CN105732681A - Fluorescent diagnosis and treatment reagent development for diagnosing and treating non-small cell lung cancer (NSCLC) and application of cells thereof - Google Patents
Fluorescent diagnosis and treatment reagent development for diagnosing and treating non-small cell lung cancer (NSCLC) and application of cells thereof Download PDFInfo
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- CN105732681A CN105732681A CN201610168496.2A CN201610168496A CN105732681A CN 105732681 A CN105732681 A CN 105732681A CN 201610168496 A CN201610168496 A CN 201610168496A CN 105732681 A CN105732681 A CN 105732681A
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- lung cancer
- fluorescent probe
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Classifications
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- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
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Abstract
The invention relates to a fluorescent probe for quickly diagnosing and accurately treating non-small cell lung cancer (NSCLC), particularly fluorine boron pyrrole compounds and application thereof. The fluorine boron pyrrole compounds are disclosed as General Formula I, and are used as the fluorescent probe for diagnosing and treating NSCLC. The fluorophore and lung cancer cells are used for locating the label of the ligand, and the probe can specifically select the NSCLC cells. The overexpressed glutathione in the lung cancer cells breaks the disulfide bond in the probe, the drugs can be slowly released in the cancer cells to generate the target treatment effect, and meanwhile, near-infrared fluorescence can be emitted, thereby generating the double effects of diagnosis and treatment. The fluorescent probe can trace the alveolar epithelial cells with pathological changes at high sensitivity, and can release the drugs to the cancer tissues in a more accurate mode, thereby lowering the general untoward effects of the drugs and enhancing the living quality of the patient. The research has important biomedical meanings for the diagnosis and treatment modes of NSCLC and the research of the drug-resistance mechanism of the NSCLC cell strain.
Description
Technical field
The present invention relates to for quick diagnosis and the fluorescent probe precisely treating nonsmall-cell lung cancer, specifically a kind of fluorine boron azoles and application thereof.
Background technology
Malignant tumor is always up threatening the first killer of human health, and in China, pulmonary carcinoma has become as modal cancer, and the pathologic basis of pulmonary carcinoma comes from the malignant proliferation of alveolar epithelial cells.In the middle of cases of lung cancer, nonsmall-cell lung cancer (NSCLC) patient accounts for more than 80%.The present main examination means of the diagnosis of NSCLC are the high resolution computed tomography (HRCT) in pulmonary carcinoma blood tumor marker and iconography；Make a definite diagnosis the clinical manifestation binding of pathological biopsy depending on patient.These diagnostic modes are based on the histological change that pulmonary carcinoma pathological development occurs to a certain extent, and along with the development of the increase of patient and medical science, these traditional means are increasingly difficult to meet early stage and quickly diagnose requirement instantly.And in treatment, excision adds the Comprehensive Treatment that chemotherapy is main and is always up treating the preferred option of this disease, and bad for cancerous protuberance growth position and occur dissemination pathological changes middle and advanced stage patient, chemotherapy is most important treatment means, and common chemotherapeutics includes cisplatin, carboplatin, gemcitabine, paclitaxel, docetaxel and pemetrexed etc..The targeted therapy risen in recent years also begins to shift the first-line treatment of patient as chemotherapy failure or early stage, as belonged to gefitinib and the Erlotinib of EGF-R ELISA-tyrosine kinase inhibitor (EGFR-TKI).But due to systemic administration, prognosis can be produced many untoward reaction such as bone marrow depression, nephrotoxicity and gastrointestinal reaction etc. by chemotherapy.
Along with the rise of precisely medical treatment, increasing new technique starts in the middle of biomedical research, and this is the quickly growing of fluorescent probe wherein.The advantage that fluorescent probe has high sensitivity and Noninvasive, it is possible to reach quick detection when disease is still in molecule pathological changes.When with fluorescent probe labeled drug, probe will can not only produce can be used for the fluorescence signal of diagnosis, medicine can also be carried to sick cell more accurately, utilize the pathophysiology feature release medicine of sick cell, reach the dual purpose diagnosed and treated.JongSeungKim etc. report a class with biotin for tumor-localizing group, with ethidium for fluorogen, carry the fluorescent probe Theranostic7 (J.S.Kimetal of 5-fluorouracil, J.Am.Chem.Soc., 2014,136,17836-17843, structural formula is as follows), this probe comes quick diagnosis and treatment mice lung cancer model by mitochondria pathway inducing cell apoptosis.But owing to its fluorescent emission is not near infrared region, it is impossible to be prevented effectively from the interference of organism itself fluorescence, ultraviolet light is very big to organism photobleaching, it is easy to damage biological sample simultaneously.XiangZhou etc. disclose a class with naphthalimide for fluorogen, and the fluorescent probe NCC (structural formula is as follows for X.Zhouetal, OrgBiomolChem, 2013,11:580-585) carrying chlorambucil is used for diagnosing and treating Hela cell.But it lacks tumor-localizing group, so in cell aspect medication, whole body can only be lacked and uses the data of probe.Therefore, exploitation has the near-infrared medicine carrying fluorescent probe of efficient tumour-specific and tumor-localizing group can not only be utilized to be carried by medicine and be discharged into cancerous issue, in combination with the advantage of fluorescence imaging, reaches tumor is diagnosed and treated dual function.The treatment of tumor certainly will be had great importance by the probe of this dual function.
Summary of the invention:
It is an object of the invention to provide a kind of fluorine boron azoles and application thereof.
For achieving the above object, the technical solution used in the present invention is:
A kind of fluorine boron azoles, fluorine boron azoles is such as shown in formula I,
In formula I,
R1For alkyl, biotin, folic acid or bipyridine salt；
R2For gefitinib, Afatinib, docetaxel, gemcitabine or camptothecine；
X is S or Se；
Y is O or N；
Z is hydrogen, halogen.
Preferably, R in formula I1For biotin or bipyridine salt；R2For gefitinib；X is S；Y is O.
The application of a kind of fluorine boron azoles, using described fluorine boron azoles as the fluorescent probe diagnosing and treating nonsmall-cell lung cancer.
A kind of fluorescent probe, fluorescent probe be shown in formula I using fluorine boron pyrylium dyes as fluorescent parent, and on parent, introduce NSCLC cell is produced positioning function biotin or bipyridine salt and the medicine gefitinib that NSCLC is produced therapeutical effect.
Described fluorescent probe is for diagnosing and treating NSCLC in cell, tissue and three aspects of living animal.
Beneficial effects of the present invention:
The present invention is for as the compound diagnosing and treating nonsmall-cell lung cancer, can not only utilize tumor-localizing group that medicine is carried to pathological tissues, utilize the glutathion of process LAN in cell, disconnect disulfide bond, thus in drug release to tumor cell, drug use rate being improved；In combination with the advantage of fluorescent vital imaging, send the fluorescence signal that can detect that, reach the early stage to tumor and quick diagnosis.This combination diagnoses and treats the probe of dual function and will the treatment of tumor be had great importance, and fluorescence signal can be utilized for the correlational study of transport of drug with drug resistance of tumor cell mechanism.
Accompanying drawing explanation
The fluorescence intensity change curve that (0-24hr) changes in time that Fig. 1 embodiment of the present invention provides.
The fluorescent probe that adopts of embodiment that Fig. 2 embodiment of the present invention provides is to hydrogen sulfide selectivity schematic diagram compared with active nitrogen and active oxygen species.
The fluorescence intensity change curve that (0 17hr) changes in time under different emission that Fig. 3 embodiment of the present invention provides.
The fluorescent probe of the employing that Fig. 4 embodiment of the present invention provides is for the Laser Scanning Confocal Microscope imaging of PC9 cell.
The fluorescent probe of the employing that Fig. 5 embodiment of the present invention provides is for PC9 cell Na2The post-stimulatory Laser Scanning Confocal Microscope imaging of S.
Detailed description of the invention
Fluorine boron azoles formula is:
In formula I,
R1For alkyl, biotin, folic acid or bipyridine salt；
R2For gefitinib, Afatinib, docetaxel, gemcitabine or camptothecine；
X is S or Se；
Y is O or N；
Z is hydrogen, halogen.
It is preferably:
R1For biotin or bipyridine salt；R2For gefitinib；X is S；When Y is O；Z is hydrogen, and the formula of described fluorine boron azoles is:
In general formula III:
R1For biotin or bipyridine salt；
Formula I occurs drug release thus causing the change of fluorescence intensity after entering lung cancer cell line, the compound of gained general formula II；
When general formula III structure is applied to diagnose and treat non-small cell lung cancer cell strain, its be with the glutathion effect of process LAN in cell after, generate there is formula IV and the compound of formula V structure, thus causing the change of fluorescence intensity and wavelength；
Lung cancer cell line can be carried out rapid screening and cause its apoptosis by general formula III.
The term " alkyl " used in the present invention includes straight chained alkyl and branched alkyl.As mentioned by single alkyl such as " propyl group ", then only refer in particular to straight chained alkyl, as mentioned by single branched alkyl such as " isopropyl ", then only refer in particular to branched alkyl.Such as, " C1-6Alkyl " include C1-4Alkyl, C1-3Alkyl, methyl, ethyl, n-pro-pyl, isopropyl and the tert-butyl group.Similar rule be also applied in this specification use other group.
The term " halogen " used in the present invention includes fluorine, chlorine, bromine and iodine.
Detailed description of the invention
Embodiment is used for further illustrating the present invention, but the invention is not restricted to embodiment.
Embodiment 1.
Preparation formula one compound:
Under argon shield, by Bio (1.215g, 5mmol) it is dissolved in 90mLN, in dinethylformamide, add DMAP (0.61g, 5mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (0.93g, 6mmol) with I-hydroxybenzotriazole (0.067g, 0.5mmol) add reaction in the middle of solution and drip fluorogen (0.529g after 30 minutes, 1mmol), room temperature reaction was cleaned by water and ethyl acetate (1:1/v/v) after 24 hours, it is spin-dried for solvent with Rotary Evaporators after obtaining ethyl acetate layer, after gained solid with methylene chloride dissolves, separate with silica gel column chromatography (200-300 order).Eluant is dichloromethane and methanol (50:1/v/v), collects green color component.
Under argon shield; by gefitinib (0.116g; two (trichloromethyl) carbonic ester (1.539g is added after 0.26mmol) being dissolved in 100mL dichloromethane; 5.2mmol) dissolve after completely under condition of ice bath, drip N; N-diisopropylethylamine (1.006g; 7.8mmol), room temperature reaction 3 hours after completion of dropwise addition.Reaction terminate after solvent evaporated on a rotary evaporator, gained solid with methylene chloride is added drop-wise to containing triethylamine (0.788g, 0.78mmol) and 2-HEDS (0.200g after dissolving, in tetrahydrofuran solution 1.3mmol), react 72 hours under 0 DEG C of condition.Reaction is spin-dried for solvent after terminating, and cleans with water and dichloromethane (1:1/v/v), is spin-dried for solvent with Rotary Evaporators after obtaining dichloromethane layer, after gained solid with methylene chloride dissolves, separates with silica gel column chromatography (200-300 order).Eluant is dichloromethane and methanol (30:1/v/v), collects yellow color component.
Under argon shield; by (2) (0.136g; two (trichloromethyl) carbonic ester (1.539g is added after 0.26mmol) being dissolved in 100mL dichloromethane; 5.2mmol) dissolve after completely under condition of ice bath, drip N; N-diisopropylethylamine (1.006g; 7.8mmol), room temperature reaction 3 hours after completion of dropwise addition.Reaction terminate after solvent evaporated on a rotary evaporator, after gained solid dissolves with oxolane, it is added drop-wise to containing N, N-diisopropylethylamine (0.034g, 0.26mmol), sodium hydride (0.012g, 0.52mmol) and (1) (0.196g, 0.26mmol) tetrahydrofuran solution in, under room temperature condition react 36 hours.Reaction is spin-dried for solvent after terminating, clean with water and dichloromethane (1:1/v/v) again, it is spin-dried for solvent with Rotary Evaporators after obtaining dichloromethane layer, after gained solid with methylene chloride dissolves, separates by aluminium sesquioxide column chromatography (200-300 order).Eluant is dichloromethane and methanol (30:1/v/v), collects aeruginous component, it is thus achieved that formula one compound 0.140g, yield 38%.1HNMR(DMSO-d6, 500MHz) and δ (ppm) 8.99 (s, 1H), 7.25-8.14 (m, 22H), 6.43 (d, J=48.9Hz, 3H), 4.36 (d, J=34.8Hz, 6H), 4.17 (s, 3H), 3.99 (s, 4H), 3.70 (s, 1H), 3.56 (s, 6H), 2.84-2.97 (m, 4H), 2.38 (s, 4H), 1.93 (s, 2H), 1.69 (s, 2H), 1.46-1.51 (m, 2H), 1.22 (s, 2H).13CNMR(DMSO-d6,125MHz)δ(ppm)173.88,170.75,163.11,157.16,153.59,150.91,145.54,144.87,140.91,139.58,139.00,138.00,137.77,132.19,129.52,127.79,119.74,118.39,111.76,102.80,99.90,85.88,68.28,66.93,66.54,64.32,61.85,60.08,57.38,55.82,54.25,52.03,48.95,37.10,33.83,28.00,25.99,24.43.LC-MS(ESI-):m/zC70H66BClF3N9O11S3calcd.1407.3778,found[M+H]+1408.3855
Embodiment 2
Preparation formula two compound:
Under argon shield; by (2) (0.194g; two (trichloromethyl) carbonic ester (1.835g is added after 0.31mmol) being dissolved in 100mL dichloromethane; 6.2mmol) dissolve after completely under condition of ice bath, drip N; N-diisopropylethylamine (1.200g; 9.3mmol), room temperature reaction 3 hours after completion of dropwise addition.Reaction terminate after solvent evaporated on a rotary evaporator, after gained solid with methylene chloride dissolves, it is added drop-wise to containing N, N-diisopropylethylamine (0.040g, 0.31mmol) with fluorogen (0.132g, in 50mL dichloromethane solution 0.25mmol), react 36 hours under room temperature condition.Reaction is cleaned with water and dichloromethane (1:1/v/v) after terminating, and is spin-dried for solvent with Rotary Evaporators, after gained solid with methylene chloride dissolves, separates by aluminium sesquioxide column chromatography (200-300 order) after obtaining dichloromethane layer.Eluant is dichloromethane and methanol (40:1/v/v), collects green color component.
Under argon shield, by bipyridine salt (0.307g, 0.625mmol) it is dissolved in 100mLN, in dinethylformamide, add DMAP (0.081g, 0.75mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (0.116g, 0.625mmol) with I-hydroxybenzotriazole (0.008g, 0.063mmol) add reaction in the middle of solution and drip (3) (0.147g after 30 minutes, 0.125mmol), room temperature reaction was spin-dried for solvent with Rotary Evaporators after 36 hours, after gained solid with methylene chloride cleans, collect aeruginous component, acquisition formula two compound, yield 18%.1HNMR(DMSO-d6,500MHz)δ(ppm)9.67–9.48(m,4H),9.41-9.40(m,4H),8.94(s,1H),7.84(s,1H),7.67(s,1H),7.58–7.32(m,19H),7.05-7.04(d,2H),6.52(s,1H),5.77(s,1H),4.50(s,3H),3.37–2.95(m,15H),2.72–2.69(m,4H),2.61–2.21(m,8H),2.15–1.93(m,2H),1.59-1.53(m,2H),1.47–1.31(m,2H),1.12–1.10(m,2H).13CNMR(DMSO-d6,125MHz)δ(ppm)174.71,171.93,158.49,156.55,153.26,149.59,148.92,148.53,147.50,147.14,146.33,136.91,131.63,129.77,129.30,127.04,126.60,126.18,122.81,122.59,101.62,60.97,48.41,47.87,45.02,42.35,40.52,40.27,39.85,39.68,39.51,34.98,32.90,30.95,25.65,25.38.LC-MS(ESI-):m/zC77H72BClF3N9O10S22 2+calcd.724.7283,found[M2+]724.7283.
Embodiment 3
The dynamic (dynamical) detection of medicament slow release is carried out as probe application in aqueous systems, simulation physiological environment using preparing gained formula one compound.Simulation physiological condition, the following experiment all carries out (HEPES buffer solution, concentration is 40mM) when pH=7.4.Formula two compound adopts 10 μMs, and glutathione concentrations adopts 5mM.As it is shown in figure 1, probe can reach the purpose of medicament slow release.
Embodiment 4
Formula two compound selectivity to glutathion slow releasing function.PH adopts HEPES buffer solution to control.Take multiple 10mL color comparison tube, and in each 10mL color comparison tube, add 10 μMs of formula two compounds, add the HEPES buffer that 40mMpH is 7.4, it is then respectively adding as shown in Figure 2, determinand is followed successively by: glutathion, peroxidating nitrosyl, nitric oxide, nitrite anions, superoxide anion, hydroxyl radical free radical, hydrogen peroxide, hypochlorite, tertbutanol peroxide, finally with ultra-pure water constant volume to 10mL.Shake up solution, after balancing 1min at 25 DEG C, working solution in each color comparison tube is poured into respectively in fluorescence ware and measures fluorescence spectrum.Formula two compound is to the selectivity of glutathion as shown in Figure 2.And glutathion is had good selectivity by formula two compound as seen from the figure, after glutathion effect, the Fluorescence Increasing that formula two compound is corresponding.Under condition determination, peroxidating nitrosyl, nitric oxide, nitrite anions, superoxide anion, hydroxyl radical free radical, hydrogen peroxide, hypochlorite, tertbutanol peroxide etc. can not make fluorescence probe change.
Embodiment 5
The time spectra response that serum GSH-PX activity is detected by formula two compound
Taking a 10mL color comparison tube, and add 10 μMs of formula two compounds in color comparison tube, add 40mMHEPESpH7.4, then add ultra-pure water to 5mL, shake up, being then respectively adding concentration is 5mM glutathion, finally with ultra-pure water/serum constant volume to 10mL.Shake up solution, balance 1min, working solution in color comparison tube is poured into fluorescence ware and measures fluorescence spectrum, take the interval fluorescence spectrum of 680-800nm.
Being represented the change of system fluorescence Spectra degree over time by Fig. 3, it was shown that increase in time, system spectrum is remarkably reinforced.
Embodiment 8
Bipyridine salt probe is used for diagnosing and treating lung cancer cell line PC9
It is about 50% that human lung adenocarcinoma cell line PC9 cell carries out being cultured to cell density according to AmericantypeTissueCultureCollection regulation.Then PC9 cell is hatched 10 minutes in 10uM bipyridine salt probe, wash 3 times by DMEM-1640 culture medium, be placed under confocal fluorescent microscope and take pictures (referring to Fig. 4)；It is subsequently adding 50 μMs of Na2S incubated cell 10 minutes, washs 3 times by DMEM-1640 culture medium, and Laser Scanning Confocal Microscope is taken pictures (referring to Fig. 5), and as shown in Figure 5, fluorescence intensity is remarkably reinforced.
Above content is in conjunction with concrete preferred implementation further description made for the present invention, it is impossible to assert that specific embodiment of the invention is confined to these explanations.For general technical staff of the technical field of the invention, without departing from the inventive concept of the premise, it is also possible to make some simple deduction or replace, protection scope of the present invention all should be considered as belonging to.As a kind of purposes that fluorescent dye is noval chemical compound of the present invention; it cannot be assumed that the compound of the present invention is only for fluorescent dye; for general technical staff of the technical field of the invention; under be used as the consideration of the identical mechanism of action of fluorescent dye based on the compounds of this invention; some simple inferences can also be made; draw other application purpose of the compound of the present invention, all should be considered as belonging to protection scope of the present invention.
Claims (5)
1. a fluorine boron azoles, it is characterised in that: fluorine boron azoles is such as shown in formula I,
In formula I,
R1For alkyl, biotin, folic acid or bipyridine salt；
R2For gefitinib, Afatinib, docetaxel, gemcitabine or camptothecine；
X is S or Se；
Y is O or N；
Z is hydrogen, halogen.
2. by the fluorine boron azoles described in claim 1, it is characterised in that: R in described formula I1For biotin, folic acid or bipyridine salt；R2For gefitinib, Afatinib, docetaxel, gemcitabine or camptothecine；X is S or Se；Y is O or N.
3. the application of the fluorine boron azoles described in a claim 1, it is characterised in that: using described fluorine boron azoles as the fluorescent probe diagnosing and treating nonsmall-cell lung cancer (NSCLC).
4. a fluorescent probe, it is characterised in that:
Fluorescent probe be shown in formula I using fluorine boron pyrylium dyes as fluorescent parent, and introduce on parent and NSCLC cell produced the biotin of positioning function, folic acid or bipyridine salt and NSCLC is produced the medicine gefitinib of therapeutical effect, Afatinib, docetaxel, gemcitabine or camptothecine.
5. by the fluorescent probe described in claim 4, it is characterised in that: described fluorescent probe is for diagnosing and treating NSCLC in cell, tissue and three aspects of live body.
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