CN1563005A - Ramification in albocarbon category and application in anoxia system - Google Patents
Ramification in albocarbon category and application in anoxia system Download PDFInfo
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- CN1563005A CN1563005A CN 200410017346 CN200410017346A CN1563005A CN 1563005 A CN1563005 A CN 1563005A CN 200410017346 CN200410017346 CN 200410017346 CN 200410017346 A CN200410017346 A CN 200410017346A CN 1563005 A CN1563005 A CN 1563005A
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- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 title claims description 5
- 206010021143 Hypoxia Diseases 0.000 title description 4
- 206010002660 Anoxia Diseases 0.000 title description 2
- 241000976983 Anoxia Species 0.000 title description 2
- 230000007953 anoxia Effects 0.000 title description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 38
- 239000001301 oxygen Substances 0.000 claims description 36
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 32
- 239000007850 fluorescent dye Substances 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 abstract description 17
- 150000001875 compounds Chemical class 0.000 abstract description 16
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 abstract description 3
- 150000002790 naphthalenes Chemical class 0.000 abstract description 3
- 230000001105 regulatory effect Effects 0.000 abstract description 3
- 241000699800 Cricetinae Species 0.000 abstract 3
- KUEFXPHXHHANKS-UHFFFAOYSA-N 5-nitro-1h-1,2,4-triazole Chemical group [O-][N+](=O)C1=NC=NN1 KUEFXPHXHHANKS-UHFFFAOYSA-N 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 40
- 239000007788 liquid Substances 0.000 description 20
- 239000007787 solid Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 241000699802 Cricetulus griseus Species 0.000 description 10
- 229910052794 bromium Inorganic materials 0.000 description 10
- 244000309466 calf Species 0.000 description 10
- 229960004756 ethanol Drugs 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 10
- 210000002966 serum Anatomy 0.000 description 10
- 238000012807 shake-flask culturing Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 8
- -1 nitro glyoxaline compound Chemical class 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical class C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical group N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 description 3
- 101100230376 Acetivibrio thermocellus (strain ATCC 27405 / DSM 1237 / JCM 9322 / NBRC 103400 / NCIMB 10682 / NRRL B-4536 / VPI 7372) celI gene Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 210000001672 ovary Anatomy 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 208000031662 Noncommunicable disease Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
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- 230000007954 hypoxia Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
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- 230000002194 synthesizing effect Effects 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 1
- 231100001074 DNA strand break Toxicity 0.000 description 1
- 241000447394 Desmos Species 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- AFPRJLBZLPBTPZ-UHFFFAOYSA-N acenaphthoquinone Chemical compound C1=CC(C(C2=O)=O)=C3C2=CC=CC3=C1 AFPRJLBZLPBTPZ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
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- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
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- 230000004060 metabolic process Effects 0.000 description 1
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- 239000010813 municipal solid waste Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000009206 nuclear medicine Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
On naphthalene derivatives are introduced with 2-nitroimidazol or 3-nitro-1,2,4-triazol group, regulating connecting arm length of substituting group to synthesize a series of compounds. Experimental results show us that: said invention compounds have obvious recognition of oxygen-presence or oxygen-poor to hamster cell V79-379A, hamster ovarial cell CHO, and hamster solid tumour Ga5 cell.
Description
Technical field
The present invention relates to a class naphthalene derivatives and an application thereof.
Background technology
Since half a century, under chemist, physician's etc. joint efforts, medical science has been obtained huge development, human by chemistry, immunity, antibiotic therapy three big means, controlled the transmissible disease that in the past mainly threatens human health basically, then become the archenemy of human health gradually such as Non Communicable Diseases (NCD) such as tumour, cardiovascular and cerebrovasculars, wherein especially with the harm of tumour for very.
In brief, tumour is exactly that the when injected organism tissue cell is on the basis of some internal factor influence, because the change of a series of matter, a kind of paraplasm of formation take place in the effect of extraneous paathogenic factor (as physics, chemistry and biology etc.).According to its difference, can be divided into innocent tumour and malignant tumour two big classes usually to the human body hazard rating.In general, innocent tumour is little to the human body hazard rating, treatment easily, and the malignant tumour then hazard rating to human body is big, and the treatment difficulty.Tumor treatment usually needs operation, chemicals or radioactive rays, malignant tumour especially, and the means of its treatment are often more violent, and are very big to patient's influence.So tumor treatment, primary is diagnosis.Must at first determine diagnosis to tumour, can clear and definite methods of treatment.The particularly important is and to accomplish early discovery and early diagnosis, just can obtain good therapeutic action.Traditional diagnosing tumor method roughly has several aspects such as medical history investigation, physical examination and auxiliary examination.But above-mentioned these detection methods all exist certain limitation in actual applications.Therefore, seeking diagnostic method more sensitive, easily row becomes and must go.
Nineteen fifty-five, Thomlinson and Gray find extensively to have anoxic cell in the malignant tumour; By 1979, people such as Brown confirmed that again tumor hypoxia has acute and chronic branch.These biological characteristicses of tumour cell further provide more solid basis and wide space to diagnosis research of malignant tumour for people.Thereby people can be by detecting the purpose that intracellular oxygen situation reaches diagnosing malignant tumor.The detection method clinical application of weary oxygen situation mainly contains following four kinds more widely in the malignant tumour at present: oxygen electrode is measured (oxygenelectrodes), tissue morphology is analyzed (histomorphometric analysis), DNA band fracture analysis (DNAstrand breaks) and weary oxygen mark are measured (hypoxia markers) (Lu Xueguan, Hu Chaosu, Feng Yan, treatment and prevention of tumour magazine, 2000,7 (3), 290-291).And weary oxygen mark measures that (weary oxygen probe) is simple because of it, the gained data reliable and the atraumatic characteristics become one of detection method of tool potentiality.
Weary oxygen specificity fluorescent probe is the combination of the nitroreduction fluorescence enhanced mechanism of weary oxygen dependence reduction Selecting Mechanism and Procedure of 2-nitroimidazole group and fluorophor.Nitro is typical aromatic ring system fluorescent quenching group, in case through biological reducing, can make fluorophor discharge fluorescence again.And nitro glyoxaline compound is by after initiatively diffusing in the cell, the single electron reduction takes place under the effect of desmo enzyme, produce free radical anion, in normal cell, because the oxidation nitro has higher electron affinity, free radical anion can be reoxidised into former compound rapidly again, is diffused into the extracellular.And when lacking enough oxygen in the cell, free radical anion will further be reduced, and its product then combines with macromole in the cell, and retention is in cell.The weary oxygen situation that therefore can reflect tumour by the extent of metabolism of nitro glyoxaline compound in tumour.
At present, be used for measuring nitro glyoxaline and mainly contain two kinds in human body intracellular metabolite degree methods: a kind of is with radioactive nuleus marker nitro glyoxaline compound usually, utilizes MRS, PET, SPECT then and measures from equipment such as video pictures.Commonly used has:
82Br-MISO,
18F-MISO,
123I-IAZA,
123I-IAZR and BATO (
99TC) mark etc.Another kind is to use the nitro glyoxaline compound specific antibody, utilizes immunohistochemistry, and enzyme linked immunosorbent assay and low cytometric analysis are analyzed (Chen Yue, Mo Tingshu, the Anren of rectifying, foreign medical science radiological medicine nuclear medicine fascicle, 1999,23,257-260).
1991, the Hodgkiss study group of Britain at first reported 3-nitro-naphthalene imide class anoxic cell fluorescent probe (Hodgkiss R.J., Begg A.C.etal., Biochem.Pharm., 41 (1991), 533-541).But they find chemical combination under study for action before and after reduction, and the fluorescence intensity ratio of its target tissue/background is little.
Summary of the invention
Summary of the invention:
The present invention chooses V
79-379A Chinese hamster cell, Chinese hamster ovary cell (Chinese hamster ovary celI) and solid tumor G
95Cell is introduced 2-nitroimidazole or 3-nitro-1,2 as application system in the naphthaline derivatives molecule, 4-triazole group is regulated substituent connection brachium, a synthetic based compound.Experimental result shows: institute's synthetic compound is at V
79-379A Chinese hamster cell, Chinese hamster ovary celI and G
95Identification to aerobic and weary oxygen in the cell is very obvious.
Technical scheme:
The said naphthaline derivatives of the present invention has following structural formula:
In the formula: X is O or S; L is (CH
2)
2(O)
m(CH
2)
n(CHOH)
1(CH
2)
pR
Wherein: m=0 or 1, n=0 or 1, l=0 or 1, p=0 or 1; R is
Or
Preferred compound is that X is O.
The synthetic route of above-claimed cpd is as follows:
Specific implementation method
The present invention is further illustrated below by embodiment, and the cited case does not limit protection scope of the present invention:
Embodiment one
4-((3 '-nitro-1 ', 2 ', 4 '-triazole)-ethylamino)-1,8-naphthalimide-N-'s (1 '-ethyl-3 '-nitro-1 ', 2 ', 4 '-triazole) (compound 1) is synthetic:
4-bromo-1,8-naphthalene acid anhydride 1g is dissolved in the 25ml N-Methyl pyrrolidone, stirs down to add excess ethyl alcohol amine, is heated to 110 ℃, reacts 2 hours.Reaction solution stirs in cooling off and falling back, and produces yellow particle shape precipitation, suction filtration, and oven dry gets 4-hydroxyethylamino-1,8-naphthalimide-N-ethanol, productive rate 99%.
4-hydroxyethylamino-1,8-naphthalimide-N-ethanol 5mmol is dissolved in the 30ml exsiccant ethyl acetate, and magnetic agitation keeps ice bath, with constant pressure funnel dropping liquid bromine 10ml dropwise, after finishing, drips phosphorus trichloride 3ml again.80 ℃ were refluxed 5 hours.Rotary evaporation is removed most of solvent, adds less water then, and the aqueous sodium hydroxide solution with 5% is regulated pH to 5-6, has solid to separate out.Use methyl alcohol: (6: 1, v/v) recrystallization got 4-bromine ethylamino-1,8-naphthalimide-N-monobromethane to ethanol.
Sodium methylate 1.35mmol is dissolved in the 5ml methyl alcohol; dropwise be added to 1.3mmol 3-nitro-1; 2; among the dry DMF of the 15ml of 4-triazole; stirring down, reaction solution is heated to 150 ℃ up to methyl alcohol is all vapored away; in the time of 140 ℃, with 0.65mmol 4-bromine ethylamino-1,8-naphthalimide-N-monobromethane is dissolved among the dry DMF of 15ml then; add to reaction solution then; add drying tube, argon shield refluxed 12 hours down, and cooling afterreaction mixture is poured in the trash ice; separate out solid; suction filtration, washing obtains crude product.Column chromatography for separation twice obtains faint yellow solid 0.21 gram, yield 52.1%.m.p.＞300℃。
1HNMR (SF:500MHz, DMSO-d
6), δ (ppm), 8.68-8.71 (d, 1H, J=7.2Hz), and 8.59-8.62 (d, 1H, J=8.4Hz), 8.44-8.46 (d, 1H, J=7.8Hz), 8.05-8.08 (d, 1H, J=7.8Hz), 7.86-7.89 (t, 1H, J=7.8Hz), 7.04 (s, 2H, nitrogen azoles-5 ' H), 4.60-4.63 (t, 2H, J=7.0Hz ,-NCH
2CH
2-), 4.42 (t, 2H, J=7.6Hz ,-NCH
2CH
2-), 4.07 (t, J=7.0Hz, 2H ,-NHCH
2CH
2-), 3.68-3.70 (t, J=7.0Hz, 2H ,-NHCH
2CH
2-).IR(KBr)，cm
-1：3300，3070，2950，1680，1550。
Embodiment two
4-((3 '-nitro-1 ', 2 ', 4 '-triazole)-oxyethyl group ethylamino)-1,8-naphthalimide-N-'s (1 '-ethoxyethyl group-3 '-nitro-1 ', 2 ', 4 '-triazole) (compound 2) is synthetic:
So that 2-(2-amino oxygen base)-ethanol is raw material, 4-(bromine oxethyl ethylamino)-1, the preparation method of 8-naphthalimide-N-(bromine oxethyl ethyl) is with embodiment one.
With 4-(bromine oxethyl ethylamino)-1,8-naphthalimide-N-(bromine oxethyl ethyl) is a raw material.Compound 2 preparation methods obtain pale yellow solid 0.19 gram, productive rate 45.3% with embodiment one.m.p.＞300℃。
1HNMR (SF:500MHz, DMSO-d
6), δ (ppm), 8.82 (d, 1H, J=7.40Hz), 8.51 (d, 1H, J=7.40Hz), 8.30 (d, 1H, J=7.2Hz), 8.11 (d, 1H, J=7.20Hz), 7.88 (t, 1H, J
1=7.20Hz), 4.60-3.20 (16H, 2-CH
2CH
2OCH
2CH
2-), 7.08 (s, 2H, nitrogen azoles-5 ' H).IR(KBr)，cm
-1：3320，1680，1550。
Embodiment three
4-((2 '-nitro-imidazoles)-oxyethyl group ethylamino)-1,8-naphthalimide-N-'s (1 '-ethoxyethyl group-2 '-nitroimidazole) (compound 3) is synthetic:
So that 2-(2-amino oxygen base)-ethanol is raw material, 4-(bromine oxethyl ethylamino)-1, the preparation method of 8-naphthalimide-N-(bromine oxethyl ethyl) is with embodiment one.
With 4-(bromine oxethyl ethylamino)-1,8-naphthalimide-N-(bromine oxethyl ethyl) is a raw material.Compound 3 preparation methods obtain pale yellow solid 0.19 gram, productive rate 39% with embodiment one.m.p.＞300℃。
1HNMR (SF:500MHz, DMSO-d
6), δ (ppm), 8.85 (d, 1H, J=7.20Hz), 8.50 (d, 1H, J=7.20Hz), 8.46 (d, 1H, J=7.2Hz), 8.20 (d, 1H, J=7.80Hz), 7.80 (t, 1H, J=7.80Hz), 4.62-3.10 (16H, 2-CH
2CH
2OCH
2CH
2-), 7.11-7.13 (d, 2H, imidazoles-4 ' H), 7.82-7.85 (d, 2H, imidazoles-5 ' H).IR(KBr)，cm
-1：3320，1680，1550。
Embodiment four
1,4,5,8-benzene-naphthalene diimide-N-N '-(1 '-ethyl-3 '-nitro-1 ', 2 ', 4 '-triazole) (compound 4) synthetic
1,4,5,8-naphthalene acid anhydride 1g is dissolved in the 40ml N-Methyl pyrrolidone, stirs down to add excess ethyl alcohol amine, is heated to 100 ℃, reacts 5 hours.Reaction solution stirs in cooling off and falling back, and produces the scarlet precipitation, suction filtration, and oven dry gets 4-hydroxyethylamino-1,4,5,8-naphthalimide-N-ethanol, productive rate 56%.With 1,4,5,8-benzene-naphthalene diimide-N-N '-bromotrifluoromethane is a raw material.Compound 4 preparation methods obtain lightpink solid 0.24 gram, productive rate 34.3% with embodiment one.m.p.＞300℃。
1HNMR(SF：500MHz，DMSO-d
6)，δ(ppm)，8.75(s，4H，naphtha)，3.90-4.10(t，4H，J＝6.40Hz，2-NCH
2CH
2-)，4.47-4.50(t，4H，J＝6.40Hz，2-NCH
2CH
2-)，。(7.08 s, 2H, nitrogen azoles-5 ' H).IR(KBr)，cm
-1：3100，2850，1680，1550。
Embodiment five
4-((3 '-nitro-1 ', 2 ', 4 '-triazole)-2 "-hydroxyl-propoxy-ethylamino)-1,8-naphthalimide-N-((1 '-oxyethyl group base-2 "-hydroxypropyl)-3 '-nitro-1 ', 2 ', 4 '-triazole) (compound 5) synthetic
4-hydroxyethylamino-1,8-naphthalimide-N-ethanol 5mmol and 20ml chloro propylene oxide mix, and add 10mmol salt of wormwood again, and heating in water bath is to 60-70 ℃, and in 7 hours reaction times, rotary evaporation falls most of solvent, and column chromatography obtains yellow solid.Yellow solid is dissolved in the 20ml exsiccant dehydrated alcohol, adds 2mmol 3-nitro-1,2 again, the 4-triazole, magnetic agitation adds drying tube, refluxes 8 hours.Rotary evaporation falls solvent, and column chromatography gets pale yellow solid 0.22 gram, yield 58.6%.m.p.＞300℃。
1HNMR (SF:500MHz, DMSO-d
6), δ (ppm): 9.20 (d, 1H, J=2Hz), 8.90 (d, 1H, J=2Hz), 8.75 (d, 1H, J=7.30Hz), 8.40 (d, 1H, J=8.20Hz), 7.80 (t, 1H, J=7.70Hz), 4.65-3.70 (18H, 2-NHCH
2CH
2OCH
2CH (OH) CH
2-), 7.10 (s, 2H, nitrogen azoles-5 ' H).IR(KBr)，cm
-1：3450，1680，1580。
Embodiment six
3-((3 '-nitro-1 ', 2 ', 4 '-triazole)-oxyethyl group ethylamino)-8-oxygen-8H-acenaphthene is synthesizing of [1,2-b] pyrroles-9-nitrile (compound 6) also
0.5g acenaphthenequinone, 0.2g propane dinitrile is dissolved in the 50ml methylene dichloride, join in short, the thick silicagel column, use dichloromethane rinse continuously fast, collect the orange bands of a spectrum of Rf=0.8, steam methylene dichloride, get red solid, be 1-dicyano methylene radical-2-oxygen-acenaphthene, yield 95%, m.p.242-244 ℃.
1.0 gram 1-dicyano methylene radical-2-oxygen-acenaphthene, 0.2 gram salt of wormwood joins in the 20ml acetonitrile, is heated to backflow, and solid 1-dicyano methylene radical-2-oxygen behind the several minutes-acenaphthene dissolving is separated out a large amount of brown crystals then very soon.Cold filtration washes salt of wormwood and solvent with water, and drying gets also [1,2-b] pyrroles-9-nitrile of 8-oxygen-8H-acenaphthene.Yield 95%, m.p.275 ℃, distillation.
0.2g 8-oxygen-8H-acenaphthene also [1,2-b] pyrroles-9-nitrile joins in the 20ml acetonitrile, adds 0.2ml 2-(2-amino oxygen base)-ethanol again, stirring at normal temperature half an hour, pressure reducing and steaming solvent, column chromatography, dark red solid, i.e. 3-hydroxy ethoxy ethylamino-8-oxygen-8H-acenaphthene [1,2-b] pyrroles-9-nitrile also.Yield 75%.m.p.＞300℃。
The 3-hydroxy ethoxy ethylamino-8-oxygen-8H-acenaphthene also preparation method of the bromination of [1,2-b] pyrroles-9-nitrile and compound 6 obtains dark-grey solid 0.21 gram, yield 32.5% with embodiment one.m.p.＞300℃。
1HNMR (SF:500MHz, DMSO-d
6), δ (ppm), 8.89-8.87 (d, 1H, J=7.60Hz), 8.58-8.56 (d, 1H, J=7.2Hz), and 7.98-7.96 (d, 1H, J=9.0Hz), 7.86-7.84 (t, 1H, J=7.80Hz), 7.02-7.00 (d, 1H, J=9.20Hz), 3.64-3.62 (t, 2H, J=4.60Hz ,-NHCH
2-), 2.52-2.50 (t, 2H, J=4.20Hz ,-NHCH
2CH
2O-), 2.60-2.58 (t, 2H, J=4.30Hz ,-OCH
2CH
2-), 4.43-4.41 (t, 2H, J=7.02Hz ,-OCH
2CH
2-), 7.05 (s, 2H, nitrogen azoles-5 ' H).IR(KBr)，cm
-1：3320，2215，1638，1580，1492。
Embodiment seven
Synthesizing of the methyl iodide quaternary amine (compound 7) of 3-(4-piperazinyl)-nitro-benzo [de] benzo [4,5] imidazoles [2,1-a] isoquinoline 99.9-7-ketone
0.5 gram 3-bromo-nitro-benzo [de] benzo [4,5] imidazoles [2,1-a] isoquinoline 99.9-7-ketone and 0.5mlN-methylpiperazine, join in the 10ml pyridine stirring and refluxing 3 hours, cooling back pressure reducing and steaming solvent, post separates then, get 3-(4-methyl-piperazinyl)-nitro-benzo [de] benzo [4,5] imidazoles [2,1-a] isoquinoline 99.9-7-ketone.Yield 56%.m.p.＞300℃；
1HNMR(400MHz，CDCl
3)δ(ppm)，8.79-8.77(d，J＝7.2Hz，1H)，8.55-8.54(d，1H，J＝5.2Hz)，8.29-8.27(d，J＝1H，8.4Hz，)，7.87-7.85(d，1H，J＝4.8Hz，)，7.72-7.68(t，1H，J＝7.8Hz)，8.55-8.54(d，1H，J＝5.2Hz)，7.47-7.45(m，2H)，7.26-7.23(m，2H)，3.38(brs，4H，N(CH
2CH
2)2NCH
3)，2.81(4H，N(CH
2CH
2)
2NCH
3)，2.49(3H，N(CH
2CH
2)
2NCH
3，)。IR(KBr)，cm
-1：1689，1589，1434；ESI-MS：[M+H]
+(m/z369)。
3-(4-methyl-piperazinyl)-nitro-benzo [de] benzo [4,5] imidazoles [2,1-a] isoquinoline 99.9-7-ketone is dissolved in methylene dichloride, drips then and wait the mole methyl iodide, stirring at normal temperature 2 hours, rotary evaporation gets product.
m.p.＞300℃。
The naphthalene compounds Application Example:
Embodiment eight
Adopt Chinese hamster ovary cell (CHO).The 250mL shake-flask culture adopts DM, the EM substratum, and other adds 10% calf serum.
At first compound 3 is mixed with low concentration solution, is added to one by one in the cell suspending liquid to obtain suitable drug level, then with this cell (Chinese hamster ovary celI) suspension respectively at normal condition (air+5%CO of 37 ℃
2) and weary oxygen condition (N
2+ 5%CO
2) cultivate down.Get the cell of different incubation times, with fluorescent microscope observation normal cell and the fluorescence difference of anoxic cell and concrete fluorescence intensity.The average fluorescent strength of cell suspending liquid under normal condition (aerobic) and weary oxygen condition that contains the different concns compound is as shown in the table.
Embodiment nine
Adopt V
79-379A Chinese hamster cell.The 250mL shake-flask culture adopts 1640 substratum, and other adds 15% calf serum.Making the concentration of compound 1 in cell suspending liquid is 10
-4Mol/L, culture condition is with embodiment eight.The average fluorescent strength of cell suspending liquid under normal condition (aerobic) and weary oxygen condition is as shown in the table.
Average fluorescent strength
Time (h) lacks the oxygen aerobic
0 179.5421 192.9655
1 185.5035 180.7217
2 195.8898 174.6445
3 193.5952 186.9579
4 195.4649 174.5916
6 190.2584 160.7458
9 200.3598 155.1216
Embodiment ten
Adopt V
79-379A Chinese hamster cell.The 250mL shake-flask culture adopts 1640 substratum, and other adds 15% calf serum.
Making the concentration of compound 2 in cell suspending liquid is 10
-4Mol/L, culture condition is with embodiment eight.The average fluorescent strength of cell suspending liquid under normal condition (aerobic) and weary oxygen condition is as shown in the table.
Average fluorescent strength
Time (h) lacks the oxygen aerobic
0 1.474807 0.838800
1 4.267896 0.157848
2 17.60800 2.828203
4 13.38325 3.944184
6 17.02611 1.701120
Embodiment 11
Adopt V
79-379A Chinese hamster cell.The 250mL shake-flask culture adopts 1640 substratum, and other adds 15% calf serum.
Making the concentration of compound 3 in cell suspending liquid is 10
-4Mol/L, culture condition is with embodiment eight.The average fluorescent strength of cell suspending liquid under normal condition (aerobic) and weary oxygen condition is as shown in the table.
Average fluorescent strength
Time (h) lacks the oxygen aerobic
0 33.66080 18.83531
1 37.27137 20.00366
2 33.20114 18.07792
3 51.17665 20.05239
4 64.22318 18.75305
6 61.16981 18.70786
9 60.21778 24.38266
Embodiment 12
Adopt solid tumor G
95Cell.The 250mL shake-flask culture adopts 1640 substratum, and other adds 15% calf serum.
Making the concentration of compound 3 in cell suspending liquid is 10
-4Mol/L, culture condition is with embodiment eight.The average fluorescent strength of cell suspending liquid under normal condition (aerobic) and weary oxygen condition is as shown in the table.
Average fluorescent strength
Time (h) lacks the oxygen aerobic
0 50.62989 22.25914
1 61.25038 48.03626
2 100.5567 78.53577
3.5 135.3523 81.91233
5.5 185.3404 107.7293
Embodiment 13
Adopt solid tumor G
95Cell.The 250mL shake-flask culture adopts 1640 substratum, and other adds 15% calf serum.
Making the concentration of compound 4 in cell suspending liquid is 10
-4Mol/L, culture condition is with embodiment eight.The average fluorescent strength of cell suspending liquid under normal condition (aerobic) and weary oxygen condition is as shown in the table.
Average fluorescent strength
Time (h) lacks the oxygen aerobic
0 18.95152 0.732899
1 0.156674 0
2 0.837902 9.00E-02
3.5 2.75E-02 0
5.5 3.692253 0
Embodiment 14
Adopt Chinese hamster ovary cell (CHO).The 250mL shake-flask culture adopts DM, the EM substratum, and other adds 10% calf serum.
Making the concentration of compound 5 in cell suspending liquid is 10
-4Mol/L, culture condition is with embodiment eight.The average fluorescent strength of cell suspending liquid under normal condition (aerobic) and weary oxygen condition is as shown in the table.
Average fluorescent strength
Time (h) lacks the oxygen aerobic
0.5 18.03982 10.03651
1.5 17.26315 13.92298
2.5 22.52242 0.792135
3.5 0.731118 0.33359
6.5 9.051865 3.523711
Embodiment 15
Adopt V
79-379A Chinese hamster cell.The 250mL shake-flask culture adopts 1640 substratum, and other adds 15% calf serum.
Making the concentration of compound 6 in cell suspending liquid is 10
-4Mol/L, culture condition is with embodiment eight.The average fluorescent strength of cell suspending liquid under normal condition (aerobic) and weary oxygen condition is as shown in the table.
Average fluorescent strength
Time (h) lacks the oxygen aerobic
0 60.2093 44.54992
1 57.8164 42.28281
2 57.3671 44.66327
3 62.44962 53.68389
4 103.8789 53.67556
6 76.49952 54.29217
9 86.28699 61.66408
Embodiment 16
Adopt Chinese hamster ovary cell (CHO).The 250mL shake-flask culture adopts DM, the EM substratum, and other adds 10% calf serum.
Making the concentration of compound 7 in cell suspending liquid is 10
-4Mol/L, culture condition is with embodiment eight.The average fluorescent strength of cell suspending liquid under normal condition (aerobic) and weary oxygen condition is as shown in the table.
Average fluorescent strength
Time (h) lacks the oxygen aerobic
0.5 68.31280 57.56550
1.5 56.27470 65.08657
2.5 153.0072 132.3576
3.5 119.2358 121.3636
6.5 112.0670 126.2885
Embodiment 17
Adopt V
79-379A Chinese hamster cell.The 250mL shake-flask culture adopts 1640 substratum, and other adds 15% calf serum.
Making the concentration of compound 7 in cell suspending liquid is 10
-4Mol/L, culture condition is with embodiment eight.The average fluorescent strength of cell suspending liquid under normal condition (aerobic) and weary oxygen condition is as shown in the table.
Average fluorescent strength
Time (h) lacks the oxygen aerobic
0 69.53562 50.70322
1 66.04834 46.71288
2 64.67352 49.09621
3 66.12604 61.53178
4 118.5017 58.23617
6 81.16457 57.98064
9 93.36516 63.56602
Claims (6)
1, a kind of naphthaline derivatives, its structure is as follows:
In the formula: X is O or S; L is (CH
2)
2(O)
m(CH
2)
n(CHOH)
1(CH
2)
pR
Wherein: m=0 or 1, n=0 or 1, l=0 or 1, p=0 or 1; R is
Or
As the said derivative of claim 1, it is characterized in that 2, wherein X is O.
3, as the said derivative of claim 2, it is characterized in that, wherein m=n=l=p=0.
4, as the said derivative of claim 2, it is characterized in that m=n=l=p=1 wherein, l=0.
5, as the said derivative of claim 2, it is characterized in that, wherein m=n=l=p=1.
6, can be used for weary oxygen fluorescent probe as said any one derivative in the claim 1～5.
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|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104945322A (en) * | 2014-03-31 | 2015-09-30 | 华东理工大学 | Compound for detecting tumor hypoxia and preparation method thereof |
| CN111808097A (en) * | 2020-07-14 | 2020-10-23 | 厦门大学 | Solvent yellow 184 derivative and preparation method and application thereof |
| CN114621223A (en) * | 2020-12-10 | 2022-06-14 | 湖南超亟检测技术有限责任公司 | Preparation method and application of pH fluorescent molecular probe with photoinduced electron transfer effect |
-
2004
- 2004-03-31 CN CN 200410017346 patent/CN1283640C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104945322A (en) * | 2014-03-31 | 2015-09-30 | 华东理工大学 | Compound for detecting tumor hypoxia and preparation method thereof |
| CN104945322B (en) * | 2014-03-31 | 2019-01-08 | 华东理工大学 | Detect the compound and preparation method thereof of tumor hypoxia |
| CN111808097A (en) * | 2020-07-14 | 2020-10-23 | 厦门大学 | Solvent yellow 184 derivative and preparation method and application thereof |
| CN111808097B (en) * | 2020-07-14 | 2021-10-22 | 厦门大学 | Solvent yellow 184 derivative and preparation method and application thereof |
| CN114621223A (en) * | 2020-12-10 | 2022-06-14 | 湖南超亟检测技术有限责任公司 | Preparation method and application of pH fluorescent molecular probe with photoinduced electron transfer effect |
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| Publication number | Publication date |
|---|---|
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