CN102898478A - High efficiency telomerase inhibitor and application of telomerase inhibitor in antitumor drug - Google Patents
High efficiency telomerase inhibitor and application of telomerase inhibitor in antitumor drug Download PDFInfo
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- CN102898478A CN102898478A CN2012102820379A CN201210282037A CN102898478A CN 102898478 A CN102898478 A CN 102898478A CN 2012102820379 A CN2012102820379 A CN 2012102820379A CN 201210282037 A CN201210282037 A CN 201210282037A CN 102898478 A CN102898478 A CN 102898478A
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- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 16
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 14
- 229940123582 Telomerase inhibitor Drugs 0.000 title claims description 8
- 239000003277 telomerase inhibitor Substances 0.000 title claims description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 51
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 16
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 150000003057 platinum Chemical class 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 27
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- 239000003446 ligand Substances 0.000 claims description 13
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
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- 229910001961 silver nitrate Inorganic materials 0.000 claims description 5
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- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 1
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- OFPUVEGIGZQSSD-UHFFFAOYSA-N diethyl-[2-oxo-2-(3-phenylmethoxyanilino)ethyl]azanium;chloride Chemical compound [Cl-].CC[NH+](CC)CC(=O)NC1=CC=CC(OCC=2C=CC=CC=2)=C1 OFPUVEGIGZQSSD-UHFFFAOYSA-N 0.000 description 1
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
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- -1 platinum ion Chemical class 0.000 description 1
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 1
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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 Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention discloses a trinuclear platinum complex (ZD028) capable of inhibiting the telomerase activity with high efficiency, a preparation method and an application of the trinuclear platinum as an antitumor drug. The trinuclear platinum complex can specifically inhibit the telomerase activity of the cancer cell, destroy a telomere maintenance mechanism which is pivotal to the cancer cell, accelerate the shortening of the telomere of the cancer cell, induce the aging of the cancer cell, and lead to death of the cancer cell to reach a purpose for treating malignant tumor, and the toxicity on normal cell is low. The conventional antitumor drug comprises doxorubicin, cisplatin and paclitaxel but not the limitation. Compared with the conventional antitumor drugs, the trinuclear platinum complex (ZD028) reduces the toxic and side effect on other organs or systems due to low toxicity on normal cells. The preparation method has the advantages of simple and easy operation and low cost, can be competed in a common chemical laboratory, and has no environmental pollution during the production process, thereby the trinuclear platinum complex (ZD028) can be used as a novel latent antitumor drug.
Description
Technical field
The present invention relates to a kind of can efficiently suppress telomerase activation three nuclear platinum complexes (
ZD028), and preparation method thereof and as the application of antitumor drug aspect.Be specifically related to efficiently to suppress telomerase activation three nuclear platinum complexes (
ZD028) the preparation method and can be used as the application of antitumor drug.
Background technology
At present, malignant tumour is the major disease of harm humans health and lives, but the anti-cancer agent research and development are to constantly update, and Chinese medicine is arranged, and Western medicine is also arranged.Long-term a large amount of clinical proof, all there is the larger common fault of toxic side effect in antitumor drug.Surgical operation is applicable to the treatment of some locality tumour early and middle portion, but the treatment of most patient's armrest art is to prevent the recurrence of tumour and distant metastasis.Although Radiotherapy chemotherapy has quite high curative ratio, often cause such as toxic side effecties such as bone marrow depression, immunocompromised, make the patient be difficult to adhere to treatment.The resistance that chemotherapeutics occurs in therapeutic process has become one of difficult problem in the present clinical treatment.Just because of these reasons, we to be ready seeking anti-cancer agent.
Cancer therapy drug take nucleic acid as target spot should be the cancer therapy drug of tool development prospect, because fundamentally Emergence and Development and the increment of anticancer of this type of medicine.G-four serobila DNA are as the special secondary structure that the important biomolecule function is arranged, the design of the cancer therapy drug take it as target spot has reasonableness and superiority, mainly due to this structure following characteristics is arranged: 1), the singularity of structure: be different from ubiquitous double-stranded DNA, special structure could provide design platform for micromolecular compound selectively; 2), the singularity of effect: special biological function is arranged, and micromolecular compound can reach the purpose of specificity anticancer by stablizing, break or change its this secondary structure; 3), be present in important gene zone in the body.Along with the development of molecular biology and structure biology, structure diversity and the biological functionality of G-four serobilas are constantly illustrated.Therefore, the drug research take various types of G-four serobilas as action target spot has caused people widely interest and attention.Title complex is induced and is formed G-four chain body structures and effectively stablize this structure, and then the activity of inhibition Telomerase, tumoricidal mechanism of telomere maintenance, accelerate the aging of cancer cells, and then cause the death of cancer cells, simultaneously because Telomerase is not have activatedly, only in cancer cells, just have high activity, so this helps to find significant selectivity that cancer cell multiplication is had strong inhibiting cancer therapy drug in normal cell.
Because metal complexes has advantages of that a lot of organic molecules hardly match, such as rich and varied coordination structure and Electronic Performance, the more important thing is that they often have some interesting characteristics, for example optics, magnetics, catalysis etc., these are to be designed to outstanding G-four serobila stablizers to bring very large potentiality and possibility.The kind of metal ion is more and more in the metal complexes of stable G-four serobilas of report at present, and it also is not a lot of that the title complex that makes up centered by noble metal platinum is till now stablized G-four serobilas.Platinum complexes starts from nineteen sixties as the research of antitumor drug, and several platinum complexes (cis-platinum, carboplatin, oxaliplatin, S 254 and Lobaplatin etc.) that are used at present clinical medicine all are that nucleic acid take the target duplex structure is as main.Although the research of the selectivity cancer therapy drug take G-four serobilas as target also only has more than 10 year, begin successively to have new micromolecular compound to enter clinical experiment, but also do not have metal complexes in these compounds.
Consider the fragrant two dimensional structure characteristics of G-four serobilas, metal platinum (II) title complex that is comparatively speaking made up by the platinum ion coordination has its unique superiority.For example this patent related three nuclear platinum complexes (
ZD028).
Bridge ligand is a series of nitrogenous heterocycles, makes the easier and G-four serobila generation pi-pi accumulation effects of title complex, and then can stablize efficiently this structure, and then improve the inhibition ability of telomerase activation.
The present invention simplifies it and synthesizes by supramolecule self-assembly organic hybrid three nuclear platinum complexes, reduce production costs, and specific organic functions group makes it have high G-four serobila targetings, high telomerase activation suppresses ability and antitumour activity by introducing.
Summary of the invention
The present invention seeks to design a kind of relate to the three nuclear platinum complexes that can efficiently suppress telomerase activation (
ZD028), and preparation method thereof and as the application of antitumor drug aspect.
Cancer therapy drug provided by the invention is the organic hybrid three nuclear platinum complexes that utilize the supramolecule self-assembly to form, and structural formula is as follows:
ZD028
The present invention has the synthetic method that excellent telomerase activation suppresses three nuclear platinum complexes of ability, utilizes the coordination configuration of plane square of supramolecule self-assembly and Pt (II) and the geometric configuration of middle bridge ligand uniqueness to make.Furtherly, be to utilize the supramolecule self-assembly that prothetic group part and bridge ligand are assembled into three nuclear structures, the three nuclear platinum complexes that obtain having high G-four serobila targetings, high telomerase activation suppress ability and antitumour activity.
The three nuclear platinum complex (called afters in this patent that can efficiently suppress telomerase activation of the present invention
ZD028), furtherly, it is synthetic to be side arm monodentate platinum part [Pt (the dien) (NO that chlorion is replaced by nitrate radical
3)] (NO
3) form by self-assembly with corresponding bridge ligand, so that having high Telomerase, this title complex suppresses ability and antitumour activity.
This three nuclear platinum complex (
ZD028) synthetic method, reaction formula is as follows:
In the reaction formula, (1) is side arm monodentate platinum part bridge ligand [Pt (the dien) (NO that chlorion is replaced by nitrate radical
3)] (NO
3) structural formula, (2) are the structural formulas of bridge ligand, (3) be final product three nuclear platinum complexes (
ZD028) structural formula.
Specifically, provided by the invention have high G-four serobila targetings, high Telomerase suppress ability and antitumour activity three nuclear platinum complexes (
ZD028) synthetic method, comprise the steps:
The dechlorination of monodentate platinum part: described monodentate platinum part is soluble in water, add again Silver Nitrate, lucifuge reaction under protection of inert gas, the centrifugal rear reservation stillness of night.
Three nuclear platinum complexes are synthetic: add described bridge ligand in the stillness of night after the above-mentioned dechlorination, lucifuge reaction under protection of inert gas, react complete after, the adding absolute ethanol washing, the centrifugal solid matter that obtains, namely target three is examined platinum complexes.
Above-mentioned protection of inert gas and lucifuge are the committed step of reaction.The wherein effect of protection of inert gas is to be that secluding air or other have the gas of oxidisability.Should be understood to, any means that can realize above-mentioned purpose, means are used for the present invention as an alternative, and this replacement does not break away from protection scope of the present invention.
As preferred scheme, described rare gas element is nitrogen; The lucifuge reaction conditions of monodentate platinum part dechlorination step is: 45 degree reactions 36 hours; The lucifuge reaction conditions of described three nuclear platinum complex synthesis steps is: 95 degree lucifuge reactions 3 days.
Can adopt following steps synthesize described three nuclear platinum complexes (
ZD028).
Monodentate platinum part [Pt (dien) Cl] ClHCl dechlorination: monodentate platinum part is dissolved in the Silver Nitrate that adds again its 3 times of molar weights in an amount of water, reacted 36 hours in 45 degree lucifuge under nitrogen protection, centrifugal with refrigerated centrifuge, discard precipitation, keep the stillness of night.
Three nuclear platinum complexes (
ZD028): adding mol ratio in the stillness of night after the above-mentioned dechlorination is the bridge ligand of 0.3:1.Whole reaction under the protection of nitrogen, in 90 degree lucifuges reactions 3 days, react complete after, add an amount of dehydrated alcohol, use again this solvent wash 3 times, the centrifugal solid matter that obtains, namely three examine platinum complexes (
ZD028).
Monodentate platinum part of the present invention is that chlorion is replaced by nitrate ion.
The present invention's discovery, described three nuclear platinum complexes can be used as telomerase inhibitor suppressing to have outstanding effect aspect the Telomerase.Say further, three nuclear platinum complexes of the present invention can be used to prepare antitumor drug.
The present invention research three nuclear platinum complexes (
ZD028) when reaching antitumous effect as telomerase inhibitor, find that tumour cell that this title complex is high expression level to a series of Telomerases [for example: A549 (human lung carcinoma cell), HepG2 (human liver cancer cell), HeLa (human cervical carcinoma cell), CNE-2 (KB cell), MCF-7 (human breast cancer cell) etc.] all have excellent Telomerase and suppress ability, but because cervical cancer occupies first of the woman cancer sickness rate and the activity of HeLa cell telomerase is unusual also very many of high and quantity, so following our embodiment mainly is as subjects take the HeLa cell.But this does not also mean that title complex of the present invention only can act on cited tumour cell, and those skilled in the art should understand, and cited tumour cell can not be as the restriction of protection domain of the present invention.
The present invention has following technique effect:
The present invention take the monodentate platinum part that is simple and easy to close as the prothetic group part with corresponding bridge ligand, by the method for supramolecule self-assembly synthetic and characterized a kind of have high G-four serobila targetings, high Telomerase suppress ability and antitumour activity three nuclear platinum complexes (
ZD028).Suppress (TRAP) experiment, long-term cell proliferation experiment and beta-galactosidase enzymes Coloration experiment by fluorescent energy resonance transfer (FRET) experiment, Telomerase and proved that this compound has excellent telomerase activation and suppresses ability and antitumour activity.
Description of drawings
Fig. 1 be three nuclear platinum complexes (
ZD028) structural representation;
Fig. 2 shown three nuclear platinum complexes (
ZD028) to the inhibition ability of telomerase activation;
Fig. 3 shown three nuclear platinum complexes (
ZD028) on the impact of HeLa cell long-period propagation
Fig. 4 is old and feeble relevant beta-galactosidase enzymes Coloration experiment in the HeLa cell, three nuclear platinum complexes (
ZD028) concentration is 15 μ M, A is control group, B is the dosing group.
Embodiment
Below in conjunction with embodiment the present invention is described in detail.
Embodiment one
Organic hybrid three nuclear platinum complexes synthetic (
ZD028): monodentate platinum part [Pt (dien) Cl] ClHCl of 0.5 mmole amount is dissolved in 6 ml waters, adds the Silver Nitrate of 1.5 mmole amounts in the dark place under nitrogen protection, 45 degree stirred 36 hours, react complete after, the centrifugal precipitation that discards, the reservation stillness of night; The bridge ligand that adds 0.15 mmole in the above-mentioned clear liquid, whole reaction under nitrogen protection in 90 degree lucifuges reactions 3 days, after reaction finishes; in reaction solution, add an amount of dehydrated alcohol; separate out light yellow solid, centrifugal light yellow solid, product vacuum-drying.Productive rate: 83%.Ultimate analysis (%),
Theoretical value: C
30H
51N
21O
18Pt
36H
2O:C, 21.36; H, 3.76; N, 17.43. experimental value: C, 21.20; H, 3.76; N, 17.52.
195Pt NMR (D
2O, δ/ppm) :-1222.20, and K
2PtCl
4Be used as internal standard substance (δ=0).
The structural formula of this compound as shown in Figure 1.
Embodiment two
Fluorescent energy resonance transfer (FRET) experiment: with the title complex of the human telomeric dna (F21T) of 10 μ M, promoter DNA (c-kit) or double-stranded DNA (dsDNA) and 10 μ L different concns (
ZD028) the solution mixing.Add 20 μ L sample solutions of gained in the LightCycler kapillary and insert Roche LightCycler 2 type quantitative real time PCR Instruments.Fixedly excitation wavelength is 470nm, the emitting fluorescence intensity of monitoring 530nm.Range of temperature is 37-99
0C, warming room is divided into 1
0C, balance 30 s post-samplings,
T mValue is calculated and is used the Origin match.Data results sees Table 1.Experimental result shows that this three nuclear platinic compound can the specific efficient human body telomere G-four serobila DNA that stablize.
Table 1 three nuclear platinum complexes (
ZD028) to the thermally-stabilised ability (△ of different DNA
T m).
Embodiment three
Telomerase suppresses (TRAP) experiment: collect the lysate of HeLa cell, join in the TRAP reaction solution that contains the respective concentration title complex, carry out pcr amplification, analyze its amplified production with 0.8% polyacrylamide gel.Data results is seen Fig. 2.Experimental result shows, this title complex be an excellence telomerase inhibitor (
Tel IC 50=30 nM).
Embodiment four
Long-term cell proliferation experiment: the HeLa cell is inoculated in the T25 tissue culture flasks, and adding in per four days contains the substratum of respective concentration title complex or contains the substratum of 0.1%DMSO.Data results is seen Fig. 3.The cell long-period increment is tested and is shown, this title complex can reduce the survival rate of cell, and then reaches antineoplastic effect.
Embodiment five
Beta-galactosidase enzymes Coloration experiment: the cell of cultivating after stopping is fixed, dyes, place 40 * microscopically to observe, take a picture.Data results is seen Fig. 4.Because beta-galactosidase enzymes is a key character of cell aging, as shown in Figure 4, this title complex can effectively accelerate the aging of cell, and then reaches antineoplastic effect.
Above comprehensive giving birth to surveyed experimental result and shown, three nuclear platinum complexes (
ZD028) suppressed the activity of Telomerase by acting on telomere G-four serobila DNA, disturbed the support mechanism of cancer cells telomere, thereby accelerated the shortening of cancer cells telomere length, and and then accelerated the aging of cell, finally caused the death of cancer cells, and very low to Normocellular toxicity, so this three nuclear platinum complex (
ZD028) can be used as a kind of potential antitumor drug.
Claims (10)
1. examine platinum complex for one kind three, it is characterized in that structural formula is as follows:
According to claim 1 three nuclear platinum complexes the preparation method, it is characterized in that reaction formula is as follows:
In the reaction formula, the structural formula of (1) monodentate platinum part that to be chlorion replaced by nitrate radical, (2) are the structural formulas of bridge ligand, (3) are the structural formulas of final product three nuclear platinum complexes.
According to claim 2 this three nuclear platinum complex the preparation method, it is characterized in that reactions steps is as follows:
The dechlorination of monodentate platinum part: described monodentate platinum part is soluble in water, add again Silver Nitrate, lucifuge reaction under protection of inert gas, the centrifugal rear reservation stillness of night;
Three nuclear platinum complexes are synthetic: add described bridge ligand in the stillness of night after the above-mentioned dechlorination, lucifuge reaction under protection of inert gas, react complete after, the adding absolute ethanol washing, the centrifugal solid matter that obtains, namely target three is examined platinum complexes.
4. the synthetic method of three nuclear platinum complexes according to claim 3 is characterized in that described rare gas element is nitrogen.
5. the synthetic method of three nuclear platinum complexes according to claim 3 is characterized in that the lucifuge reaction conditions of described monodentate platinum part dechlorination step is: 45 degree reactions 36 hours.
6. the synthetic method of three nuclear platinum complexes according to claim 3 is characterized in that the lucifuge reaction conditions of described three nuclear platinum complex synthesis steps is: 95 degree lucifuge reactions 3 days.
According to claim 3 three nuclear platinum complexes synthetic method, it is characterized in that reactions steps is as follows:
The dechlorination of monodentate platinum part: described monodentate platinum part is dissolved in the Silver Nitrate that adds again 3 times of molar weights in an amount of water, and the lucifuge reaction is 36 hours under nitrogen protection, and is centrifugal with refrigerated centrifuge, discards precipitation, keeps the stillness of night;
Three nuclear platinum complexes are synthetic: adding mol ratio in the stillness of night after the above-mentioned dechlorination is the described bridge ligand of 0.3:1, under the protection of nitrogen, reacts 3 days in 95 degree lucifuges; react complete after; add dehydrated alcohol, the centrifugal solid matter that obtains, i.e. target three nuclear platinum complexes.
8. three nuclear platinum complexes according to claim 1 are in the application aspect telomerase inhibitor.
9. three application of nuclear platinum complex in the preparation antitumor drug according to claim 1.
10. three nuclear platinum complexes according to claim 1 are as the efficiently application of telomerase inhibitor aspect the antineoplaston drug combination.
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| CN107417734A (en) * | 2017-07-19 | 2017-12-01 | 中山大学 | A kind of platinum complex with two-Photon Absorption Properties and its preparation method and application |
| CN111635438A (en) * | 2020-06-24 | 2020-09-08 | 江苏第二师范学院（江苏省教育科学研究院） | Preparation method and application of polyaryl alkyl modified binuclear platinum (II) complex |
| CN113307829A (en) * | 2021-05-08 | 2021-08-27 | 苏州科技大学 | Platinum (II) complex with hydroxamic acid derivative as ligand and preparation method and application thereof |
| CN113336798A (en) * | 2021-05-20 | 2021-09-03 | 江汉大学 | Trinuclear platinum complex based on trimeprazine and preparation method and application thereof |
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| CA3081536A1 (en) * | 2017-11-06 | 2019-05-09 | Queen's University At Kingston | Platinum compounds for binding guanine quadraplexes |
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| 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 |
| CN102516315A (en) * | 2011-12-12 | 2012-06-27 | 中山大学 | Trinuclear platinum complex possessing Y type structure and its targeting for gastric adenocarcinoma cells |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107417734A (en) * | 2017-07-19 | 2017-12-01 | 中山大学 | A kind of platinum complex with two-Photon Absorption Properties and its preparation method and application |
| CN107417734B (en) * | 2017-07-19 | 2019-08-20 | 中山大学 | A kind of platinum complex and its preparation method and application with two-Photon Absorption Properties |
| CN111635438A (en) * | 2020-06-24 | 2020-09-08 | 江苏第二师范学院（江苏省教育科学研究院） | Preparation method and application of polyaryl alkyl modified binuclear platinum (II) complex |
| CN111635438B (en) * | 2020-06-24 | 2023-01-24 | 江苏第二师范学院（江苏省教育科学研究院） | Preparation method and application of polyaryl alkyl modified binuclear platinum (II) complex |
| CN113307829A (en) * | 2021-05-08 | 2021-08-27 | 苏州科技大学 | Platinum (II) complex with hydroxamic acid derivative as ligand and preparation method and application thereof |
| CN113307829B (en) * | 2021-05-08 | 2022-05-24 | 苏州科技大学 | Platinum (II) complex with hydroxamic acid derivative as ligand and preparation method and application thereof |
| CN113336798A (en) * | 2021-05-20 | 2021-09-03 | 江汉大学 | Trinuclear platinum complex based on trimeprazine and preparation method and application thereof |
| CN113336798B (en) * | 2021-05-20 | 2023-03-14 | 江汉大学 | Trinuclear platinum complex based on trimeprazine and preparation method and application thereof |
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