CN104693244A - Application of 4,4'-bipyridine bridged tetranuclear platinum complex in preparation of anti-telomerase negative tumor medicine - Google Patents
Application of 4,4'-bipyridine bridged tetranuclear platinum complex in preparation of anti-telomerase negative tumor medicine Download PDFInfo
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- CN104693244A CN104693244A CN201510069157.4A CN201510069157A CN104693244A CN 104693244 A CN104693244 A CN 104693244A CN 201510069157 A CN201510069157 A CN 201510069157A CN 104693244 A CN104693244 A CN 104693244A
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- negative tumor
- telomerase
- bipyridine
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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
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
Abstract
The invention discloses an application of a 4,4'-bipyridine bridged tetranuclear platinum complex in preparation of an anti-telomerase negative tumor medicine. Proliferation of telomerase negative tumor cells can be effectively inhibited.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to the application of 4,4'-Bipyridine bridging four core platinum complex in the anti-telomerase negative tumor medicine of preparation.
Background technology
Telomere (telomere) is a kind of special construction of eukaryote end of chromosome, and by the DNA of repeating unit and form in conjunction with the protein on it, its effect is the integrity keeping chromosome structure and function.Divide each time along with cell, telomere all can shorten a bit.The telomere of Normal human cells shortens to a certain degree, and cell will apoptosis, thus loses division growth ability.The cancer cells of about 80% maintains the stable of telomere length by expressing Telomerase (telomerase), obtains the ability of divide without limit; The cancer cells of about 20% does not express Telomerase (telomerase negative tumor cell) in addition, they extend telomere by the alternative pathway mechanism being called as ALT (Alternative Lengthening of Telomeres), thus maintain telomere length.Because Telomerase does not exist in the normal tissue cell of the mankind, it is special anticancer target.The feature of telomerase negative tumor comprises: account for about 20% of human body tumour cell; This tumour cell lacks (or check less than) telomerase activation; This tumour cell adopts ALT (Alternative Lengthening of Telomeres) mechanism to extend telomere; The telomeric dna (C-Circle DNA or T-Circle DNA) of ring-type is rich in this tumour cell; Observable APB (Associated Promyelocytic leukaemia Body) is had in this tumour cell of the overwhelming majority.
Increasing research shows, adopts the cancer cells of ALT mechanism to have and stronger invades profit, transfer ability, extremely low to the treatment success ratio of such cancer at present, is badly in need of developing the medicine for ALT tumour and method.In addition, up-to-date research shows, the medicine of Targeting Telomerase can allow tumour cell activate ALT mechanism, therefore, suppresses ALT mechanism to be also the domestic demand of the cancer therapy taking Telomerase as target and ultimate scheme.
Summary of the invention
The object of the invention is the technical problem for solving above, a kind of approach that effectively can suppress telomerase negative tumor cell proliferation is provided.
For this reason, the invention provides with the application of the 4,4'-Bipyridine bridging four core platinum complex of following formula (I) in the anti-telomerase negative tumor medicine of preparation:
Be known with above formula (I) compound, negatively charged ion is nitrate radical (NO
3 -) ion, have high water-soluble, good thermal stability.
According to application of the present invention, described telomerase negative tumor is osteosarcoma.
According to application of the present invention, described medicine contains pharmaceutically acceptable carrier or vehicle.
Experiment proves, formula I 4,4'-Bipyridine bridging four core platinum complex, for multiple telomerase negative tumor cell, includes but not limited to such as human osteosarcoma etc., all has the effectiveness that remarkable inhibition tumor cell is bred.
Accompanying drawing explanation
Fig. 1 is cell proliferation curve.
Fig. 2 is beta-galactosidase enzymes Coloration experiment result.
Fig. 3 is that flow cytometry detects apoptotic result.
Embodiment
The present invention is set forth further below in conjunction with specific embodiment.Should be understood that these embodiments are only not used in restriction range of application of the present invention for illustration of the present invention.
In the present embodiment, for human osteosarcoma formula I (4,4 '-dipyridyl bridging four core platinum complex) suppressing the effectiveness in telomerase negative tumor cell proliferation, but be understood that, although only its purposes for the preparation of the medicine of anti-telomerase negative tumor is described for human osteosarcoma, but " telomerase negative tumor " cell alleged by the present invention refers to the tumour cell lacking (or check less than) telomerase activation, do not express Telomerase, includes but not limited to such as human osteosarcoma, glioma etc.Experiment proves, formula I (4,4'-Bipyridine bridging four core platinum complex), for multiple telomerase negative tumor cell, includes but not limited to such as human osteosarcoma etc., all has the effectiveness that remarkable inhibition tumor cell is bred.
1 materials and methods
1.1 experiment material
Lung fiber mother (MRC-5, normal cell) cell strain, human cervical carcinoma's (HeLa, Telomerase positive) cell strain, human osteosarcoma (U2OS and SAOS2, telomerase negative) cell strain are purchased from Chinese Typical Representative species preservation center (CTCC).
1.2 experimental technique
1) MRC-5, HeLa, U2OS and SAOS2 cell is inoculated in 10cm respectively
2tissue Culture Dish in, inoculum density is 1 × 10
6/ ware, after waiting cell 6 hours adherent, carefully changes substratum, adds 10mL and contains the substratum of respective concentration formula I (4,4'-Bipyridine bridging four core platinum complex) or isopyknic substratum containing 0.1%DMSO.This operation repeated once every 2 days.
2), in breeding, the Shi Junxu that at every turn goes down to posterity uses cell counter to count every ware cell, and then therefrom gets the renewed vaccination of part cell, and inoculum density is still 1 × 10
6/ ware, until total cellular score <1 × 10 in culture dish
6individual cannot inoculate till.
3) cell getting propagation end carries out beta-galactosidase enzymes Coloration experiment and the experiment of fluidic cell apoptosis respectively.
4) beta-galactosidase enzymes Coloration experiment: after a) cell cultures stops, directly outwell substratum, then use 1 × PBS rinse 3 times; B) in cell, add stationary liquid, under normal temperature, fix 15min; C) after discarding stationary liquid, then 1 × PBS rinse is used 3 times, each 5min; D) concrete dying operation process operates according to the method that the X-gal staining kit in the green skies provides; E) staining fluid is added, 37 DEG C and isolate CO
2overnight incubation; F), after dyeing terminates, continue with 1 × PBS rinse 3 times, cell is placed in 10 × basis of microscopic observation, photograph.
5) fluidic cell apoptosis experiment: a) gather all cells (comprising the cell floated), adherent cell 0.25% trypsinization is collected, centrifugal, and with 1 × PBS rinse 2 times, abandoning supernatant, retains precipitation (cell); B) cell gathered is used
fluor 488annexin V and PI carries out two dye, and concrete dying operation process is according to Alexa
the method that 488annexin V/Dead Cell Apoptosis Kit test kit provides operates; C) cell suspending liquid after dyeing well is directly tested with flow cytometer, and experimental data carries out process matching by FlowJo software.
2 results
2.1 cell proliferation curves
During cell cultures the 32nd day, the growth curve of 4 cells as shown in Figure 1.Experimental result shows, title complex (the formula I 4 of multiple concentration, 4 '-dipyridyl bridging four core platinum complex) can't impact the propagation of normal cell (MRC-5) and telomerase-positive cells (HeLa), but but can reduce the propagation of telomerase negative cell (U2OS and SAOS2) significantly.
2.2 beta-galactosidase enzymes Coloration experiments
During cell aging, beta-galactosidase enzymes SA-β-Gal activity level rises, and can be determined rapidly the quantity of senile cell by the level (Senescence β-Galactosidase Staining) detecting beta-galactosidase enzymes in cell.As shown in Figure 2, there is obvious aging phenomenon in human osteosarcoma (SAOS2) cell of telomerase negative after compound (formula I 4,4'-Bipyridine bridging four core platinum complex) process.
2.3 flow cytometry detects apoptosis
In normal cell, phosphatidylserine (PS) is only distributed in the inner side of cell membrane lipid bilayer, and it is early stage at apoptosis, by the existence detecting cell outer surface PS, phosphatidylserine (PS) on cytolemma, by turning on one's side laterally in adipose membrane, therefore can determine whether cell is in apoptosis early stage.Annexin V and PS has high affinity, can be used for the quantity determining apoptotic cell.Propidium iodide (Propidium Iodide, PI) is a kind of nucleic acid dye, and it can not through the complete cytolemma of normal cell or viable apoptotic cell, but the cell to apoptosis middle and advanced stage, and PI can make nuclear targeting through cytolemma.Annexin V and PI is mated and uses, just can identify the cell being in different apoptosis period.On the scatter diagram of bivariate flow cytometer, left lower quadrant display viable cell, right lower quadrant is viable apoptotic cell, and left upper quadrant is apoptotic cell in mid-term, and right upper quadrant is apoptosis late cell.
From above experimental result, formula I 4,4'-Bipyridine bridging four core platinum complex effectively can suppress the propagation of telomerase negative tumor cell, and Tumor suppression grows, and can be used for the medicine preparing effective anti-telomerase negative tumor.
Claims (3)
1. the application of 4,4'-Bipyridine bridging four core platinum complex in the anti-telomerase negative tumor medicine of preparation of formula (I):
2. application according to claim 1, is characterized in that, described telomerase negative tumor is osteosarcoma.
3. application according to claim 1, is characterized in that, described medicine contains pharmaceutically acceptable carrier or vehicle.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510069157.4A CN104693244B (en) | 2015-02-09 | 2015-02-09 | Application of the core platinum complex of 4,4 ' bipyridyl bridging four in anti-telomerase negative tumor medicine is prepared |
| PCT/CN2015/094908 WO2016127681A1 (en) | 2015-02-09 | 2015-11-18 | Use of 4,4'-bipyridine bridged tetranuclear platinum complex in preparation of anti-telomerase negative tumour medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510069157.4A CN104693244B (en) | 2015-02-09 | 2015-02-09 | Application of the core platinum complex of 4,4 ' bipyridyl bridging four in anti-telomerase negative tumor medicine is prepared |
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| Publication Number | Publication Date |
|---|---|
| CN104693244A true CN104693244A (en) | 2015-06-10 |
| CN104693244B CN104693244B (en) | 2017-10-20 |
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| CN201510069157.4A Expired - Fee Related CN104693244B (en) | 2015-02-09 | 2015-02-09 | Application of the core platinum complex of 4,4 ' bipyridyl bridging four in anti-telomerase negative tumor medicine is prepared |
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| WO (1) | WO2016127681A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440602A (en) * | 2018-04-17 | 2018-08-24 | 深圳大学 | Four core complex of iridium and the preparation method and application thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115160376B (en) * | 2022-07-13 | 2023-11-21 | 南京师范大学 | Cinnamic acid modified cyclometalated iridium (III) complex and synthetic method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1925750A (en) * | 2004-01-15 | 2007-03-07 | Alt解决方案公司 | Modulation of LINE-1 reverse transcriptase |
| CN102250150A (en) * | 2011-05-17 | 2011-11-23 | 中山大学 | Organic hydridized tetra-core platinum complex and preparation method thereof as well as application technology field of complex in antitumor medicament preparation |
-
2015
- 2015-02-09 CN CN201510069157.4A patent/CN104693244B/en not_active Expired - Fee Related
- 2015-11-18 WO PCT/CN2015/094908 patent/WO2016127681A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1925750A (en) * | 2004-01-15 | 2007-03-07 | Alt解决方案公司 | Modulation of LINE-1 reverse transcriptase |
| CN102250150A (en) * | 2011-05-17 | 2011-11-23 | 中山大学 | Organic hydridized tetra-core platinum complex and preparation method thereof as well as application technology field of complex in antitumor medicament preparation |
Non-Patent Citations (2)
| Title |
|---|
| JERRY W. SHAY等,: "Cancer and Telomeres—An ALTernative to Telomerase", 《SCIENCE》 * |
| XIAO-HUI ZHENG等,: "Pt(II) squares as selective and effective human telomeric G-quadruplex binders and potential cancer therapeutics", 《DALTON TRANS.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108440602A (en) * | 2018-04-17 | 2018-08-24 | 深圳大学 | Four core complex of iridium and the preparation method and application thereof |
| CN108440602B (en) * | 2018-04-17 | 2020-06-05 | 深圳大学 | Tetranuclear iridium complex and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104693244B (en) | 2017-10-20 |
| WO2016127681A1 (en) | 2016-08-18 |
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