CN109776357A - A small molecule inhibitor containing cycloheptatrienolone and its application in inhibiting ornithine decarboxylase (ODC) - Google Patents
A small molecule inhibitor containing cycloheptatrienolone and its application in inhibiting ornithine decarboxylase (ODC) Download PDFInfo
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- CN109776357A CN109776357A CN201910185996.0A CN201910185996A CN109776357A CN 109776357 A CN109776357 A CN 109776357A CN 201910185996 A CN201910185996 A CN 201910185996A CN 109776357 A CN109776357 A CN 109776357A
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- odc
- ornithine decarboxylase
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- micromolecular inhibitor
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- 102000052812 Ornithine decarboxylases Human genes 0.000 title claims abstract description 79
- 108700005126 Ornithine decarboxylases Proteins 0.000 title claims abstract description 79
- 239000003112 inhibitor Substances 0.000 title claims abstract description 47
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 14
- 150000003384 small molecules Chemical class 0.000 title abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 10
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- 238000002360 preparation method Methods 0.000 claims abstract description 5
- MDYOLVRUBBJPFM-UHFFFAOYSA-N tropolone Chemical compound OC1=CC=CC=CC1=O MDYOLVRUBBJPFM-UHFFFAOYSA-N 0.000 claims description 20
- 238000011282 treatment Methods 0.000 claims description 7
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 abstract description 6
- -1 cycloheptatrienol ketone Chemical class 0.000 abstract description 5
- 244000000010 microbial pathogen Species 0.000 abstract description 4
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- 238000000034 method Methods 0.000 description 16
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- 102000004169 proteins and genes Human genes 0.000 description 11
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- 238000006243 chemical reaction Methods 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
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- 239000007788 liquid Substances 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
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- 239000006228 supernatant Substances 0.000 description 6
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- 230000004044 response Effects 0.000 description 5
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- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 4
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- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 3
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明提供一种含环庚三烯酚酮小分子抑制剂，该小分子抑制剂为4‑[3‑(2‑羟基‑3‑氧代‑1,4,6‑环庚三烯‑1‑基)‑3‑氧代‑1‑丙烯基]苄腈，其结构式为：本发明将该含环庚三烯酚酮小分子抑制剂在抑制鸟氨酸脱羧酶(ODC)上的应用，以及在制备治疗肿瘤药物中的应用，及在制备治疗病原微生物感染药物中的应用，并取得显著效果。
The invention provides a cycloheptatrienol ketone-containing small molecule inhibitor, the small molecule inhibitor is 4-[3-(2-hydroxy-3-oxo-1,4,6-cycloheptatriene-1 -base)-3-oxo-1-propenyl] benzonitrile, its structural formula is: The invention provides the application of the cycloheptatrienol ketone-containing small molecule inhibitor in inhibiting ornithine decarboxylase (ODC), the application in the preparation of a drug for treating tumors, and the application in the preparation of a drug for treating pathogenic microorganism infection , and achieved remarkable results.
Description
Technical field
The present invention relates to ornithine decarboxylase (Ornithine decarboxylase；ODC micromolecular inhibitor) and its
Using, and in particular to the micromolecular inhibitor of source of people ornithine decarboxylase and its application in inhibition and killing tumor cell.
Background technique
Protein is one of main constituents of organism, is the main matter for completing various vital movements.Various
In protein, protease is most important to vital movement, the intracorporal biochemical reaction process of almost all creatures all by protease into
Row catalysis.There is the activity of various protease stringent regulatory mechanism to cause once its regulatory mechanism goes wrong in organism
The hyperactivity of protease, too low or complete deactivation, can all cause corresponding various diseases.Therefore, it is adjusted by drug
The activity for controlling protease makes it restore and be maintained at normal level, has very important theory significance and realistic meaning.With knot
Drug design based on structure, is the very important means designed using protein as the drug of target.
Polyamines (polyamines) is a kind of positively charged cation micro molecule generated from amino acid metabolism, in all lifes
All exist in object, it is all indispensable to cell growth, differentiation, survival and natural biological function etc..The more positive charges of polyamines band
Characteristic, enable them to make by forming electrostatic with negatively charged large biological molecule (DNA, RNA, protein, cell membrane etc.)
With to regulate and control very extensive biological process, including chromosome knob is configured to, DNA is synthesized and stabilization, DNA replication dna, transcription
It is generated with translation, protein phosphorylation, ribosomes, ion channel and regulation, the radicals scavenging of film surface receptor etc..Natural
There are many kinds of polyamines.In mammals, there are three types of naturally occurring, i.e. putrescine (putrescine), spermidine
(spermidine), spermine (spermine), they are essential to mammal normal growth and development.Since polyamines has
Important biological function, Intracellular levels are by stringent regulation.It is more such as tumour cell in the cell quickly bred
Amine level and ODC expression also can rise and lack of proper care.Polyamine level increase, along with cell Proliferation accelerate, apoptosis reduce, with
And tumor-infiltrated and metastasis related gene expression raising etc..Therefore, the regulation of polyamines, becomes oncotherapy and drug is ground
An important means in hair.
The starting material of Polyamine Metabolism is ornithine (ornithine), it is arginine in urea cycle (urea
Cycle the reaction product being catalyzed in) by arginase (arginase).ODC is first enzyme of polyamines route of synthesis, catalysis from
Ornithine (ornithine) arrives the reaction of putrescine, and step catalysis reaction is also a rate-limiting step of polyamines route of synthesis.Cause
This, synthesizes ODC inhibitor, inhibits the generation of putrescine, be a currently very popular oncotherapy approach.Simultaneously as sick
Pathogenic microorganism is also required to normal polyamine level, and ODC inhibitor also becomes for pathogenic microorganism (as led to African typanosomiasis nagana
Trypanosoma bocagei) important target.
Currently, the inhibitor DFMO (alpha-difluoromethyl ornithine) of ODC has been used for clinic, assists the chemotherapy of cancer.
But it is weaker with the binding ability of ODC, and activity is very high, and due to being the suicide inhibitor for forming covalent bond with ODC, poison
Side effect is very big.Therefore, it is highly desirable to develop the ODC new inhibitor with more preferable effect.
Summary of the invention
The purpose of the present invention is provide a kind of for the novel small of ODC by computer assisted high-flux medicaments sifting
Molecule inhibitor is applied to the inhibitor of ornithine decarboxylase, may can be used for preparing treatment tumour, pathogenic microorganism
The drug of infection.Specifically:
A kind of micromolecular inhibitor containing tropolone, the structural formula of the micromolecular inhibitor are as follows:
Application on ornithine decarboxylase (ODC) is being inhibited using above-mentioned micromolecular inhibitor containing tropolone.
Using application of the micromolecular inhibitor containing tropolone in preparation tumor.
The method that above-mentioned micromolecular inhibitor containing tropolone is used to inhibit ornithine decarboxylase (ODC), including
Following steps:
1) building of ODC prokaryotic expression plasmid
The gene order of ODC is inserted into pET28a plasmid, is constructed by BamH I and Xho I restriction enzyme site
PET28a-hODC plasmid, is verified through DNA sequencing；
2) expression of ODC albumen
The pET28a-hODC plasmid that step 1) constructs is passed through into CaCl2Method is transformed into e. coli strain bl21, is led to
It crosses kanamycins to be screened, the bacterial strain that then will be grown on Luria-Bertani (LB) culture plate containing kanamycin,
It is seeded in LB liquid medium containing kanamycin, cultivates in 37 DEG C, 250rpm to logarithmic growth phase, then add isopropyl
Thiogalactoside (IPTG) to 0.5mM, 28 DEG C inducing expression 4 hours, finally, bacterium is collected by centrifugation；
3) purifying of ODC albumen
The bacterium that will be collected in step 2), is suspended again with lysate, then carries out cell cracking by ultrasonic method, then
By lysate in 4 DEG C, 12000 turns/min, after centrifugation, retain supernatant；Supernatant is finally utilized into Ni-NTA His label protein knot
It closes filler to be combined and purify, obtains source of people ODC albumen, the elution buffer of ODC albumen is 50mM trihydroxy methyl amino first
Alkane (Tris)/HCl, pH 8.0,300mM NaCl, 1mM DTT, 100mM imidazoles (imidazole)；
4) Activity determination of ODC albumen
In EP pipe, the ODC albumen of 400uL substrate reactions mixture, 50ug is added, EP pipe is placed on 37 DEG C after mixing
30min in water-bath；The trichloroacetic acid that 400uL 10% is added terminates reaction, and room temperature is centrifuged 5000rpm, 5min, then takes out
100uL supernatant is mixed with the NaOH solution of 200uL 4mol/L, and 400uL n-amyl alcohol is added, is sufficiently mixed, 2000rpm centrifugation
5min, then upper liquid 200uL is transferred in new EP pipe, it is equal that the sodium tetraborate mixing that 200uL0.1mol/LpH is 8.0 is added
Even, addition 200uL10mmol/L trinitrobenzene sulfonic acid mixes abundant, addition 400uL DMSO, is sufficiently mixed 1min, 3000rpm
It is centrifuged 5min；Upper liquid is finally taken out into 96 orifice plates, with the light absorption value at microplate reader detection 426nm, obtains not enzyme OD
Value
5) detection of the inhibitor to the inhibitory activity of ODC albumen
Ornithine decarboxylation is added after 400uL substrate reactions mixture is added in the method according to step 4) immediately
The micromolecular inhibitor of enzyme, the same step 4) of subsequent operation；
It is calculated by the following formula out ODC inhibiting rate:
Compare it is poor=plus micromolecular inhibitor control group mean OD value-do not add micromolecular inhibitor control group mean OD value,
The inhibitor that wherein control group is added in step 5) is DFMO inhibitor；
Test it is poor=plus micromolecular inhibitor experimental group mean OD value-micromolecular inhibitor experimental group group is not added to be averaged OD
Value；
ODC inhibiting rate=[(control difference-experiment is poor)/control is poor] × 100%.
Lysate described in the step 3) be 50mM trishydroxymethylaminomethane (Tris)/HCl, pH 8.0,
The mixed liquor of 300mM NaCl, 1mM DTT, 1mM PMSF, 5mM imidazoles (imidazole).
Substrate reactions mixture in the step 4) is in the phosphate buffer (PBS) that 150mM pH is 7.1
Dissolve 17.57ul beta -mercaptoethanol, 55.84mg 1.5mM EDTA disalt sodium, 75nM phosphopyridoxal pyridoxal phosphate (PLP) liquid storage, 2mM bird
Propylhomoserin hydrochloride.
The ornithine decarboxylase be source of people ornithine decarboxylase, non-source of people ornithine decarboxylase or with source of people ornithine
The putrescine substrate of decarboxylase and the protein of phosphopyridoxal pyridoxal phosphate binding site very high homology.
According to above scheme, first with Pocket pharmaceutical grade protein pocket analysis software, with the crystal structure of source of people ODC
Based on, its putrescine substrate and PLP ligand binding pocket are analyzed, and generate the theoretical mould of the protein pocket
Type.Then, 190,000 small molecules in SPECS small-molecule drug library are docked to above-mentioned using protein docking procedure DOCK
In protein bag model, and filter out at least containing 15 non-hydrogen heavy atoms, at least formed 2 hydrogen bonds, at least one it is hydrophobic in
The heart, docking marking are no more than -10 small molecule.Protein-small molecule docking procedure is further utilized to above-mentioned small molecule again
Autodock is successively docked to again in above-mentioned protein pocket, is carried out further docking and is calculated, finally picks out docking
Marking is lower than -7 small molecule.
The present invention also provides a kind of composition, contain to inhibition a effective amount of ring provided by the invention of ornithine decarboxylase
Heptantriene phenolic ketone micromolecular inhibitor or its analog and pharmaceutically useful carrier.It is preferred that the composition is pharmaceutical composition
Object contains to the micromolecular inhibitor provided by the invention of therapeutically effective amount or its analog and pharmaceutically useful carrier.
More preferable described pharmaceutical composition is to treat or prevent the medicine group of the disease of inhibition generation response of ornithine decarboxylase (ODC)
Object is closed, wherein ornithine decarboxylase (ODC) preferably humanized's ornithine decarboxylase (ODC)；It further include containing for preventing and treating bird ammonia
The micromolecular inhibitor provided by the invention or its analog and medicine of the condition effective amount of the inhibition generation response of acid decarboxylase
The carrier being applicable on.
Micromolecular inhibitor of the invention or its analog and above-mentioned composition can be used for inhibiting ornithine decarboxylase
(ODC), preferred humanized's ornithine decarboxylase (ODC), wherein described inhibit to be therapeutic purposes or non-treatment purpose.It is preferred that this hair
Bright micromolecular inhibitor or its analog are used to prepare the drug for inhibiting ornithine decarboxylase (ODC), preferably humanized bird ammonia
Acid decarboxylase (ODC).Therefore the present invention also provides the methods for inhibiting ornithine decarboxylase activity, and this method is including being needed to press down
The object of ornithine decarboxylase (ODC) processed applies a effective amount of micromolecular inhibitor of the invention or its analog or above-mentioned group
Object is closed, wherein described inhibit to be therapeutic purposes or non-treatment purpose.
The present invention also provides treatments to the method for the disease of the inhibition generation response of ornithine decarboxylase, and this method includes
To the individual application prevention for needing this treatment or prevention or treat upper a effective amount of inhibition ornithine decarboxylase (preferably humanized
Ornithine decarboxylase (ODC)) micromolecular inhibitor of the invention or its analog or above-mentioned composition.
Micromolecular inhibitor of the invention or its analog can be used for preparing treatment and generate to the inhibition of ornithine decarboxylase
The drug or pharmaceutical composition of the disease of response, wherein ornithine decarboxylase (ODC) or its analog inhibit ornithine decarboxylase
Activity, the disease includes tumour or cause pathogeny imcrobe infection, preferably above-mentioned tumour.Protozoan infection refers to ornithine decarboxylation
The inhibition of enzyme generates the tumor disease or cause pathogeny imcrobe infection disease of response.
Detailed description of the invention
Fig. 1 is inhibitory effect of the micromolecular inhibitor to source of people ornithine decarboxylase of embodiment 1.
Fig. 2 is fragmentation effect of the embodiment 1 using mtt assay detection inhibitor to tumour cell.
Specific embodiment
Embodiment 1
Related micromolecular inhibitor containing tropolone are as follows: 4- [3- (2- hydroxyl -3- oxo -1,4,6- cycloheptyl three
Alkene -1- base) -3- oxo -1- acrylic] benzonitrile, structural formula is as shown in the figure.
Activity test method is as follows:
1. the building of source of people ODC prokaryotic expression plasmid
The gene order of source of people ODC is inserted into pET28a plasmid by BamH I and Xho I restriction enzyme site, is constructed
PET28a-hODC plasmid out is verified through DNA sequencing.
The gene order of source of people ODC:
atgaacaactttggtaatgaagagtttgactgccacttcctcgatgaaggttttactgccaaggacat
tctggaccagaaaattaatgaagtttcttcttctgatgataaggatgccttctatgtggcagacctgggagacatt
ctaaagaaacatctgaggtggttaaaagctctccctcgtgtcacccccttttatgcagtcaaatgtaatgatagca
aagccatcgtgaagacccttgctgctaccgggacaggatttgactgtgctagcaagactgaaatacagttggtgca
gagtctgggggtgcctccagagaggattatctatgcaaatccttgtaaacaagtatctcaaattaagtatgctgct
aataatggagtccagatgatgacttttgatagtgaagttgagttgatgaaagttgccagagcacatcccaaagcaa
agttggttttgcggattgccactgatgattccaaagcagtctgtcgtctcagtgtgaaattcggtgccacgctcag
aaccagcaggctccttttggaacgggcgaaagagctaaatatcgatgttgttggtgtcagcttccatgtaggaagc
ggctgtaccgatcctgagaccttcgtgcaggcaatctctgatgcccgctgtgtttttgacatgggggctgaggttg
gtttcagcatgtatctgcttgatattggcggtggctttcctggatctgaggatgtgaaacttaaatttgaagagat
caccggcgtaatcaacccagcgttggacaaatactttccgtcagactctggagtgagaatcatagctgagcccggc
agatactatgttgcatcagctttcacgcttgcagttaatatcattgccaagaaaattgtattaaaggaacagacgg
gctctgatgacgaagatgagtcgagtgagcagacctttatgtattatgtgaatgatggcgtctatggatcatttaa
ttgcatactctatgaccacgcacatgtaaagccccttctgcaaaagagacctaaaccagatgagaagtattattca
tccagcatatggggaccaacatgtgatggcctcgatcggattgttgagcgctgtgacctgcctgaaatgcatgtgg
gtgattggatgctctttgaaaacatgggcgcttacactgttgctgctgcctctacgttcaatggcttccagaggcc
gacgatctactatgtgatgtcagggcctgcgtggcaactcatgcagcaattccagaaccccgacttcccacccgaa
gtagaggaacaggatgccagcaccctgcctgtgtcttgtgcctgggagagtgggatgaaacgccacagagcagcct
gtgcttcggctagtattaatgtgtag
The above-mentioned source of people ODC sequence that we use, with database (http://www.ncbi.nlm.nih.gov/
Nuccore/NM_002539.1 the sequence in) has a base variation, and (C of box label is T in database sequence, corresponding
Amino acid cysteine is become from arginine), but do not influence its activity.
2. the expression of source of people ODC albumen
Above-mentioned pET28a-hODC plasmid is passed through into CaCl2Method is transformed into e. coli strain bl21, and by card, that is mould
Element is screened.The bacterial strain that will be grown on Luria-Bertani (LB) culture plate containing kanamycin, is seeded to containing card
In the LB liquid medium of that mycin, 37 DEG C, 250rpm cultivate to logarithmic growth phase, then add IPTG (isopropylthio half
Lactoside) to 0.5mM, 28 DEG C inducing expression 4 hours.Finally, bacterium is collected by centrifugation.
3. the purifying of source of people ODC albumen
By the bacterium of above-mentioned collection, with lysate (50mM Tris/HCl, pH 8.0,300mM NaCl, 1mM DTT, 1mM
PMSF, 5mM imidazole.) it suspends again, cell cracking is then carried out by ultrasonic method.Then by lysate 4 DEG C,
After 12000 turns of centrifugations, retain supernatant.Supernatant is combined and is purified using Ni-NTA His label protein combination filler, people
The elution buffer of source ODC albumen is 50mM Tris/HCl, pH 8.0,300mM NaCl, 1mM DTT, 100mM
imidazole。
4. the Activity determination of source of people ODC albumen
In the EP pipe of 1.5mL, (the dissolution in 150mM PBS (pH 7.1) of 400uL substrate reactions mixture is added
17.57ul beta -mercaptoethanol, 55.84mg 1.5mM EDTA disalt sodium, 75nM PLP liquid storage, 2mM ornithine hydrochloride).So
Afterwards, the ODC albumen of 50ug is added.EP pipe is placed on 30min in 37 DEG C of water-baths after mixing.Then it is added the three of 400uL 10%
Monoxone terminates reaction.Room temperature is centrifuged 5000rpm, 5min.100uL supernatant is taken out, it is mixed with the NaOH solution of 200uL 4mol/L
It closes, adds 400uL n-amyl alcohol, be sufficiently mixed.2000rpm is centrifuged 5min, upper liquid 200uL is transferred in new EP pipe,
200uL sodium tetraborate (0.1mol/L, pH8.0) is added to be sufficiently mixed.Then 200uL trinitrobenzene sulfonic acid (10mmol/ is added
L), it is sufficiently mixed.400uL DMSO is added, 1min is sufficiently mixed.3000rpm is centrifuged 5min.Upper liquid is taken out to 96 orifice plates
In, with the light absorption value at microplate reader detection 426nm.
5. the detection of the inhibitory activity of inhibitor on human source ODC albumen
In above-mentioned Activity determination step, after 400uL substrate reactions mixture is added, small-molecule drug is added immediately and mixes
It closes.Subsequent step is the same.
It is calculated by the following formula out ODC inhibiting rate
Compare poor=enzyme not enzyme control group mean OD value of control group mean OD value-
Test poor=enzyme not enzyme experimental group group mean OD value of experimental group mean OD value-
Inhibiting rate=(control difference-experiment poor)/control is poor × and 100%
The inhibitory effect of the micromolecular inhibitor obtained according to the method described above is as shown in Figure 1, as can be seen from the figure exist
50% or more inhibit concentration when, which can inhibit the activity of ODC, and rejection ability is suitable with the DFMO of 2.5mM.
6. using mtt assay detection inhibitor to the fragmentation effect of tumour cell
By A549 cell inoculation into 96 porocyte culture plates, 2000 cells/wells of inoculum density, culture medium RPMI-
1640,10% calf serum, 1% chain/penicillin, the hole volume 100uL/.After being cultivated 24 hours in 37 DEG C of cell incubators, add
Enter the 100uL diluted small-molecule drug of RPMI-1640 or culture medium.After continuing culture 60 hours, culture medium is sucked, is added
After 100uL MTT (final concentration 250ug/mL), continue culture 4 hours.Then culture solution is sucked, 150uL DMSO is added, is shaking
Low-speed oscillation 15min on bed, dissolves crystal sufficiently.Finally, reading the light absorption value at 490nm using microplate reader.
The mtt assay detection inhibitor obtained according to the method described above is to the fragmentation effect of tumour cell as shown in Fig. 2, from figure
It can be seen that the drug is able to suppress and killing tumor cell, but presses down below 50% in the concentration inhibited 50% or more
Ability is very weak when the concentration of system.
Claims (4)
1. a kind of micromolecular inhibitor containing tropolone, which is characterized in that the structural formula of the micromolecular inhibitor are as follows:
2. micromolecular inhibitor containing tropolone described in claim 1 is inhibiting answering on ornithine decarboxylase (ODC)
With.
3. application of the micromolecular inhibitor containing tropolone described in claim 1 in preparation tumor.
4. micromolecular inhibitor containing tropolone described in claim 1 is in preparation treatment cause pathogeny imcrobe infection drug
Application.
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