on bioinformatics and computer technology,
The specificity obtained through virtual screening suppresses the micromolecular compound of NAC1 albumen.The invention further relates to contain the small molecule chemical combination
The pharmaceutical composition of thing, and disclose the method that the compound medicine is used for disease treatment, particularly controlling in malignant tumour
Purposes in treatment.
Background technology
Malignant tumour is to endanger a kind of disease of human health.With oncomolecularbiology, genomics, protein science
Development, the regulatory factor largely to play a crucial role in tumor development is revealed.On this basis, antitumor drug is ground
The great change of hair theory.Research and develop focus just from conventional cell cytotoxic drug to during for tumor development key regulatory because
Sub- direction is developed, these target spot new drugs can reach high selectivity, hypotoxicity for the difference between normal cell and tumour cell
Therapeutic effect, so as to overcome, the poor selectivity of conventional cell cytotoxic drug, toxic side effect are strong, are also easy to produce the shortcomings of drug resistance, are
This, neoplasm targeted therapy enters a brand-new development phase.In recent years, with molecular biology, X-ray crystallography
Development, largely the three-dimensional structure with the relevant large biological molecule of tumour is determined；The fast development of computational science, area of computer aided
Drug design is come into being, and penetrates into the links of new drug development, is greatly enhanced the success rate of medicament research and development, and reduction is ground
Cost is sent out, shortens the R＆D cycle, at present as one of core technology of innovation drug research.
BTB/POZ family gene NACC1 gene code cell transcription factors NAC1 (nucleus accumbens-1, lie prostrate every
Core 1) expression, it is positioned at human chromosome area Ch19p13.2, is a newly discovered new carcinogen.NAC1 is more
(such as oophoroma, cervical carcinoma, carcinoma of endometrium, breast cancer etc.) universal high expression in kind gynecological tumor, and in normal structure not
It is shown in Table and reaches.BTB domains (also referred to as POZ domains) are the important feature domains of mediating proteins interaction, the BZB structures of NAC1
Domain (1-129 amino acid sequences) is formed necessary to NAC1 dimer complex, and the NAC1 dimer complex of formation can be with
Participate in a variety of biological function regulation and control：Such as anti-apoptotic, the propagation that promotees, promote invasion and attack transfer, anti-ageing wait for a long time.
There is experiment to show, NAC1 participates in suppressing cis-platinum, ovarian cellular apoptosis caused by taxol, and apoptotic signal is escaped
Ease is closely related with the occurrence and development of tumour.Since NAC1 is simply specifically in the high expression of tumour cell, and take part in swollen
Resistance of the knurl to apoptotic signal, therefore may can cancel its Apoptosis inhibitor function for the micromolecular compound of the molecule, and
It would be possible to be combined with chemotherapeutics such as cis-platinum, taxols, open up an oncotherapy new strategy.
At present, although having developed some compounds for suppressing tumour growth, but people still need to develop new tool
There is the compound for suppressing tumour growth or inducing apoptosis of tumour cell.
The content of the invention
The present invention seeks to：A kind of compound for having and suppressing growth of tumour cell or inducing apoptosis of tumour cell is provided,
It is a further object of the present invention to provide the pharmaceutical composition made of the compound.
The technical scheme is that：
2- (4- tert-butyl benzenes epoxide)-N- (2- { [(4- tert-butyl benzenes epoxide) acetyl group] amino } ethyl) acetamides or
Acceptable salt or ester or the purposes of derivative or their mixture in its pharmacy, health care conduct and learning or bromatology, its feature exist
In：It is used to prepare treatment tumour, suppresses the material of growth of tumour cell, and/or inducing apoptosis of tumour cell.
Further, the purposes is the inhibitor for preparing people's neucleus accumbens 1.
Further, the tumour or tumour cell are the tumour or tumour cell for expressing people's neucleus accumbens 1.
Further, 1 expression quantity of people's neucleus accumbens of the tumour or tumour cell is higher than normal cell 30%~50%.
Further, the tumour is selected from the group：Breast cancer, lung cancer, stomach cancer, prostate cancer, oophoroma, colon cancer, liver
Cancer, cervical carcinoma, carcinoma of endometrium or B Lymphatic System tumours, preferable tumour are selected from the group：Oophoroma, cervical carcinoma, breast cancer, son
Endometrial carcinoma；More preferably tumour is selected from the group：Oophoroma.
The present invention another technical solution be：
Offer-kind of composition, the composition contain：
(1) compound 2- (4- tert-butyl benzenes epoxide)-N- (2- { [(4- tert-butyl benzenes epoxide) acetyl group] amino } ethyl)
Acceptable salt or ester or derivative or their mixture on acetamide or its pharmacy, health care conduct and learning or bromatology；
(2) apoptosis medicine or tumor vessel is caused to suppress medicine；
(3) acceptable carrier or excipient in pharmacy, health care conduct and learning or bromatology.
Further, the cause apoptosis medicine such as carboplatin, adriamycin, tamoxifen, 5 FU 5 fluorouracil, Coumarin fluorine urine
Pyrimidine, harringtonine, cytarabine, Flutamide, ifosfamide, deoxyfluorouridine, Glass molybdenum, come bend azoles, Teniposide,
Angiostatin, endostatin or Avastin etc., more preferably cis-platinum or taxol.
Further, the 2- (4- tert-butyl benzenes epoxide)-N- (2- { [(4- tert-butyl benzenes epoxide) acetyl group] amino }
Ethyl) weight ratio is 1 between acetamide and cause apoptosis medicine:1000 to 1000:1, preferred weight ratio 1:500-500:1, more
Preferred weight ratio is 1:100-100:1, further preferably weight ratio is 1:50-50:1.
Further, the 2- (4- tert-butyl benzenes epoxide)-N- (2- { [(4- tert-butyl benzenes epoxide) acetyl group] amino }
Ethyl) acetamide accounts for the l-95wt%, more preferably preferably 5-90wt%, 10-80wt%10-80wt% of composition total weight.
Further, the formulation of the composition is tablet, capsule, powder agent, granule, supensoid agent or injection.
When the composition is unit formulation or multi-form, wherein the compound, its acceptable salt pharmaceutically or in health care conduct and learning
Or the content of ester or their mixture is 0.05-50000mg/ agent, preferably 0.1-10000mg/ agent, more preferably 0.5-
5000mg/ agent.
It is an advantage of the invention that：
(a) micromolecular compound of the present invention designed by for people's NAC1 albumen, can efficient targeting suppression anti-apoptotic point
Son ----NAC1 albumen, for treatment of cancer；
(b) micromolecular compound of the invention can also combine with other medicines and treatment means, for malignant tumour
Treatment；
(c) micromolecular compound of the invention has good penetrability, and toxic side effect is small, simple in structure, is readily synthesized etc. excellent
Point.
Brief description of the drawings
Fig. 1 shows that compound AN3294110 can inhibit the formation of NAC1 albumen dimers；
Fig. 2 shows the cell growth inhibition of compound AN3294110 enhancing cis-platinums, and wherein compound used therefor concentration is 10
μM, cis-platin concentrations are 20 μM；
Fig. 3 shows the Apoptosis of AN3294110 enhancing cisplatin inductions, and wherein compound used therefor concentration is 10 μM, suitable
Platinum concentration is 20 μM.
Embodiment
The in-depth study by extensive, it is found that the expression of the intracellular NAC1 of Partial tumors often raises, suppress NAC1's
Expression and function can suppress the propagation of tumour cell and the oncogenic activity of inside and outside.For this reason, the present inventor is by computer aided manufacturing
Drug design is helped to sift out several micromolecular compounds that may be combined with NAC1 from hundreds thousand of a candidate compounds, with
With the method for vitro binding assay and MTT these compounds are carried out with the second wheel screening afterwards, obtaining one first can be strong
Strong enhancing cis-platinum is to the compound AN3294110 of ovarian cancer cell line SKOV3 inhibited proliferations, i.e. micromolecular compound 2-
(4- tert-butyl benzenes epoxide)-N- (2- { [(4- tert-butyl benzenes epoxide) acetyl group] amino } ethyl) acetamide.
Specifically, the research of the present inventor shows, high selectivity expression of the NAC1 in oophoroma tumor tissue, and
Expression is had no in normal ovarian epithelium tissue, prompts NAC1 to occur and grow closely related with tumour.In low expression NAC1
ES2 ovarian cancer cell lines in, the overexpression of NAC1 can substantially resist the apoptosis of cisplatin induction, promote cell growth, prompt it
It is probably a molecule with Anti-G value.In the ovarian cancer tumor cell of high expression NAC1, suppress the expression of NAC1
Sensitiveness of the ovarian cancer cell to cisplatin induction apoptosis can be strengthened, suppress the clonality of tumour cell.Prompt NAC1 very
It is probably the action target spot for treating oophoroma.The research of the present inventor shows that the NAC1 molecules of Anti-G value are given birth in cell
Play an important role during long regulation and control, Apoptosis, tumor development etc..Therefore, NAC1 is likely in clinical tumor
Diagnose and treat in be used as potential candidate targets.
On this basis, the present inventor has screened substantial amounts of compound, so that obtaining a kind of can effectively suppress tumour
Micromolecular compound, the micromolecular compound are right specifically in protein level targeting anti-apoptotic molecule-NAC1 albumen
The biological behaviour for expressing the tumour cell of NAC1 is intervened, so as to effectively suppress the function of NAC1, reaches antitumous effect.
Lower mask body introduction：
As used herein, term " micromolecular compound of the invention ", " compound AN3294110 " or " chemical combination of the present invention
Thing ", " amide derivatives of ethylenediamine of the invention " are used interchangeably, and all point out micromolecular compound 2- (4- tert-butyl benzene oxygen
Base)-N- (2- { [(4- tert-butyl benzenes epoxide) acetyl group] amino } ethyl) acetamides and its pharmaceutically acceptable salt and activity
Derivative.
2- (4- tert-butyl benzenes epoxide)-N- (2- { [(4- tert-butyl benzenes epoxide) acetyl group] amino } ethyl) acetamide is one
Kind targets the lead compound of 1 albumen of people's nucleus accumbens septi (NAC1), its structural formula is as follows：
2- (4- tert-butyl benzenes epoxide)-N- (2- { [(4- tert-butyl benzenes epoxide) acetyl group] amino } ethyl) acetamide is one
Kind of known compound, commercially buys and (is such as purchased from from Dutch Specs companies), organic synthesis side that also can be conventional
Method prepares.
1st, active ingredient
In the present invention, it is preferred to " active ingredient " refer to such micromolecular compound：The compound and people NAC1
Albumen can be combined with each other, and the compound is reduced to the cisplatin combined growth for making oophoroma SKOV3 cells
Less than 50% (reducing at least 50%), is preferably reduced to less than 38%, is more preferably reduced to less than 35%, or be reduced to with
Upper numerical value is between the scope of endpoint.
The amide derivatives of ethylenediamine used can be by pharmaceutically or the acceptable acid of physiology or alkali spread out in the present invention
Raw salt form uses.These salt include but is not limited to：The salt formed with following inorganic acid：As hydrochloric acid, sulfuric acid, nitric acid or
Phosphoric acid；The salt formed with following organic acid, such as acetic acid, oxalic acid, succinic acid or maleic acid；And other salt, include but not limited to：
The salt formed with alkali or alkaline earth metal (such as sodium, potassium, calcium or magnesium).A kind of particularly preferred salt is sodium salt or sylvite.
Present invention additionally comprises in the form of ester (such as carbamate) or other conventional " pro-drugs " (when with this
Form be administered when, active part can be changed into vivo) existing for the compounds of this invention.
The micromolecular compound of the present invention can effectively suppress the function of people's NAC1 albumen, so as to suppress the increasing of tumour cell
Grow, promote the apoptosis of tumour cell.Specifically, micromolecular compound of the invention is directed to people's NAC1 albumen in molecular level, right
The biological behaviour of the tumour cell of positive expression people's NAC1 albumen is reversed.Experiment is proved：(1) expression of NAC1 is suppressed
It can inhibit the propagation of tumour cell with function, promote apoptosis of tumor cells；(2) suppress the expression of NAC1 in vivo and function can inhibit
The external oncogenicity of tumour cell；(3) expression of suppression NAC1 and function can inhibit the growth in tumour cell body.
2nd, pharmaceutical composition
Present invention additionally comprises the amide derivatives containing ethylenediamine and its drug regimen of pharmaceutically acceptable salt or ester
Thing.The amide derivatives and its pharmaceutical composition of the ethylenediamine of the present invention can be used for treating cancer tumour, i.e., are applied to mammal
With the amide derivatives of the ethylenediamine of safe and effective amount.
The compounds of this invention can be combined with other chemotherapeutics, as taxol, carboplatin, adriamycin, tamoxifen, 5- fluorine urine are phonetic
Pyridine, Tegadifur, harringtonine, cytarabine, Flutamide, ifosfamide, deoxyfluorouridine, Glass molybdenum, come
Bend azoles or Teniposide etc.；Tumor vessel suppresses medicine, and such as angiostatin, endostatin, Avastin, can pass through suppression
NAC1 controls, alleviates or cures the treatment of disease, such as the cancer such as oophoroma.In addition, the compound of the present invention can also be with resisting
The Chinese medicine (or its preparation) of tumour shares.
A kind of preferable pharmaceutical composition is also containing cause apoptosis medicine, such as cis-platinum.
When the amide derivatives of ethylenediamine or its pharmaceutically acceptable salt or ester are used to treat tumour, it can be with one kind
Or a variety of pharmaceutically acceptable carriers or excipient mixing, such as solvent, diluent, so as to form pharmaceutical composition.
Liquid carrier includes：Sterile water, polyethylene glycol, nonionic surface active agent and edible oil (such as corn oil, peanut
Oil and sesame oil).Solid-state carrier includes：Starch, lactose, calcium monohydrogen phosphate, microcrystalline cellulose, sucrose and white bole, as long as being adapted to
The characteristic of active ingredient and required specific administration mode.Also can be advantageously in the adjuvant for preparing usually used in pharmaceutical composition
By including such as flavor enhancement, pigment, preservative and antioxidant such as vitamin E, vitamin C, 2,6-di-tert-butyl p-cresol
(BHT) and butylhydroxy anisole (BHA).
In general, the pharmaceutical composition of the present invention includes following formulation：Oral administered dosage form：Such as tablet, capsule, dispersible
Powder, particle or suspension (supensoid agent) (containing such as from about 0.05-5% suspending agents (cosolvent)), syrup (contain such as from about 10-
50% sugar) and elixir (containing about 20-50% ethanol)；Or with sterile injectable solution or suspended form (in isotonic medium
In contain about 0.05-5% cosolvents) carry out parenteral administration.These pharmaceutical preparations are usually containing the pact mixed with carrier
0.001-99.9wt%, preferably 0.5-99.5wt%, preferably 2.5-90wt%, the activity of more preferably 5%-60wt% (weight)
Component (amide derivatives of ethylenediamine or its pharmaceutically acceptable salt or ester), is based on the total weight of the composition.
When preparing pharmaceutical composition, in general, these compounds of the invention can be formulated in nontoxic, inert and medicine
On in acceptable aqueous carrier medium, its pH ordinarily be about 5-8, and preferable pH is about 6-8, although pH value can be with being formulated
The property of material and illness to be treated and be varied from.
Prepared pharmaceutical composition can be administered by conventional route, including (but being not limited to)：In knurl,
It is intramuscular, peritonaeum is interior, intravenous, subcutaneous, intracutaneous, oral or topical administration.It is preferred that intravenous administration approach.
The amide derivatives of ethylenediamine used in the present invention also can parenteral or intraperitoneal administration.Also can suitably be mixed with
These reactive compounds are prepared in the water of surfactant (such as hydroxypropyl cellulose) (as free alkali or pharmaceutically acceptable
Salt) solution or suspension.Dispersion liquid can also be prepared in glycerine, liquid, polyethylene glycol and its mixture in the oil.Normal
Contain preservative under rule storage and use condition, in these preparations to prevent microorganism from growing.
Being adapted to the medicament forms of injection includes：Aseptic aqueous solution or dispersion liquid and aseptic powder (are used for extemporaneous preparation of sterile
Inject solution or dispersion liquid).In all situations, these forms must be sterile and must be that fluid is arranged with being easy to syringe
Go out fluid.It must be stable under conditions of manufacture and storage, and must be able to prevent the pollution of microorganism (such as bacterium and fungi)
Influence.Carrier can be solvent or decentralized medium, wherein containing as water, alcohol (such as glycerine, propane diols and liquid polyethylene glycol), it
Appropriate mixture and vegetable oil.
, can also be with other oncotherapy means (such as radiotherapy) when using the amide derivatives of ethylenediamine of the present invention
Or other therapeutic agent (such as cis-platinum) combinations.
The effective dose of active ingredient used can change with the pattern and the severity of disease to be treated of administration.So
And usually when the compounds of this invention daily with about 0.01-100mg/kg the weight of animals (preferably 0.02-20mg/kg weight, more
The administration of good ground 0.l-l0mg/kg weight) dosage when giving, gratifying effect can be obtained, preferably daily with 1-4 times
Dosage is given, or is administered with sustained release forms.For most of large mammal, daily accumulated dose be about 5-5000mg or
Higher, preferably 10-1000mg.Suitable for dosage form for oral administration, comprising with solid-state or liquid pharmaceutically acceptable carrier
The reactive compound of the about 0.5-500mg of mixing.This dosage is adjusted to provide optimum therapeutic response.For example, by treating
An urgent demand of situation, can be given once daily dosage separated several times, or dosage is reduced pari passu.
In terms of easily prepared and administration position, preferable pharmaceutical composition is fluid composition.The acid amides of ethylenediamine spreads out
The intravenously administrable of biology is preferable.
3rd, Halth-care composition
, in the present invention, can also be by the amide derivative of ethylenediamine in addition to preparing pharmaceutical composition and being used to treat tumour
Acceptable salt or ester or extract are used to prepare Halth-care composition on thing or its health care conduct and learning, for auxiliary treatment swells
Knurl.
In the present invention, the acid amides for the ethylenediamine that Halth-care composition contains safe and effective amount (such as 0.01-99wt%) spreads out
Acceptable carrier in acceptable salt or ester or extract and health care conduct and learning on biology or its health care conduct and learning.
The present invention Halth-care composition can as pharmaceutical composition the ethylenediamine containing same amount amide derivative
Acceptable salt or ester or extract on thing or its health care conduct and learning.In general, in Halth-care composition ethylenediamine amide derivatives
Content can be more lower slightly, such as acceptable salt in the amide derivatives of the ethylenediamine containing 0.01-50wt% or its health care conduct and learning
Or ester.
The Halth-care composition of the present invention, any conventional dosage form can be made by conventional method, preferably
Tablet, oral liquid, granule and capsule preparations.
4th, food additives
It is used for adjuvant therapy of tumors in addition to preparing pharmaceutical composition and being used to treat tumour and as Halth-care composition
In addition, in the present invention, acceptable salt or ester on the amide derivatives of ethylenediamine or its bromatology or extract can also be used
In preparing food additives, for adding in food, the anti-tumor capacity and adjuvant therapy of tumors of object are improved.
In the present invention, the acid amides of ethylenediamine of the food additives containing safe and effective amount (such as 0.01-99wt%) spreads out
Acceptable carrier on biology or its bromatology upper acceptable salt or ester or extract, and bromatology.
The present invention food additives can as pharmaceutical composition or Halth-care composition the second two containing same amount
Acceptable salt or ester or extract on the amide derivatives of amine or its bromatology.In general, in food additives ethylenediamine acyl
The content of amine derivative can be less than the content in health products, such as the amide derivatives of the ethylenediamine containing 0.01-50wt% or its food
Acceptable salt or ester in conduct and learning.
In addition, in appropriate circumstances, will be acceptable in the amide derivatives of the ethylenediamine of the present invention or its bromatology
Salt or ester or extract directly as food additives using being also feasible, as long as they do not interfere with food taste and/
Or appearance.
The food additives of the present invention, can be made any conventional form by conventional method, for example, solution, powder,
Syrup etc..
In order to make the foregoing objectives, features and advantages of the present invention clearer and more comprehensible, it is further with reference to embodiment
Illustrate technical scheme.But the invention is not restricted to listed embodiment, it should also be included in of the presently claimed invention
Other any known changes in interest field.
" one embodiment " or " embodiment " referred to herein refers to may be included at least one implementation of the present invention
A particular feature, structure, or characteristic." in one embodiment " that different places occur in the present specification not refers both to same
A embodiment, nor the single or selective embodiment mutually exclusive with other embodiment.
The experimental method of actual conditions is not specified in the following example, usually according to normal condition, such as Sambrook etc.
People,《Molecular cloning：Laboratory manual》(New York, CSH Press, New York:Cold Spring Harbor
Laboratory Press, 1989) condition described in, or according to the condition proposed by manufacturer.
Unless otherwise stated, otherwise percentage and number are calculated by weight.Unless otherwise defined, it is all used in text
Professional and scientific terms have the same meanings as commonly understood by one of ordinary skill in the art.It is in addition, any similar or equal to described content
Deng method and material all can be applied in the present invention.The preferred methods and materials described herein are for illustrative purposes only.
Cell line
SKOV3 cell lines：Purchased from ATCC, this is a kind of ovarian cancer tumor cell system of positive expression NAC1.
The cultural method of SKOV3 cell lines is as follows：By cell inoculation in the DMEM (InVitrogen containing 10% calf serum
Company) in nutrient solution, 37 degrees Celsius are placed in, cellar culture in the CO2 incubators that volume fraction is 5%, without medicine culture before experiment
Two weeks.
Embodiment
1st, the screening of micromolecular compound (AN3294110)
Carried out using computer assisted virtual screening method.
The dimeric structure of the POZ domain of NAC1 is obtained first from RCSB PDB, analyzes the combination mould of dimer
Formula, calculates the surface configuration of acceptor and hydrophobe property etc. using the SiteFinder functions of MOE, determines to be most suitable for small
200,000 compounds of SPECS compound libraries are carried out pre-treatment, use Oprea's by the avtive spot that molecule inhibitor combines
Leadlikeness filter filter the ADMET properties of compound, retain the molecule for being suitable as lead compound.
Energy minimization is carried out respectively to each compound, it is then successively using rigidity and flexible docking mode, small molecule is right respectively
It is connected to the foregoing active site of acceptor.Calculations incorporated free energy, the molecule for taking combination to be less than -10kcal/mol.Calculate molecule
Topological structure fingerprint, cluster analysis is carried out according to the Tanimoto similarities between fingerprint, comprehensive marking is carried with structure diversity
Structure diversity subset is taken, judges with reference to the visualization to receptor-ligand binding mode, picks out final candidate molecules.
Wherein, AN3294110 micromolecular compounds structural formula shown in formula I, 2- (4- tert-butyl benzenes epoxide)-N- (2-
{ [(4- tert-butyl benzenes epoxide) acetyl group] amino } ethyl) acetamide.
(Formulas I)
2nd, micromolecular compound (AN3294110) can inhibit the dimer of target NAC1 albumen and be formed.
For the AN3294110 (being purchased from Specs companies of Holland) selected, examined by immunoprecipitate, Western blot
Micromolecular compound is surveyed to form the dimer of target NAC1 albumen.
As a result confirm that AN3294110 can inhibit the formation of NAC1 albumen dimers, as shown in Figure 1.
3rd, growth inhibition of the micromolecular compound (AN3294110) to tumour cell
The present embodiment employs conventional mtt assay.Specific method is as follows：
SKOV3 cells are spread into 96 orifice plate overnight incubations with the density of 3000 cells/wells.Then, micromolecular compound
AN3294110 is with cisplatin combined adding hole of the various concentrations (1.25,2.5,5,10,25,50 μM) individually or with 20 μM of final concentrations
In.48 it is small when after, add 10 μ l of MTT (5mg/ml) in every hole, 37 degrees Celsius be incubated 4 it is small when after inhale and abandon supernatant.With 150 μ l bis-
After methyl sulfoxide dissolving purple crystal, microplate reader (Bio-Rad companies) is placed in, detects the absorbance at 570nm.
The results show that AN3294110 can significantly increase the suppression of cis-platinum cell proliferation in 10uM final concentrations, and its list
Solely application does not cause cell significant toxic action, as shown in Figure 2.
4th, detection of the micromolecular compound (AN3294110) to the enhancement effect of cis-platinum killing tumor cell
Ovarian cancer cell line SKOV3 cells are taped against in 24 orifice plates with the density in 20000/hole, when incubation 16-24 is small
Afterwards, AN3294110 is added to 10 μM of final concentration.4 it is small when after, add cis-platinum to 20 μM of final concentration.Act on 48 it is small when after, use
Fluidic cell is used after Annexin V and 7-aminoactinomycin D dyeing (Millipore companies) mark apoptotic cell
Instrument (Beckton Dickinson companies FACS Calibur) detects.
The results are shown in Figure 3：It has been combined apoptosis rate (about 40%) conspicuousness of 20 μM and AN329411010 μM of cis-platinum
Higher than the cell (about 12%) for individually using cis-platinum.It is in addition, consistent with MTT results：Compound is used alone not cause significantly
The apoptosis (5%) of cell.
The compound of the present invention specific can suppress 1 albumen dimer of people's nucleus accumbens septi and form 4 (hPEBP4), therefore can be used for
The high tumour for expressing the albumen for the treatment of, such as oophoroma.
The above embodiments of the present invention the result shows that, the compounds of this invention can stably suppress NAC1, and collaboration cis-platinum kills
Hinder tumour cell.
In conclusion the invention discloses one kind to target 1 anti-tumor small molecular compound of people's nucleus accumbens septi and combinations thereof,
Can efficient targeting suppress anti-apoptotic molecule ----NAC1 albumen, for treatment of cancer；Can also be with other medicines and treatment
Means are combined, the treatment for malignant tumour；With good penetrability, toxic side effect is small, simple in structure, the advantages that being readily synthesized.
It should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to preferable
The present invention is described in detail in embodiment, it will be understood by those of ordinary skill in the art that, can be to the technology of the present invention
Scheme technical scheme is modified or replaced equivalently, without departing from the spirit and scope of technical solution of the present invention, it should all cover in this hair
Among bright right.
Claims (9)
1.2- (4- tert-butyl benzenes epoxide)-N- (2- { [(4- tert-butyl benzenes epoxide) acetyl group] amino } ethyl) acetamides or its
Acceptable salt or ester or derivative or their mixture are being prepared for suppressing target in pharmacy, health care conduct and learning or bromatology
The dimer for marking NAC1 albumen is formed, suppression of the enhancing cis-platinum to tumor cell proliferation, collaboration cis-platinum killing tumor cell, with it is suitable
Platinum is combined to the purposes in the medicine of the suppression of oophoroma.
2. purposes according to claim 1, it is characterised in that：It is used to prepare the inhibitor of people's neucleus accumbens 1.
3. purposes according to claim 1, it is characterised in that：The tumour cell is that the tumour of expression people neucleus accumbens 1 is thin
Born of the same parents.
4. purposes according to claim 3, it is characterised in that：1 expression quantity of people's neucleus accumbens of the tumour cell is higher than just
Normal cell 30%~50%.
5. purposes according to claim 1, it is characterised in that：The tumour cell is selected from oophoroma, cervical carcinoma, breast cancer
Or carcinoma of endometrium.
6. a kind of composition, it is characterised in that the composition contains：
(1) compound 2- (4- tert-butyl benzenes epoxide)-N- (2- { [(4- tert-butyl benzenes epoxide) acetyl group] amino } ethyl) acetyl
Acceptable salt or ester or derivative or their mixture on amine or its pharmacy, health care conduct and learning or bromatology；
(2) apoptosis drugs Cisplatin is caused；
(3) acceptable carrier or excipient in pharmacy, health care conduct and learning or bromatology.
7. composition according to claim 6, it is characterised in that described 2- (the 4- tert-butyl benzenes epoxide)-N- (2-
{ [(4- tert-butyl benzenes epoxide) acetyl group] amino } ethyl) weight ratio is 1 between acetamide and cause apoptosis medicine:10.9-2.9:
1。
8. composition according to claim 6, it is characterised in that described 2- (the 4- tert-butyl benzenes epoxide)-N- (2-
{ [(4- tert-butyl benzenes epoxide) acetyl group] amino } ethyl) acetamide accounts for the 10-80wt% of composition total weight.
9. composition according to claim 6, it is characterised in that the formulation of the composition is tablet, capsule, powder
Agent, granule, supensoid agent or injection.
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| CN109966499A (en) * | 2019-04-25 | 2019-07-05 | 苏州大学 | Synergistic anti-breast cancer diversion medicaments composition and application thereof |
| CN110152001B (en) * | 2019-05-20 | 2021-08-10 | 昆山德瑞生物科技有限公司 | Use of small molecule compound and composition thereof |
| CN112851627B (en) * | 2021-03-08 | 2022-03-18 | 苏州大学 | Small molecule compounds, uses and compositions thereof |
| CN115089719A (en) * | 2022-06-15 | 2022-09-23 | 苏州大学 | Synergistic ovarian cancer immunotherapy pharmaceutical composition and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005089807A2 (en) * | 2004-03-15 | 2005-09-29 | Wyeth | Antibody calicheamicin conjugates for passive targeting |
-
2016
- 2016-03-25 CN CN201610178193.9A patent/CN105726527B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005089807A2 (en) * | 2004-03-15 | 2005-09-29 | Wyeth | Antibody calicheamicin conjugates for passive targeting |
Non-Patent Citations (4)
| Title |
|---|
| NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response;Y Zhang 等;《Oncogene》;20110711;第30卷;第1055-1064页 * |
| NAC-1, a potential stem cell pluripotency factor, contributes to paclitaxel resistance in ovarian cancer through inactivating Gadd45 pathway;N Jinawath 等;《Oncogene》;20090323;第28卷;第1941-1948页 * |
| NAC1对肿瘤细胞糖酵解的调控作用及机制研究;任忆捷;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20160215(第2期);全文 * |
| 核转录因子NAC1在肿瘤发生和发展中的作用和机制研究:对自噬和细胞衰老的调控作用;张熠;《苏州大学博士论文》;20121130;全文 * |
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