CN108338982A - Application of the Cephalothin Sodium in antileukemie drug - Google Patents
Application of the Cephalothin Sodium in antileukemie drug Download PDFInfo
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- CN108338982A CN108338982A CN201711440505.XA CN201711440505A CN108338982A CN 108338982 A CN108338982 A CN 108338982A CN 201711440505 A CN201711440505 A CN 201711440505A CN 108338982 A CN108338982 A CN 108338982A
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- Prior art keywords
- drug
- cephalothin sodium
- cephalothin
- sodium
- target proteins
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Classifications
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- A—HUMAN NECESSITIES
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The present invention provides Cephalothin Sodiums to prepare for preventing or treating the application in the drug of leukaemia, especially Cephalothin Sodium is being prepared for preventing or treating the application in the drug of mixed lineage leukemia, the present invention chooses the histone-lysine methyltransferase DOT1L for the gene rearrangement for participating in mixed lineage leukemia as target proteins, using SPR technique, filtering out has the Cephalothin Sodium of inhibiting effect as inhibitor the target proteins, by being combined Cephalothin Sodium come the activity of suppression target albumen with target proteins, to prevent DOT1L from participating in the rearrangement process of mll gene, and then achieve the purpose that prevent and treat leukaemia.In addition, the present invention also provides a kind of drugs for preventing or treating leukaemia.
Description
Technical field
The present invention relates to drug fields, in particular to application of the Cephalothin Sodium in antileukemie drug
Background technology
Mixed lineage leukemia (Mixed Lineage Leukemia, MLL) is a kind of Malignancy, due to
Mll gene forms MLL fusion proteins and gains the name after resetting, and mll gene is located at No. 11 2 areas 3 of chromosome with (11q23), the base
It is related with Malignancy because resetting.Mll gene is reset positive acute leukemia and can be sent out from birth to adulthood
It is raw, show as acute myeloid leukemia (acute myeloid leukemia, AML) or acute lymphoblastic leukemia (acute
Lymphoblastic leukemia, ALL).Although having certain error, in a research for pertinent literature
In by being found after integrating 7969 patients AML and the data of 1252 patients ALL, 11q23 chromosome translocations or mll gene weight
Row is happened in 22% patient ALL and 5.2% patient AML.It is the white blood of MLL there are about 14% children with acute myeloid leukemia
Disease, the wherein incidence of baby MLL are 65%；The children for suffering from MLL leukaemia in acute lymphoblastic leukemia account for 6%, 80%
For baby.Studies have shown that the most grade malignancy of leukaemia for being related to mll gene rearrangement is high, belongs to acute leukemia, there is uniqueness
Biological characteristics seek peace Clinical symptoms, show as white blood cell count(WBC) height, complete remission rate (Complete Remission, CR)
It is low, it is insensitive to conventional chemotherapy, and life cycle is short, prognosis is poor.It is individually classified as 11q23/MLL leukaemia by WHO at present.
It is known that histone-lysine methyltransferase DOT1L (disruptor of telomeric sliencing
It is 1like) upper highly conserved in evolution, the 79th lysine of nucleosome histone H 3 can be catalyzed and methylated, be first sent out
The existing histone-lysine methyltransferase without SET structural domains.DOT1L participates in the rearrangement process of mll gene, and mixing pedigree is white
The universal feature of blood disease is that the mll gene being located at 11q23 is reset, and C-terminal SET domain loss makes mll gene and partner gene
(AF4, AF9, AF10 and ENL) is merged, and forms MLL fusion proteins, and MLL fusion proteins can recruit DOT1L to target gene simultaneously
It interacts, makes its H3K79 high methylation, it is leucocythemia related because of great expression, induce the generation of leukaemia.Cause
This, DOT1L can be used as the therapy target of mixed lineage leukemia.In conclusion the methylation activity of DOT1L is MLL diseases hair
Therefore the major reason of disease provides pharmacology foundation by inhibiting the activity of DOT1L that can be mediated for the treatment of MLL diseases.So
And due to lacking the DOT1L inhibitor of specificity, current main target is exactly to find the DOT1L that some are effective and toxicity is low
Micromolecular inhibitor.
Surface plasma resonance technology (Surface Plasmon Resonance, SPR) is a kind of optical technology, to gold
The variation for belonging to chip surface refractive index is very sensitive, can be applied to different fields.SPR phenomenons were initially sent out in 1902 by Wood
It is existing, it is for the first time just to start to develop rapidly at the end of the 20th century, present SPR in nineteen eighty-three with the sensing analysis of SPR technique
Technology is widely used in the mutual function analysis and new drug development of large biological molecule.The technical principle of SPR is mainly：When flat
Plane polarized light generates disappearance when (suitable with critical angle) is incident on prism metal film surfaces at a certain angle, in metal surface
Wave, when evanescent waves are similar to the frequency of surface plasma that free electron vibration in metal surface generates, the two resonates, instead
It penetrates luminous intensity drastically to decline, by the way that target protein is fixed on chip surface, small molecule solution is flowed through into chip surface, if small molecule
When compound has combination with target protein, the variation of refractive index is had, observes the dynamic knot between target protein and micromolecular compound
It closes and dissociation process analyzes the combination situation between them.SPR technique have it is highly selective, highly sensitive, analyze speed is fast,
For the quick screening of reactive compound, the curve and data of dynamic bind between target protein and compound can be obtained, is passed through
Analysis fitting is carried out to data and acquires equilibrium dissociation constant KD values.SPR technique can pass through the parent of target protein and micromolecular compound
With force effect size come quick screening compounds, be both not required to sample carry out it is immune labeled, will not damage sample, consumption it is small,
Real-time and Dynamic Detection.Therefore, it is screened and the istone lysine in the relevant albumen of mixed lineage leukemia using SPR technique
The inhibitor of transmethylase DOT1L is a kind of new method of important discovery anti-leukemia medicine.
But so far, application of the Cephalothin Sodium in the leukaemia such as anti-mixed lineage leukemia has not been reported.
Invention content
The present invention provides Cephalothin Sodiums to prepare for preventing or treating the application in the drug of leukaemia, feature
It is, Cephalothin Sodium is：
The present invention provides Cephalothin Sodiums to prepare for preventing or treating answering in the drug of mixed lineage leukemia
With.
In above application, Cephalothin Sodium is and the istone lysine first in the relevant albumen of mixed lineage leukemia
The inhibitor of based transferase (DOT1L).
The present invention also provides a kind of drugs for preventing or treating leukaemia, which is characterized in that including：As activity
The Cephalothin Sodium of ingredient and one or more pharmaceutically acceptable carriers.
In said medicine, the carrier includes diluent, excipient, filler, adhesive, wetting agent, disintegrant, suction
It is that pharmaceutical field is frequent to receive accelerating agent, surfactant, absorption carrier, lubricant and synergist, the substance that carrier includes
The conventional substances used.
In said medicine, the drug is the injection, tablet, ball for including the Cephalothin Sodium and the carrier
Agent, capsule, suspending agent or emulsion.
In addition, No. CAS of Cephalothin Sodium according to the present invention is 58-71-9, combined by Tianjin international bio medicine
Research institute's high-flux medicaments sifting center provides.
The present invention provides Cephalothin Sodiums to prepare for preventing or treating the application in the drug of leukaemia, especially
Cephalothin Sodium is being prepared for preventing or treating the application in the drug of mixed lineage leukemia, and Cephalothin Sodium can pass through
Inhibit to induce the activity of the DOT1L of leukaemia to prevent DOT1L from participating in the rearrangement process of mll gene, to reach prevention and control
Treat the purpose of leukaemia.
Description of the drawings
It in order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, below will be to institute in embodiment
Attached drawing to be used is needed to be briefly described, it should be apparent that, the accompanying drawings in the following description is only some implementations of the present invention
Example, for those of ordinary skill in the art, without creative efforts, can also obtain according to these attached drawings
Obtain other attached drawings.
Fig. 1 is combination of the Cephalothin Sodium in accordance with some embodiments to histone-lysine methyltransferase (DOT1L)
The schematic diagram of curve.
Specific implementation mode
Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete
Site preparation describes, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, the every other embodiment that those of ordinary skill in the art are obtained belong to what the present invention protected
Range.
Cephalothin Sodium is：
No. CAS of Cephalothin Sodium according to the present invention is 58-71-9, by Tianjin International Joint Academy of Biotechnology ＆ Medicine
High-flux medicaments sifting center provides.
In the present invention, with the histone-lysine methyltransferase DOT1L in the relevant albumen of mixed lineage leukemia
Expression, the methods of purifying step and method for screening compound bibliography method (Basavapathruni A, Jin L,
Daigle S R,et al.Conformational adaptation drives potent,selective and
durable inhibition of the human protein methyltransferase DOT1L[J].Chemical
biology&drug design,2012,80(6):971-980.)。
Using SPR technique screening and the histone-lysine methyltransferase in the relevant albumen of mixed lineage leukemia
Target proteins (histone-lysine methyltransferase DOT1L) are tied on CM5 biochips, when one by the inhibitor of DOT1L
The solution containing Cephalothin Sodium for determining concentration flows through biochip, and Cephalothin Sodium can cause chip list after being combined with target proteins
The variation of the response RU generated on face, so that it may to obtain the curve and number of dynamic bind between target proteins and Cephalothin Sodium
According to, by data carry out analysis fitting acquire equilibrium dissociation constant KDValue, and then obtain Cephalothin Sodium to target proteins
Inhibition level, wherein the instrument that biochip response measures is interaction of biomacromolecules analyzer Biacore3000
(GE)。
The binding of target proteins (histone-lysine methyltransferase DOT1L)：Target proteins storage buffer solution group is divided into
20mM Tris, 200mM NaCl, 1mM EDTA, 1mM DTT, 3%Glycerol, pH 8.0.By glucan-modified CM5 cores
Piece is placed in Biacore3000, runs buffer, prime 3 times, after waiting for that baseline is walked surely, starts the binding procedure of target proteins,
By activator 1- (3- the dimethylamino-propyls) -3- ethyls carbon two of the activator n-hydroxysuccinimide NHS of 70 μ L and 70 μ L
Imines EDC uniformly mixing after, start sample introduction, setting flow velocity be 10 μ L/min, 70 μ L of sample introduction, with activate chip surface dissociate
Carboxyl, target proteins are diluted to 100 μ g/mL with the sodium acetate solution of pH 5.0, start sample introduction, and flow velocity is 10 μ L/min, sample introduction
Covalent bond occurs for the carboxyl of 20 μ L, the amino and chip surface that dissociate in target proteins, and target proteins are bundled on chip,
Since chip surface there remains some sites not combined with target proteins, the position not combined with target proteins is closed with ethanol amine
Point, flow velocity are 10 μ L/min, 70 μ L of sample introduction, the RU values that record target proteins are combined with chip, by RU value of the closing-after steady
The bound values final as target proteins with the difference of the RU values before activation.
The cefoxitin sodium solution of various concentration is flowed through into chip, flow velocity is 10 μ L/min, measures its RU value, obtains chemical combination
The binding curve and data of object and target proteins.Using the time as X-axis, response RU, which is Y-axis, can obtain target proteins and cefoxitin
Kinetic curve between sodium.The target proteins recorded by Biacore3000 are related to the dynamics that Cephalothin Sodium combines
Parameter, according to response value and the reaction time, using the balance of BIAEVAL Data Analysis Software analysis of compounds and target proteins
Dissociation constant KDValue.The concentration of the Cephalothin Sodium of [A] to flow through chip is set, [B] is the concentration of target proteins, and [AB] is head
The concentration of spore thiophene sodium and target proteins conjugate sets S-adenosylmethionine (SAM) as the positive control of target proteins
Close object.According to the kinetic binding data between compound and albumen, the equilibrium dissociation constant K of each Cephalothin Sodium is calculatedD
=([A] * [B])/[AB].
The equilibrium dissociation constant of positive reference compound SAM is 5.57e-7, equilibrium dissociation constant is smaller, and compound is to target
The inhibiting effect of albumen is stronger.For equilibrium dissociation constant<e-5Cephalothin Sodium carry out secondary screening, each Cephalothin Sodium sets
Several different concentration are set, the combination situation of target proteins and Cephalothin Sodium are measured, according to the knot obtained under various concentration
Curve is closed, the equilibrium dissociation constant K of each Cephalothin Sodium and target proteins is measured with BIAEVAL softwaresDValue considers secondary screening
Protein binding situation of compound when whether can repeat out primary dcreening operation, exclude the possibility of false positive.
Pass through the flat of the equilibrium dissociation constant of Cephalothin Sodium and target proteins and positive reference compound and target proteins
Weighing apparatus dissociation constant is compared, so that it may to judge the histone in the relevant albumen of Cephalothin Sodium pair and mixed lineage leukemia
The inhibition of lysine methyltransferase DOT1L.
Fig. 1 shows the combination of the cefoxitin sodium solution and histone-lysine methyltransferase DOT1L of various concentration
Curve, abscissa are the time (s), and expression is Cephalothin Sodium and the SPR reaction time of DOT1L, and ordinate is the sound of reaction
It should be worth, indicate compound and protein binding degree, value is bigger, and binding force is stronger, and corresponding inhibiting effect is also stronger.Fig. 1 is shown
Respectively by 1 μM (being indicated by the curve 1 in Fig. 1), 500nM (being indicated by the curve 2 in Fig. 1), 250nM (by the curve 3 in Fig. 1
Indicate), the solution containing Cephalothin Sodium of 62.5nM (being indicated by the curve 4 in Fig. 1), 0nM (being indicated by the curve 5 in Fig. 1)
Chip is flowed through, flow velocity is 10 μ L/min, measures its RU value, obtains the binding curve and data of Cephalothin Sodium and target proteins.
As seen from Figure 1, curve 5 indicate Cephalothin Sodium be zero, i.e., without inhibitor the case where, response at this time
RU is essentially a zero, indicates that target proteins are not bound with compound, curve 1,2,3,4 indicates Cephalothin Sodium and target proteins group egg
White lysine methyltransferase (DOT1L) has combination, shows that Cephalothin Sodium has an inhibiting effect to DOT1L, and from song
Line 1 constantly reduces, response RU becomes smaller, this shows to curve 4 with the concentration of the Cephalothin Sodium in cefoxitin sodium solution
Concentration with cefoxitin sodium solution becomes smaller, and is tapered into target proteins DOT1L combinations, to target proteins DOT1L
Inhibiting effect become smaller.In conclusion Cephalothin Sodium has inhibiting effect to DOT1L, and with the increase of concentration, inhibit to make
With gradually increasing.
The histone-lysine methyltransferase DOT1L that the present invention chooses the gene rearrangement for participating in mixed lineage leukemia makees
The Cephalothin Sodium for having inhibiting effect to the target proteins is filtered out as inhibitor, is led to using SPR technique for target proteins
The activity that Cephalothin Sodium is combined to come with target proteins suppression target albumen is crossed, to prevent DOT1L from participating in the weight of mll gene
It is drained through journey, and then achievees the purpose that prevent and treat leukaemia.In addition, Cephalothin Sodium is a kind of little molecules in inhibiting that toxicity is low
Agent can be widely used in the drug of prevention and treatment leukaemia.
The above is merely preferred embodiments of the present invention, be not intended to limit the invention, it is all the present invention spirit and
Within principle, any modification, equivalent replacement, improvement and so on should all be included in the protection scope of the present invention.
Claims (6)
1. Cephalothin Sodium is being prepared for preventing or treating the application in the drug of leukaemia, which is characterized in that cefoxitin
Sodium is：
2. Cephalothin Sodium described in claim 1 is being prepared for preventing or treating answering in the drug of mixed lineage leukemia
With.
3. application according to claim 1 or 2, which is characterized in that the Cephalothin Sodium is and mixed lineage leukemia
The inhibitor of histone-lysine methyltransferase DOT1L in relevant albumen.
4. a kind of drug for preventing or treating leukaemia, which is characterized in that including：Cephalothin Sodium as active constituent
And one or more pharmaceutically acceptable carriers.
5. drug according to claim 4, which is characterized in that the carrier includes diluent, excipient, filler, glues
Mixture, wetting agent, disintegrant, sorbefacient, surfactant, absorption carrier, lubricant and synergist.
6. drug according to claim 4, which is characterized in that the drug be include the Cephalothin Sodium and the load
Injection, tablet, pill, capsule, suspending agent or the emulsion of body.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711440505.XA CN108338982A (en) | 2017-12-27 | 2017-12-27 | Application of the Cephalothin Sodium in antileukemie drug |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711440505.XA CN108338982A (en) | 2017-12-27 | 2017-12-27 | Application of the Cephalothin Sodium in antileukemie drug |
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| CN108338982A true CN108338982A (en) | 2018-07-31 |
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| CN201711440505.XA Pending CN108338982A (en) | 2017-12-27 | 2017-12-27 | Application of the Cephalothin Sodium in antileukemie drug |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110327349A (en) * | 2019-07-10 | 2019-10-15 | 昆明医科大学 | Cephalosporin analog antibiotic is as the application and its anticancer drug for preparing anticancer drug |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0742015A1 (en) * | 1990-11-06 | 1996-11-13 | Bristol-Myers Squibb Company | Prodrugs for beta-lactamase and uses thereof |
| EP0745390A2 (en) * | 1995-05-31 | 1996-12-04 | Bristol-Myers Squibb Company | Polymeric prodrugs for beta-lactamase and uses thereof |
| WO2002096430A1 (en) * | 2001-06-01 | 2002-12-05 | Kylix B.V. | Cephalosporin derivatives as anti-cancer agents |
| CN104546863A (en) * | 2015-02-09 | 2015-04-29 | 江苏澳格姆生物科技有限公司 | Application of cefalotin sodium in preparation of medicine for inhibiting tumour cell transfer and diffusion |
| CN106255500A (en) * | 2014-04-03 | 2016-12-21 | 法国居里学院 | For treating the new cephalosporins derivatives of cancer |
-
2017
- 2017-12-27 CN CN201711440505.XA patent/CN108338982A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0742015A1 (en) * | 1990-11-06 | 1996-11-13 | Bristol-Myers Squibb Company | Prodrugs for beta-lactamase and uses thereof |
| EP0745390A2 (en) * | 1995-05-31 | 1996-12-04 | Bristol-Myers Squibb Company | Polymeric prodrugs for beta-lactamase and uses thereof |
| WO2002096430A1 (en) * | 2001-06-01 | 2002-12-05 | Kylix B.V. | Cephalosporin derivatives as anti-cancer agents |
| CN106255500A (en) * | 2014-04-03 | 2016-12-21 | 法国居里学院 | For treating the new cephalosporins derivatives of cancer |
| CN104546863A (en) * | 2015-02-09 | 2015-04-29 | 江苏澳格姆生物科技有限公司 | Application of cefalotin sodium in preparation of medicine for inhibiting tumour cell transfer and diffusion |
Non-Patent Citations (1)
| Title |
|---|
| YUQIANG WANG等: "synthesis and preliminary cytotoxicity study of a cephalosporin-CC-1065 analogue prodrug", 《BMC CHEMICAL BIOLOGY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110327349A (en) * | 2019-07-10 | 2019-10-15 | 昆明医科大学 | Cephalosporin analog antibiotic is as the application and its anticancer drug for preparing anticancer drug |
| CN110327349B (en) * | 2019-07-10 | 2021-12-28 | 昆明医科大学 | Application of cephalosporin antibiotics in preparation of anti-cancer drugs and anti-cancer drugs thereof |
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Application publication date: 20180731 |