CN116655703A - High-targeting telomere G4 stabilizer and application thereof in antitumor drugs - Google Patents
High-targeting telomere G4 stabilizer and application thereof in antitumor drugs Download PDFInfo
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- CN116655703A CN116655703A CN202310536959.6A CN202310536959A CN116655703A CN 116655703 A CN116655703 A CN 116655703A CN 202310536959 A CN202310536959 A CN 202310536959A CN 116655703 A CN116655703 A CN 116655703A
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Classifications
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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
-
- 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
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- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a tetranuclear platinum compound and application thereof, wherein the tetranuclear platinum compound has a structure shown as a formula (I), and an in vitro G4 targeting experiment result shows that the tetranuclear platinum compound has high targeting to telomere G4, has excellent telomerase activity inhibition capability, can quickly promote shortening of telomere length, has excellent anti-tumor activity, and effectively avoids huge toxic and side effects of clinical platinum chemotherapeutic drugs.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a tetranuclear platinum compound serving as a high-targeting telomere G4 stabilizer and application thereof in anti-tumor drugs.
Background
Telomeres are special structures of linear chromosome ends of eukaryotic cells, and have the functions of protecting chromosome ends and maintaining genome stability. Telomeres at the ends of linear chromosomes can avoid recognition of the ends of linear chromosomes as DNA damage and inhibit DNA damage response mechanisms. In human cells, telomeres consist of the telomere DNA repeat 5'-TTAGGG-3' with the telomere binding protein "Shellerin". However, due to the "end replication problem" present in linear DNA semi-preserved replication, telomeric DNA is lost a short segment at each cycle of cell division. In human cells, the telomeric DNA is shortened by 50-300bp every time the cell divides. When telomeric DNA shortens to a limit length, it loses the function of protecting the chromosome, thereby activating DNA damage signals within the cell, which goes into senescence or apoptosis programs.
An important feature of cancer cells is the ability to divide indefinitely, and to avoid cell senescence, apoptosis, caused by telomere shortening, 85% of cancer cells express telomerase. Telomerase is composed of reverse transcriptase hTERT and RNA template hTR, and can synthesize sequence TTAGGG by using self RNA as template, and adds it to terminal of telomere, so as to prolong telomere. Because normal human somatic cells do not express telomerase, telomerase is a specific target for cancer treatment. However, since the molecular mechanism of telomerase extension telomeres in cells is less known, development of drugs for the purpose of inhibiting telomerase has been slow.
G4 is a class of classical nucleic acid three-dimensional structures formed by folding guanine (G) -rich DNA or RNA repeats. The G tetrad is a structural unit of G4, 4G forms a ring-shaped plane through Hoogsteen hydrogen bonding, and two or more layers of G tetrad form G4 through pi-pi stacking. Because of the multi-aspect differences of the G tetrad structure, loop, groove region, central ion channel and the like, the polymorphism of the G4 structure (which can be basically divided into parallel type, antiparallel type and mixed type) and the obvious difference from the common double-helix DNA structure are caused, and the polymorphism structure becomes an ideal target point for the design of targeted drugs. Telomere DNA has abundant TTAGGG linear repeated sequence, the sequence can self-assemble into G-tetrad from 4G by Hoogsteen hydrogen bond under certain condition, and multiple G-tetrad forms G4 by pi-pi stacking action.
The formation of telomere G4 can effectively inhibit the activity of telomerase, so that the telomere G4 can not maintain the stability of the telomere length, and the death of tumor cells is induced. Platinum chemotherapeutics are the most widely used antitumor drugs in clinical line at present, but because the platinum chemotherapeutics only target double-stranded DNA (deoxyribonucleic acid) singly, the platinum chemotherapeutics lack of tumor cell targeting and have higher clinical toxic and side effects. On the basis, the invention provides a platinum derivative tetranuclear platinum compound, and the derivative is particularly suitable for diseases with high expression of telomerase, especially tumors and cancers.
Disclosure of Invention
The invention provides a tetranuclear platinum compound and application thereof, and the tetranuclear platinum compound has better anti-tumor activity.
A tetranuclear platinum compound has a structure shown in a formula (I):
the invention designs a novel tetranuclear platinum compound based on platinum and pyrazine by a drug design method. The in vitro anti-tumor activity test result shows that the tetranuclear platinum compound (I) has higher anti-tumor activity.
The invention also provides application of the tetranuclear platinum compound, and the tetranuclear platinum compound is used for preparing antitumor drugs.
Preferably, the tetranuclear platinum compound treats telomerase-positive tumors and diseases related to telomerase-positive tumors by inducing the formation and stabilization of telomere G4, inhibiting the activity of telomerase, and promoting the shortening of telomere length.
Preferably, the telomerase positive tumor and diseases associated with telomerase positive tumors, including but not limited to: cancers, such as liver cancer (including small cell liver cancer), bladder cancer, breast cancer, colon cancer, kidney cancer, lung cancer, esophagus cancer, gall bladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer, and skin cancer (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, mantle cell lymphoma, hairy cell lymphoma, and Burkett's lymphoma; hematopoietic tumors of the myeloid lineage, including acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia; multiple myeloma; tumors of mesenchymal origin, including fibroids and rhabdomyosarcoma; other tumors, including melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid cyst carcinoma and kaposi's sarcoma.
Most preferably, the tetranuclear platinum compound has the following structural formula:
the invention also provides a pharmaceutical preparation which comprises an effective component and a pharmaceutical adjuvant, wherein the effective component comprises the tetranuclear platinum compound.
Preferably, the pharmaceutical preparation is any one of injection, tablet, capsule, aerosol, suppository, film, dripping pill, ointment, controlled release agent, sustained release agent or nanometer preparation.
Compared with the prior art, the invention has the beneficial effects that: based on platinum and pyrazine, a novel tetranuclear platinum compound is designed and synthesized through a drug design method. The compounds have high targeting and affinity for telomere G4 due to their higher spatial matching with telomere G4, in addition to the ability of the side arms to bind to the groove of telomere G4. Therefore, the tetranuclear platinum complex has excellent telomerase activity inhibition capability, can rapidly promote the shortening of the telomere length, and has excellent anti-tumor activity. And the tetranuclear platinum has weak toxic and side effects on normal cells and tissues due to the specificity of the tetranuclear platinum on telomere G4.
The present invention will be described in detail below with reference to specific drawings and examples for the purpose of facilitating understanding. It is to be expressly noted that the specific examples and the drawings are for illustrative purposes only and are not to be construed as limiting the scope of the present invention. It will be apparent to those skilled in the art from this disclosure that various modifications and variations can be made to the present invention within the scope of the invention, and these modifications and variations are also within the scope of the invention.
Drawings
FIG. 1 is a study of the targeting of telomere G4 by the synthesis of tetranuclear platinum compounds in test example 1;
FIG. 2 is a graph showing the effect of synthesis of tetranuclear platinum compounds on telomerase activity in test example 2;
FIG. 3 is a graph showing the effect of synthesis of tetranuclear platinum compounds on telomere length in test example 3;
FIG. 4 is a graph showing the effect of synthesis of tetranuclear platinum compounds on telomerase positive tumor cell proliferation in test example 4;
FIG. 5 is a graph showing the toxicity and side effects of the synthetic tetranuclear platinum compound of test example 5 on kidney.
Detailed Description
The invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
EXAMPLE 1 Synthesis of (E) -1- [ (2-aminoethyl) amino ] -4- (2, 4-dimethoxyphenyl) but-3-en-2-one platinum compound
2, 4-Dimethoxybenzaldehyde (1 mol 0.167 g) and 1- ((2-aminoethyl) amino) propan-2-one (1 mol 0.12 g) were dissolved in 8ml of absolute ethanol, and a 5% NaOH solution was added thereto for reaction at room temperature for 8 hours. After the reaction was completed, the reaction was quenched and the absolute ethanol was removed in vacuo. Extracting with ethyl acetate and saturated sodium chloride solution, drying the organic layer with anhydrous magnesium sulfate, concentrating, and purifying by column chromatography to obtain (E) -1- [ (2-aminoethyl) amino]-4- (2, 4-dimethoxyphenyl) but-3-en-2-one compound in 63.2% yield. ESI-MS M/z 365.1 (M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.07(d,J＝8.7Hz,1H),7.85(d,J＝15.6Hz,1H),6.81(d,J＝7.7Hz,1H),6.78(s,1H),6.65(d,J＝12.6Hz,1H),4.12(s,2H),3.90(s,3H),3.82(s,3H),3.15(s,1H),2.76-2.60(m,4H),1.6(s,2H).
1 mmol of (E) -1- [ (2-aminoethyl) amino group]The 4- (2, 4-dimethoxyphenyl) but-3-en-2-one compound was placed with 1.2 mmol of potassium chloroplatinite in a 25ml round bottom flask and 15ml Dimethylformamide (DMF) was added and the whole was reacted under nitrogen protection at 90℃in the absence of light for 24h. Precipitating with absolute ethanol, and recrystallizing with absolute ethanol: diethyl ether=3:2 to obtain pure (E) -1- [ (2-aminoethyl) amino]-4- (2, 4-dimethoxyphenyl) but-3-en-2-one platinum compound in a yield of 95%. ESI-MS M/z 529.1 (M+H) + 。
EXAMPLE 2 Synthesis of novel tetranuclear platinum Compounds
An amount of 0.5 millimoles of (E) -1- [ (2-aminoethyl) amino group]Dissolving 4- (2, 4-dimethoxy phenyl) but-3-en-2-one platinum compound in 6 ml of water, adding 1.0 mmol of silver nitrate in dark under the protection of nitrogen, stirring at 60 ℃ for 12 hours, centrifuging at ultralow temperature after the reaction is finished, discarding the precipitate, and reserving the clear solution; and adding 0.5 millimole of pyrazine into the clear liquid, carrying out the whole reaction for 4 days at 60 ℃ in a dark place under the protection of nitrogen, adding a large amount of absolute ethyl alcohol into the reaction liquid after the reaction is finished, separating out yellow solid, centrifuging to obtain yellow solid, and carrying out vacuum drying on the product. Yield 89.5%, elemental analysis (%), theoretical: c (C) 69 H 90 N 16 O 12 Pt 4 ·15H 2 O (2386.12) C,33.73; h,5.07; n,9.39. Experimental value C,34.01; h,5.13; n,9.05. 195 Pt NMR(D 2 O,δ/ppm)：-917，K 2 PtCl 4 Is used as an internal standard (δ=0).
Test example 1 study of Synthesis of tetranuclear platinum Compounds on telomere G4 targeting
Targeting of the synthesized tetranuclear platinum compound to telomere G4 is examined through fluorescence energy resonance transfer (FRET) experiments, and the specific operation steps are as follows: the telomere G4 with double fluorescent markers, the promoter region c-myc and the double stranded DNA oligonucleotide sequences were synthesized in vitro and concentration calibrated by the parameters given by the synthesis company. Annealing in vitro to form corresponding G4 and double helix structures. Wherein the telomere G4 oligonucleotide sequence is: 5' -FAM-d [ AGGGTTAGGGTTAGGGTTAGGG ]]TAMRA-3'; the promoter c-myc oligonucleotide sequence is: 5' -FAM-d [ TGGGGAGGGTGGGGAGGGTGGGGAAGG ]]TAMRA-3'; the double-stranded DNA oligonucleotide sequences were: 5' -FAM-d [ TATAGCTATA ]]-HEG-d[TATAGCTATA]-TAMRA-3’。HEG linker is[(-CH 2 -CH 2 -O-) 6 ]The fluorescence donor FAM is 6-carboxyfluoroscein, and the fluorescence acceptor TAMRA is 6-carboxy-tetramethylrhodomine. The oligonucleotide sequences and tetranuclear platinum compounds are mixed uniformly according to the molar weight of 1:1, added into a Roche (LightCycler) PCR tube, and subjected to a test by a Roche fluorescent quantitative PCR instrument (LightCycler type 2 fluorescent quantitative PCR instrument) after standing for one hour. The temperature is changed within 37-99 ℃, the temperature rising interval is 1 ℃/min, the temperature is balanced for 30 seconds after rising, sampling is carried out, T m The values are given by the instrument's own melting point analysis program.
As shown in FIG. 1, the 2.0 mu M synthesis of tetranuclear platinum compound can significantly improve the melting temperature delta T of telomere G4 m 30.2℃but does not significantly increase the melting temperature (. DELTA.T) of c-myc G4 m 5.3 ℃) and has no effect on the melting temperature of the double-stranded DNA. The experimental results fully indicate that the synthesized tetranuclear platinum compound has higher targeting property on telomere G4. Test example 2 influence of Synthesis of tetranuclear platinum Compounds on telomerase Activity
Since telomerase activity is primarily regulated by its RNA subunits TERC and reverse transcriptase hTERT. Therefore, we mainly examined the expression levels of these two main components by RT-qPCR. The specific experimental process is as follows: heLa cells at 2X 10 5 Density was laid out in 6-well plates and control and dosing groups (0.5. Mu.M, 1.0. Mu.M and 2.0. Mu.M) were set, and after 48 hours of drug treatment cells were lysed in iceberg with Trizol, RNA was collected and purified. Then according to the instructions in the reverse transcription kitPerforming reverse transcription on the extracted RNA to obtain cDNA; and adding TERC and TERT primers, YBR Green, cDNA and water for RT-PCR detection.
The experimental results are shown in fig. 2, and compared with the control group, the synthesized compound can obviously reduce the content of TERC and hTERT mRNA in telomerase positive cells HeLa cells after being treated by adding drugs. And the greater the drug concentration, the stronger the inhibition of TERC and hTERT mRNA levels.
Test example 3 influence of Synthesis of tetranuclear platinum Compounds on telomere Length
The relative length of telomeres was detected by a telomere quantitative fluorescence in situ hybridization assay (Q-FISH). The specific experimental process is as follows: heLa cells were treated with 1. Mu.g/ml Nocodazole for 3.5h to arrest most cells in M phase (cell morphology was rounded and adhesion was reduced). All cells were collected, resuspended in a small amount of PBS, slowly dropped into hypotonic solution, and left at 37℃for 30 minutes. Then, after adding a few drops of the fixing solution (ethanol: acetic acid=3:1), the mixture was centrifuged and the supernatant was discarded. The cells were resuspended in fixative, and the cell suspension was dropped from above onto a clean pre-chilled slide and air dried overnight at room temperature. Telomeres of HeLa cells were hybridized with a telomere probe and photographed under a fluorescence microscope. The relative length of telomeres is calculated according to the intensity of telomere probes. As shown in fig. 3, each chromosome of the control group had a very bright red spot (the brighter red indicates longer telomere length), and the red spot on the cell chromosome of the 2.0 μm tetranuclear platinum dosing group was significantly darkened and reduced (indicating shorter telomere length); the experimental result of Q-FISH shows that synthesizing tetranuclear platinum compound can obviously promote the shortening of the HeLa telomere length of telomerase positive tumor cells.
Test example 4 influence of Synthesis of tetranuclear platinum Compounds on telomerase-positive tumor cell proliferation
The effect of synthetic compounds on the proliferation of telomerase positive cells HeLa was assessed by long term cell proliferation experiments. The specific experimental process is as follows: heLa cells were grown at 2X 10 5 Individual cells/dish were seeded in 10cm dishes; after cell attachment, the culture was continued by adding 0.5. Mu.M, 1.0. Mu.M and 2.0. Mu.M compounds. After 2 days of drug treatment, pancreatin is digested, cells are collected, and cells are collectedThe counter counts the total cells and calculates the total cells according to the formula [ PDs (algebra of cell proliferation) =2m/N (M: total number of cells after proliferation N: initial number of cells implanted)]Cell proliferation algebra was calculated and finally the corresponding graph was drawn on Graphpad Prism 7.0. The above procedure was repeated once every 2 days of dosing for a total of 5 replicates. The experimental results are shown in fig. 4, compared with the control group, the dosing treatment of the synthetic tetranuclear platinum significantly inhibits the proliferation rate of HeLa cells, and the inhibition strength is positively correlated with the drug concentration.
Test example 5 investigation of toxic side effects of Synthesis of tetranuclear platinum Compound on kidney
Blood creatinine (Cr) is a muscle metabolite, and creatinine concentration in the blood is an important indicator reflecting glomerular filtration function. Clinically, cr concentration is an important indicator for assessing kidney function and monitoring kidney disease. In order to further evaluate the toxic and side effects of the synthesized tetranuclear platinum compound on kidney, the effect of clinical first-line chemotherapy drug cisplatin on Cr of mice is measured by adopting a creatininase method. The experimental process is as follows: the chromium content of the blood of the mice was measured by administering cisplatin, tetranuclear platinum compound or physiological saline (control group) at 2mg/kg by tail vein, taking blood from the orbit of the mice after 7 days, and by creatininase method. As shown in fig. 5, compared with the control group, the blood Cr content of the mice in the cisplatin-administered group is significantly increased (indicating that the mice have a great toxic or side effect on the kidney), and the blood Cr content of the mice in the synthetic tetranuclear platinum-administered group is equivalent to that in the control group (indicating that the mice have almost no toxic or side effect on the kidney).
Claims (8)
1. A tetranuclear platinum compound is characterized in that the structure is shown as a formula (I):
2. the use of a tetranuclear platinum compound according to claim 1, for the preparation of an antitumor agent.
3. The use of a tetranuclear platinum compound according to claim 2, wherein the tetranuclear platinum compound is used for the treatment of telomerase positive tumors and diseases associated with telomerase positive tumors.
4. The use of a tetranuclear platinum compound according to claim 3, wherein the tetranuclear platinum compound treats telomerase positive tumors and diseases associated with telomerase positive tumors by inducing the formation of telomere G4, inhibiting the activity of telomerase, promoting the shortening of telomere length.
5. The use of a tetranuclear platinum compound according to claim 3, wherein the telomerase positive tumor and diseases associated with telomerase positive tumors, including but not limited to: cancer, cancer; hematopoietic tumors of lymphoid lineage; bone marrow hematopoietic tumor stromal cell derived tumors, and other tumors.
6. The use of a tetranuclear platinum compound according to claim 5, wherein the telomerase positive tumor and diseases associated with telomerase positive tumors, including but not limited to: liver cancer, small cell lung cancer, bladder cancer, breast cancer, colon cancer, kidney cancer, lung cancer, esophagus cancer, gall bladder cancer, ovary cancer, pancreas cancer, stomach cancer, cervical cancer, thyroid cancer, skin cancer, squamous cell carcinoma, leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, mantle cell lymphoma, hairy cell lymphoma, burkett lymphoma, acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia; multiple myeloma, fibroma, rhabdomyosarcoma, melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid cyst carcinoma and kaposi's sarcoma.
7. A pharmaceutical formulation comprising an active ingredient and a pharmaceutical excipient, wherein the active ingredient comprises the tetranuclear platinum compound of claim 1.
8. The pharmaceutical formulation of claim 7, wherein the pharmaceutical formulation is any one of an injection, a tablet, a capsule, an aerosol, a suppository, a film, a drop pill, an ointment, a controlled release formulation, a sustained release formulation, or a nano formulation.
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