CN110200983A - Application of the Teniposide in Killing Mycobacterium Tuberculosis drug - Google Patents
Application of the Teniposide in Killing Mycobacterium Tuberculosis drug Download PDFInfo
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- CN110200983A CN110200983A CN201910440671.2A CN201910440671A CN110200983A CN 110200983 A CN110200983 A CN 110200983A CN 201910440671 A CN201910440671 A CN 201910440671A CN 110200983 A CN110200983 A CN 110200983A
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- teniposide
- mycobacterium tuberculosis
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- 239000003814 drug Substances 0.000 title claims abstract description 31
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 title claims abstract description 28
- 229960001278 teniposide Drugs 0.000 title claims abstract description 28
- 229940079593 drug Drugs 0.000 title claims abstract description 27
- 241000187479 Mycobacterium tuberculosis Species 0.000 title claims abstract description 20
- 201000008827 tuberculosis Diseases 0.000 claims abstract description 12
- 230000002365 anti-tubercular Effects 0.000 claims description 10
- 239000004615 ingredient Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 238000011161 development Methods 0.000 abstract description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 abstract description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 abstract description 2
- 206010025323 Lymphomas Diseases 0.000 abstract description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 abstract description 2
- 238000011160 research Methods 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- 210000004027 cell Anatomy 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 9
- 230000004083 survival effect Effects 0.000 description 9
- 210000002540 macrophage Anatomy 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 7
- 230000031700 light absorption Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 102000007537 Type II DNA Topoisomerases Human genes 0.000 description 2
- 108010046308 Type II DNA Topoisomerases Proteins 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- XFDUHJPVQKIXHO-UHFFFAOYSA-N 3-aminobenzoic acid Chemical compound NC1=CC=CC(C(O)=O)=C1 XFDUHJPVQKIXHO-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241000989747 Maba Species 0.000 description 1
- 241001646725 Mycobacterium tuberculosis H37Rv Species 0.000 description 1
- 108700035964 Mycobacterium tuberculosis HsaD Proteins 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical class COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- JUJBNYBVVQSIOU-UHFFFAOYSA-M sodium;4-[2-(4-iodophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=N1 JUJBNYBVVQSIOU-UHFFFAOYSA-M 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to application of the Teniposide in Killing Mycobacterium Tuberculosis drug.Clinically Teniposide is mainly used for treating malignant lymphoma, acute lymphoblastic leukemia；And the research of the invention finds that it has the function for the treatment of tuberculosis, there is good Development volue；It is first public that there is apparent against mycobacterium tuberculosis effect to belong to for application and Teniposide of the Teniposide of the present invention in Killing Mycobacterium Tuberculosis drug.
Description
Technical field
The present invention relates to technical field of bioengineering, in particular to Teniposide answering in Killing Mycobacterium Tuberculosis drug
With.
Background technique
Tuberculosis is chronic infectious disease caused by being infected by mycobacterium tuberculosis, and current tuberculotherapy drug is not able to satisfy
The requirement of patient and tuberculosis prevention and treatment.Due to the drug resistant generation of tulase, the appearance of especially multi-drug resistant and extensive drug resistance situation,
So that tuberculosis prevention and treatment is faced with stern challenge.According to statistics, in China's tuberculosis patient, multi-drug resistant disease incidence is 8.32%,
Amounting to is about 120,000 people, and total quantity is only second to India and occupies second place of the world, and extensive drug resistance disease incidence is then 0.68%, is amounted to big
About 10,000 people endanger considerably beyond AIDS.Therefore, control tuberculosis needs the research and development of new high-efficiency antituberculotic.
Teniposide is a kind of podophyllinic acid lactone derivative, is the inhibition of topoisomerase II (topoisomerase II)
Agent is clinically mainly used for treating malignant lymphoma, acute lymphoblastic leukemia.
The entitled 4'- demethyl epipodophyllotoxin-β-D- thenylidene glucopyranoside of Teniposide chemistry, molecular formula
For C32H32O13S, molecular weight 656.654, structural formula is as follows:
The study find that this medical instrument plays the role for the treatment of tuberculosis, there is good Development volue.
Summary of the invention
The purpose of the present invention is research and develop efficient antituberculosis drug, it was found that the treating tuberculosis of Teniposide acts on and anti-
Application in mycobacterium tuberculosis drug helps to shorten the tuberculosis course for the treatment of, and saves medicament research and development cost and treatment cost.
Technical solution of the present invention is mainly application of the Teniposide in Killing Mycobacterium Tuberculosis drug.
Further, mycobacterium tuberculosis is specially mycobacterium tuberculosis H37Rv。
The present invention also provides Teniposides to prepare the application in antituberculotic.
In one embodiment of the present of invention scheme, the antituberculotic that a kind of effective component is Teniposide is provided.
This antituberculotic can be applied to treatment tuberculosis.
The present invention has the advantages that
(1) present invention firstly discovers that Teniposide has apparent against mycobacterium tuberculosis effect；
(2) present invention firstly provides Teniposides to prepare the application in antituberculotic；
(3) " old medicine is newly used " will greatly reduce development cost, promote the recycle value of old medicine；
(4) ancillary drug of the Teniposide as treating tuberculosis is expected to shorten the course for the treatment of, and saves treatment cost.
Detailed description of the invention
Fig. 1 is the tulase inhibiting rate in the embodiment of the present invention 1 under different pharmaceutical concentration；
Fig. 2 is influence of the various concentration Teniposide to the survival rate of cell in the embodiment of the present invention 2；
Fig. 3 is influence of the Teniposide to mycobacterium tuberculosis survival rate in cell in the embodiment of the present invention 3.
Specific embodiment
The present invention will be further described with reference to the accompanying drawings and detailed description, and following embodiment is intended to illustrate hair
Bright rather than limitation of the invention further.
The present invention measures Teniposide Killing Mycobacterium Tuberculosis H using MABA method37The activity of Rv (number ATCC27294),
Teniposide has against mycobacterium tuberculosis effect as the result is shown.
The conventional means that technological means used in following embodiment is well known to those skilled in the art, all raw materials are equal
For versatile material.
Embodiment 1
Body outer disinfecting activity measurement
1. the preparation of various concentration drug
Aseptically, Teniposide is configured to the solution that concentration is 10uM with DMSO, after completely dissolution, reused
Solution is diluted to eight concentration gradients by DMSO, and drug concentration is made to be respectively as follows: 1uM, 500uM, 250uM, 125uM, 62.5uM,
31.25uM, 15.6uM, 7.8uM be stored in -80 DEG C it is spare；
2. the preparation of mycobacterium tuberculosis (Mtb)
Mycobacterium tuberculosis H37Rv (number ATCC27294) is incubated in 7H9-OADC culture medium, by logarithmic growth phase
Mtb (OD600=0.6~0.8) be diluted to OD600=0.01, be laid in 96 porocyte culture plates with the hole 99uL/；
In the bacterium of culture be added the above-mentioned concentration gradient of 1ul drug, make drug final concentration be respectively as follows: 10uM, 5uM,
2.5uM, 1.25uM, 625uM, 312uM, 156uM, 78uM separately take above-mentioned eight groups of solution of same concentrations that 1ul DMSO is added and make
For control experiment；It is placed in the shaken cultivation case that temperature is 37 DEG C and continues culture 7 days, measure 600nm wavelength using microplate reader
The light absorption value at place；
Drug calculates the activity of bacterial growth with following formula:
Inhibiting rate (%)=[(A0-A)/A0] × 100%；Wherein, A0For the light absorption value of DMSO control, A is various concentration medicine
The light absorption value of object processing.
The drug for measuring 8 concentration, obtained inhibiting rate data are as shown in table 1, and it is bent to draw dosage-inhibiting rate according to table 1
As shown in Figure 1, obtaining MIC, each drug concentration is repeated 3 times line, and obtained result is indicated using average stdev；
Tulase inhibiting rate under 1 different pharmaceutical concentration of table
| Drug concentration (uM) | 10.00 | 5.00 | 2.50 | 1.25 | 0.625 | 0.312 | 0.156 | 0.078 |
| Inhibiting rate (%) | 99.07 | 98.60 | 11.74 | 1.74 | 6.74 | 0.00 | 0.00 | 0.00 |
Experimental result shows that Teniposide has very strong inhibiting effect to mycobacterium tuberculosis, when concentration is 5uM,
Inhibiting rate has reached 98.6%；Teniposide is calculated to the MIC50 of Mtb by dosage-inhibiting rate curve are as follows: 3.24uM.
Embodiment 2
The differentiation of 1.U937 macrophage (number BNCC100967): by the U937 macrophage of suspension be incubated at containing
In the RPMI-1640 culture medium of 10%FBS, and being placed in temperature is 37 DEG C, contains 5%CO2Cell incubator in cultivate, add
Enter the PMA of final concentration of 20ng/ml, overnight incubation is divided into macrophage, is cleaned twice with PBS, is disappeared using pancreatin
It after changing, being resuspended, is added in 96 porocyte culture plates, makes cell number 1x104 of every hole；
2. the measurement of cell survival rate: after above-mentioned U937 macrophage culture for 24 hours, the drug of various concentration is added, makes
Drug final concentration of 10uM, 5uM, 2.5uM, each concentration distinguish 3 repeated experiments, using DMSO as parallel control experiment,
DMSO identical with injection volume is added in control group, respectively 3 repeated experiments, it is molten that 10ul WST-1 is added in every hole after 48h
Liquid, continues to cultivate 4h under conditions of temperature is 37 DEG C, measures OD450nm light absorption value using microplate reader；
Cell survival rate is calculated according to following formula:
Cell survival rate %=[A/A0] × 100,
Wherein, A0For the light absorption value of DMSO control, A is the light absorption value of various concentration drug-treated.
Fig. 2 indicates influence of the various concentration Teniposide to the survival rate of cell；Wherein, " * * ", which is represented, has conspicuousness poor
Different, " ns " represents no statistical difference.
Experimental result shows that Teniposide concentration is 10uM, 5uM, 2.5uM, and corresponding cell survival rate is respectively as follows:
61%, 90%, 101%；When drug concentration is 5uM, cell survival rate is compared with the control group without statistical difference.
Embodiment 3:
The differentiation of 1.U937 macrophage: the U937 macrophage of suspension is incubated at the RPMI-1640 containing 10%FBS
In culture medium, and being placed in temperature is 37 DEG C, contains 5%CO2Cell incubator in cultivate, final concentration of 20ng/ml is added
PMA, overnight incubation is divided into macrophage, washed twice with PBS, and after pancreatin digestion, being resuspended, it is thin that 96 holes are added
In born of the same parents' culture plate, make cell number 1x104 of every hole；
2. intracellular bactericidal activity measurement: after above-mentioned U937 macrophage culture for 24 hours, Teniposide, which is added, keeps it dense eventually
Degree is 5uM, and each concentration distinguishes 3 repeated experiments, and parallel control experiment is used as using DMSO, is added in control group and drug body
The identical DMSO of product, 3 repeated experiments, culture medium is sucked after 4h, is washed twice with PBS respectively, after fresh culture 72h is added
Lysate is added, is coated on 7H10 plate after gradient dilution, calculates bacterium colony after 3 weeks；
As a result as shown in Fig. 3, cell is handled using 5uM Teniposide, it is opposite to the survival rate of tulase in cell
There was only 2.23% in control group, and without apparent cytotoxicity under this concentration, can be used for developing efficient, less toxic resist
Tubercular drugs.
Finally, it should be noted that above embodiments are only to illustrate the present invention and not limit technology described in the invention
Scheme；Those skilled in the art should understand that still can modify to the present invention or equivalent replacement；And all are not
It is detached from the technical solution and its improvement of the spirit and scope of the present invention, the model in claim restriction of the invention should all be covered
In enclosing.
Claims (6)
1. application of the Teniposide in Killing Mycobacterium Tuberculosis drug.
2. application according to claim 1, which is characterized in that the mycobacterium tuberculosis is mycobacterium tuberculosis H37Rv。
3. Teniposide is preparing the application in antituberculotic.
4. a kind of antituberculotic, which is characterized in that the effective ingredient is Teniposide.
5. a kind of application of antituberculotic as claimed in claim 4.
6. a kind of application of antituberculotic according to claim 5, which is characterized in that the antituberculotic is being treated
Application in tuberculosis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910440671.2A CN110200983B (en) | 2019-05-24 | 2019-05-24 | Application of teniposide in anti-mycobacterium tuberculosis drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910440671.2A CN110200983B (en) | 2019-05-24 | 2019-05-24 | Application of teniposide in anti-mycobacterium tuberculosis drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110200983A true CN110200983A (en) | 2019-09-06 |
| CN110200983B CN110200983B (en) | 2022-05-03 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910440671.2A Expired - Fee Related CN110200983B (en) | 2019-05-24 | 2019-05-24 | Application of teniposide in anti-mycobacterium tuberculosis drugs |
Country Status (1)
| Country | Link |
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| CN (1) | CN110200983B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110664811A (en) * | 2019-09-18 | 2020-01-10 | 深圳市第三人民医院 | Application of afatinib in anti-mycobacterium tuberculosis drugs |
-
2019
- 2019-05-24 CN CN201910440671.2A patent/CN110200983B/en not_active Expired - Fee Related
Non-Patent Citations (2)
| Title |
|---|
| 祁轶男等: "基于靶点的喹啉类抗结核药物研究进展", 《中南药学》 * |
| 金薇等: "替尼泊苷注射液含量及有关物质的HPLC-ECD分离检测", 《华东师范大学学报(自然科学版)》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110664811A (en) * | 2019-09-18 | 2020-01-10 | 深圳市第三人民医院 | Application of afatinib in anti-mycobacterium tuberculosis drugs |
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| Publication number | Publication date |
|---|---|
| CN110200983B (en) | 2022-05-03 |
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Granted publication date: 20220503 |