CN102241969A - Small-molecule fluorescent probes for quinazoline alpha1-adrenergic receptors and application of small-molecule fluorescent probes - Google Patents
Small-molecule fluorescent probes for quinazoline alpha1-adrenergic receptors and application of small-molecule fluorescent probes Download PDFInfo
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- 239000007850 fluorescent dye Substances 0.000 title claims abstract description 16
- 150000003384 small molecules Chemical class 0.000 title claims abstract description 13
- 102000030619 alpha-1 Adrenergic Receptor Human genes 0.000 title abstract description 5
- 108020004102 alpha-1 Adrenergic Receptor Proteins 0.000 title abstract description 5
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 31
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 30
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 12
- KVSLPQXJQYNHIK-UHFFFAOYSA-N c1ccc2ncncc2c1.Cc1ccc(cc1)S(O)(=O)=O.Cc1ccc(cc1)S(O)(=O)=O Chemical compound c1ccc2ncncc2c1.Cc1ccc(cc1)S(O)(=O)=O.Cc1ccc(cc1)S(O)(=O)=O KVSLPQXJQYNHIK-UHFFFAOYSA-N 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 claims description 4
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical class O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 229960000956 coumarin Drugs 0.000 claims description 2
- 235000001671 coumarin Nutrition 0.000 claims description 2
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- -1 methoxyl group Chemical group 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 238000011160 research Methods 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 125000003277 amino group Chemical group 0.000 abstract 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 16
- 102000005962 receptors Human genes 0.000 description 13
- 108020003175 receptors Proteins 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 230000006907 apoptotic process Effects 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
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- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 4
- 239000000951 adrenergic alpha-1 receptor antagonist Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- AUMKUQAWVQJGTR-UHFFFAOYSA-N 6,7-dimethoxy-2-piperazin-1-ylquinazolin-4-amine;hydrochloride Chemical compound Cl.N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N1CCNCC1 AUMKUQAWVQJGTR-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000674 adrenergic antagonist Substances 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 206010025482 malaise Diseases 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
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- IUNJCFABHJZSKB-UHFFFAOYSA-N 2,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(O)=C1 IUNJCFABHJZSKB-UHFFFAOYSA-N 0.000 description 2
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
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- YKGGGCXBWXHKIZ-UHFFFAOYSA-N fluorescein (acid form) Chemical compound OC(=O)C1=CC=CC=C1C1=C2C=CC(=O)C=C2OC2=CC(O)=CC=C21 YKGGGCXBWXHKIZ-UHFFFAOYSA-N 0.000 description 2
- 239000003163 gonadal steroid hormone Substances 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical class CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 229940082496 Adrenoreceptor antagonist Drugs 0.000 description 1
- 102000011727 Caspases Human genes 0.000 description 1
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- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
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- HRRBJVNMSRJFHQ-UHFFFAOYSA-N Naftopidil Chemical compound COC1=CC=CC=C1N1CCN(CC(O)COC=2C3=CC=CC=C3C=CC=2)CC1 HRRBJVNMSRJFHQ-UHFFFAOYSA-N 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 description 1
- 206010066901 Treatment failure Diseases 0.000 description 1
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- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- QAUVAHYHKLRJCQ-UHFFFAOYSA-N benoxathian Chemical compound COC1=CC=CC(OC)=C1OCCNCC1OC2=CC=CC=C2SC1 QAUVAHYHKLRJCQ-UHFFFAOYSA-N 0.000 description 1
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- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
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- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 description 1
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- 229960005181 morphine Drugs 0.000 description 1
- DUCNHKDCVVSJLG-UHFFFAOYSA-N n-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]-3-methyl-4-oxo-2-phenylchromene-8-carboxamide Chemical compound COC1=CC=CC=C1N1CCN(CCCNC(=O)C=2C3=C(C(C(C)=C(O3)C=3C=CC=CC=3)=O)C=CC=2)CC1 DUCNHKDCVVSJLG-UHFFFAOYSA-N 0.000 description 1
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- 229960001999 phentolamine Drugs 0.000 description 1
- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 description 1
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical class C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
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- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
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- VCKUSRYTPJJLNI-UHFFFAOYSA-N terazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1CCCO1 VCKUSRYTPJJLNI-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to small-molecule fluorescent probes for quinazoline alpha1-adrenergic receptors and application of the small-molecule fluorescent probes. The general formula is shown as (I) or (II), and in the formula, R refers to various substituents such as hydroxyl, methyl, amino group, halogen and the like, R1 refers to mono-substituent or multi-substituent of hydroxyl, methyl, amino group, halogen or methoxyl, and R2 and R3 refer to various fluorescent groups. The fluorescent probe molecules can be used for marking the alpha1-adrenergic receptors, have good medicine activity, and can serve as tool medicines to research the pharmacological and physiological characteristics of the alpha1-adrenergic receptors. In addition, the preparation method for the compounds has the advantages of mild reaction conditions, cheap and readily available raw materials, and simple operation and posttreatment.
Description
Technical field
The present invention relates to quinazoline derivative and as α
1The small molecules fluorescent probe of-adrenergic receptor and the application in the anti-prostate cancer medicine of preparation belong to technical field of pharmaceuticals.
Background technology
Prostate cancer (prostatic carcinoma or prostatic cancer, English is abbreviated as PCa) be the modal malignant tumour of male reproductive system, incidence probability increased with the age, tangible regional disparity is arranged, the European and American areas is higher, it is reported to be only second to lung cancer, is second [DeMarzo, A.M. of cancer mortality among the male sex crowd; Nelson, W.G.; Isaacs, W.B.; Epstein, J.I.Pathological and molecular aspects of prostate cancer.Lancet 2003,361,955-964].Though China's prostate cancer sickness rate is American-European low, but along with aging population trend in recent years and problem of environmental pollution, the trend that the sickness rate of prostate cancer is significantly increased, the sickness rate of China's prostate cancer has been risen to per 100,000 male sex, 12.6 people [Zhang, L. in 2000 by per 100,000 male sex, 2.9 people in 1991 according to statistics; Wu, S.; Guo, L.R.; Zhao, X.J.Diagnostic strategies and the incidence of prostate cancer:reasons for the low reported incidence of prostate cancer in China.Asian J.Androl.2009,11,9-13].The morbidity of prostate cancer is parallel with the age, and according to foreign statistic, the right side of fifty male sex is rare; 50-60 year morbidity accounts for 1/3 of prostate cancer; Account for 1/2 more than 70 years old; Account for 3/4[Nelson, W.G. more than 80 years old; De Marzo, A.M.; Isaacs, W.B.Prostate cancer.N.Engl.J.Med.2003,349,366-381].
Main clinically at present operation, male sex hormone removal and the radiation therapy treatment prostate cancer of adopting, but success ratio is not high, the key of its treatment failure is that patients with prostate cancer is after treatment for some time, cancer cells can become androgen independence by androgen-dependent, make the growth of tumour cell uncontrollable, therefore still there are not safe and effective therapeutic method [Walsh, P.C. at present for prostate cancer; DeWeese, T.L.; Eisenberger, M.A.Clinical practice.Localized prostate cancer.N.Engl.J.Med.2007,357,2696-2705].In recent years, the treatment with chemotherapy medicine disturbs processes such as growth of tumour cell, metabolism, propagation, the final apoptosis of tumor cells that triggers, become the effective ways of oncotherapy, thereby the focus of relation between apoptosis and the cancer and the cell death inducing effect in cancer therapy becoming tumor research.Wherein there are some researches show α
1-adrenergic receptor antagonist can be induced the prostate cancer cell apoptosis, therefore, contains α by structure
1The fluorescent probe molecule of-receptor antagonist activity molecule fragment is to α
1The key factor of adjustable prostatic cell apoptosis is found in the research of-acceptor and downstream intracellular signal transduction pathway, is expected to obtain to prevent, brand-new strategy [(a) Watson, the R.W. of Clinics and Practices prostate cancer; Fitzpatrick, J.M.Targeting apoptosis in prostate cancer:focus on caspases and inhibitors of apoptosis proteins.BJU Int.2005,96Suppl 2,30-34; (b) Lorenzo, P.I.; Arnoldussen, Y.J.; Saatcioglu, F.Molecular mechanisms of apoptosis in prostate cancer.Crit.Rev.Oncog.2007,13,1-38.].
α
1-adrenergic receptor is the important member in the G-protein linked receptor family, comprises three kinds of hypotype: α at present
1A, α
1BAnd α
1D[Zhong, H.; Minneman, K.P.Alpha1-adrenoceptor subtypes.Eur J Pharmacol 1999,375,261-276].α
1-adrenergic receptor antagonist is usually used in alleviating relevant the blocking symptom and treat hypertension [Rosini, M. of benign prostatic hyperplasia (BPH) clinically; Bolognesi, M.L.; Giardina, D.; Minarini, A.; Tumiatti, V.; Melchiorre, C.Recent advances inalpha1-adrenoreceptor antagonists as pharmacological tools and therapeuticagents.Curr.Top.Med.Chem.2007,7,147-162].Present α
1-adrenergic receptor antagonist mainly is divided into 3 classes on the pharmacophoric group chemical structure, comprise quinazoline ditosylate salt (prazosin, doxazosin and terazosin etc.), phenylpiperazine class (naftopidil and upidosin etc.) and fragrant oxygen alkanamine class (tamsulosin and benoxathian etc.).What be worth that we pay close attention to is to have a series of reports to confirm the α of various structure types recently
1-adrenergic receptor antagonist not only has apoptosis-induced effect to the cell of benign prostatic hyperplasia, and the male sex hormone dependence and the non-dependence prostate cancer cell of vitro culture all had apoptosis-promoting effect [Stamatiou, K.; Skolarikos, A.; Sofras, F.The impact of alpha1-adrenoceptors on prostate cancer growth.Urology 2008,71,756-757].Therefore, α
1-adrenergic receptor antagonist not only can be treated benign prostatic hyperplasia, can also treat advanced prostate cancer by inducing the prostate cancer cancer cell-apoptosis, and to α
1-adrenergic receptor coherent signal path is studied, and might find to prevent, diagnose and treat the novel action target of prostate cancer.
The α of utilization pharmacology means research at present
1-adrenergic receptor has certain degree of difficulty to the prostate cancer cell effect of apoptosis, and this is because α
1Though-adrenergic receptor antagonist has had very big improvement than before on activity, aspect tissue selectivity, still remain further to be optimized; On the other hand, α
1The three-dimensional crystalline structure of-adrenergic receptor is not resolved as yet, is difficult to from based on molecular level these experimental phenomenas being made an explanation.What is more important does not also have an ideal α so far
1-adrenergic receptor small molecules fluorescent probe emerges, these feasible modern technologies research α such as immunofluorescence label and flow cytometry that adopt
1The difficulty of-adrenergic receptor and prostate cancer cell apoptosis relation strengthens.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of quinazoline ditosylate salt α is provided
1Small molecules fluorescent probe of-adrenergic receptor and preparation method thereof, optical activity, biological activity and the application in pharmacy.
For achieving the above object, the present invention adopts following technical proposals:
A kind of quinazoline ditosylate salt α
1The small molecules fluorescent probe of-adrenergic receptor has following general structural formula: (I) or (II).
In the formula: R is various substituting groups such as hydroxyl, methyl, amino or halogen; R
1For the single of hydroxyl, methyl, amino, halogen or methoxyl group replaces or multi-substituent; R
2, R
3Be various fluorophores.
Preferably, R is amino in the formula; R
1Be earlier 6,7 dimethoxys; R
2For containing the coumarin kind compound of carboxyl, R3 is the fluorescein isothiocyanate compounds.
Preferably, be following compound:
1-(4-amino-6,7-dimethoxy-2-quinazolyl)-4-[(7-hydroxyl-3-1,2-chromene ketone group) carbonyl] piperazine (a1),
1-(4-amino-6,7-dimethoxy-2-quinazolyl)-4-{[1-(7-hydroxyl-3-1,2-chromene ketone group)-4-1,2,3 ,-triazol radical] carbonyl } piperazine (a2),
5-[4-(4-amino-6,7-dimethoxy-2-quinazolyl) piperazine-1-sulfonyl amido]-2-(6-hydroxyl-3-oxo-3H-xanthene-9-yl) phenylformic acid (a3).
Compound of the present invention is as α
1The application of the small molecules fluorescent probe of-adrenergic receptor.
The application of compound of the present invention in the anti-prostate cancer medicine of preparation.
Compound of the present invention is as instrument medicine research α
1The pharmacology of-adrenergic receptor, physiologic character and application how to regulate and control prostate cancer cell apoptosis signal transduction path.
Compound of the present invention is at α
1Application in-adrenergic receptor antagonist or the agonist activity research.
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
Example one: 1-(4-amino-6,7-dimethoxy-2-quinazolyl)-4-[(7-hydroxyl-3-1,2-chromene ketone group) carbonyl] preparation of piperazine (a1)
The synthetic route of a1:
The preparation of intermediate (a1-1):
The 100mL flask adds 2.76g 2,4-Dihydroxy benzaldehyde and 25mL dehydrated alcohol, stirring makes the solution becomes clarification, adds the 3.84g diethyl malonate again, in the time of stirring, 0.17g morphine quinoline and 66mg acetate are dissolved in the 10mL dehydrated alcohol, then it are added above-mentioned reaction solution, reflux and stir 9h, ice bath cooling reaction solution, separate out a large amount of precipitations, filter drying, get yellow needle-like solid 2.37g, productive rate is 50.64%.
The preparation of intermediate (a1-2):
The 100mL flask drops into 2.37g a1-1, the NaOH of adding 40mL 2M, and stirring at room 14h, the HCl that adds 2M shows acid to solution, separates out a large amount of precipitations, filters, and drying gets yellow solid 1.85g, and productive rate is 90%.
The preparation of a1:
The 100mL two-neck bottle adds 0.1g a1-2,40mL toluene and 2mL SOCl2 successively, stirs and makes dissolving, in the time of 70 ℃, adds two DMF, stirs 4h, and decompression steams solvent, adds twice toluene (each 15mL) again, and evaporate to dryness gets faint yellow solid;
The 100mL flask, 0.1g 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline hydrochloride is dissolved among the 25mL THF, add 2mL TEA, the solution becomes clarification is with the faint yellow solid of step reaction gained in the 30mL THF dissolving, under the condition of ice bath, slowly splash into, rise to stirring at room 4h, be spin-dried for, column chromatography purification (sherwood oil: ethyl acetate=1: 3), get yellow solid 0.03g, productive rate is 21.4%, mp:221-222 ℃.
1HNMR(600MHz，DMSO-d
6)δppm：10.76(s，1H)，8.11(s，1H)，7.61(d，J＝8.4Hz，1H)7.42(s，1H)，7.17(s，2H)，6.84(dd，J＝8.4，2.4Hz，1H)，6.77(d，J＝2.4Hz，1H)，6.74(s，1H)，3.83(s，3H)，3.79(s，5H)，3.71(t，2H)，3.65(t，2H)，3.41(t，2H)；
13CNMR(300MHz，DMSO-d
6)δppm：164.1，162.6，161.7，158.6(2C)，158.5，156.2，154.8，145.6，143.6，130.9，120.4，114.2，111.3，105.6，104.3，103.5，102.6，56.4，55.9，47.2，44.5，43.9，42.0；
ESI-MS：m/z478.4[M+H]
+；
IR(KBr，cm
-1)：3355(NH
2)，3224(Ar-OH).
Example two: 1-(4-amino-6,7-dimethoxy-2-quinazolyl)-4-{[1-(7-hydroxyl-3-1,2-chromene ketone group)-4-1,2,3 ,-triazol radical] carbonyl } preparation of piperazine (a2)
The synthetic route of a2:
The preparation of intermediate a2-1:
The 250mL flask adds 2.76g 2, and 4-Dihydroxy benzaldehyde, 2.34g acetylaminoacetic acid, 4.92g sodium acetate, anhydrous and 85mL aceticanhydride reflux and stir 5h, in reaction solution impouring frozen water, separate out a large amount of precipitations, filter, drying gets yellow solid 2.03g, and productive rate is 38.9%.
The preparation of intermediate a2-2:
The 250mL flask drops into 0.3g a2-1, adds 10mL concentrated hydrochloric acid and 5mL ethanol, refluxes and stirs 1h, and is cold slightly, adds frozen water in reaction solution, and ice bath cooling reaction solution slowly adds 0.24gNaNO
2, to stir after 10-15 minute, gradation adds 0.34gNaN
3, behind the stirring 1h, filter, water washing and precipitating, drying gets brown solid 0.2g, and (sherwood oil: ethyl acetate=10: 1) get pure product 0.12g, productive rate is 52.2% to cross post.
The preparation of intermediate a2-3:
0.12g a2-2 is dissolved in 2mL ethanol and the 2mL water, adds 0.13g propynoic acid, 0.11g sodium ascorbate, 120 μ L 0.5M CuSO4 successively, stirring at room 40h in the dark filters, collecting precipitation, and drying gets taupe brown solid 0.1g, and productive rate is 62.5%.
The preparation of a2:
The 100mL flask, add 80mg a2-3 and 30mL methylene dichloride, stirring makes its dissolving, adds 97 μ LN-methylmorpholines again, stirs after 30 minutes, 43 μ L isobutyl chlorocarbonates are dissolved in the 20mL methylene dichloride, cryosel is bathed down and is slowly splashed into, after 40 minutes, with 0.12g 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline hydrochloride and 257 μ LTEA are dissolved in the 20mL methylene dichloride, slowly splash into, rise to stirred overnight at room temperature, steam reaction solution, get yellow solid, cross post (sherwood oil: ethyl acetate=1: 8), get target compound 30mg, productive rate is 19%, dec:180 ℃.
1HNMR(600MHz，DMSO-d
6)δppm：8.87(s，1H)，8.57(s，1H)，7.66(d，J＝8.4，1H)，7.44(s，1H)，7.18(s，2H)，6.78(d，J＝8.4Hz，1H)，6.76(s，1H)，6.69(s，1H)；
ESI-MS：m/z?545.3[M+H]
+；
IR(KBr，cm
-1)：3351(NH
2)，3185(Ar-OH).
Example three: 5-[4-(4-amino-6,7-dimethoxy-2-quinazolyl) piperazine-1-sulfonyl amido]-preparation of 2-(6-hydroxyl-3-oxo-3H-xanthene-9-yl) phenylformic acid (a3)
The synthetic route of a3:
The preparation of a3:
The 50mL flask adds 146.6mg 2-piperazinyl-4-amino-6,7-dimethoxyquinazoline hydrochloride, 0.5mLTEA and 15mL methylene dichloride, stirring makes its dissolving, under the condition of ice bath, 116.8mg FITC is dissolved in 4mL DMF, slowly splash into, rise to room temperature, stir 45h in the dark, screw out solvent, be oily matter, add ethyl acetate and methyl alcohol, separate out a large amount of precipitations, filter, collecting precipitation is with 2M NaOH dissolving, the elimination insolubles, add 2M HCl and show acid, separate out a large amount of solids, filter to solution, dry, get tawny solid 0.13g, productive rate is 65%, dec:252 ℃.
1HNMR(600MHz，DMSO-d
6)δppm：12.23(s，1H)，10.20(s，2H)，9.99(s，1H)，8.92(s，1H)，8.71(s，1H)，8.04(s，1H)，7.85(d，J＝8.4，1H)，7.75(s，1H)，7.50(s，1H)，7.20(d，J＝8.4，1H)，6.66-6.71(m，2H)，6.60(s，3H)，4.20(s，3H)，4.03(s，4H)，3.86-3.90(m，7H)；
ESI-MS：m/z679.4[M+H]
+；
IR(KBr，cm
-1)：3381(NH
2)，3077(Ar-OH).
Optical activity is measured:
Annotate: above all optical properties are all measured in the phosphoric acid buffer of PH=7.4.
Biological activity determination:
Radioligand method detection compound is to α
1Three kinds of hypotype (α of-adrenergic receptor
1A, α
1B and α
1D) avidity:
Annotate: the positive drug phentolamine is to α
1A, α
1BAnd α
1DK
iAnd IC
50Be respectively 0.6,4.8,7.6 and 11,10.8,12.5.
Claims (5)
1. quinazoline ditosylate salt α
1The small molecules fluorescent probe of-adrenergic receptor has following general structural formula: (I) or (II)
In the formula: R is hydroxyl, methyl, amino or halogen; R
1For the single of hydroxyl, methyl, amino, halogen or methoxyl group replaces or multi-substituent; R
2, R
3Be various fluorophores.
2. a kind of quinazoline ditosylate salt α according to claim 1
1The small molecules fluorescent probe of-adrenergic receptor is characterized in that, R is amino in the formula; R
1Be 6,7 dimethoxys; R
2For containing the coumarin kind compound of carboxyl; R
3Be the fluorescein isothiocyanate compounds.
3. a kind of quinazoline ditosylate salt α according to claim 2
1The small molecules fluorescent probe of-adrenergic receptor is characterized in that, is following compound:
1-(4-amino-6,7-dimethoxy-2-quinazolyl)-4-[(7-hydroxyl-3-1,2-chromene ketone group) carbonyl] piperazine,
1-(4-amino-6,7-dimethoxy-2-quinazolyl)-4-{[1-(7-hydroxyl-3-1,2-chromene ketone group)-4-1,2,3 ,-triazol radical] carbonyl } piperazine,
5-[4-(4-amino-6,7-dimethoxy-2-quinazolyl) piperazine-1-sulfonyl amido]-2-(6-hydroxyl-3-oxo-3H-xanthene-9-yl) phenylformic acid.
4. compound as claimed in claim 1 is as α
1The application of the small molecules fluorescent probe of-adrenergic receptor.
5. the application of compound as claimed in claim 1 in the anti-prostate cancer medicine of preparation.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105062465A (en) * | 2015-07-31 | 2015-11-18 | 山东大学 | Environment-sensitive alpha1-adrenergic receptor near infrared fluorescence ligands and application thereof |
| CN109293673A (en) * | 2018-10-10 | 2019-02-01 | 中国药科大学 | A kind of prolyl hydroxylase small-molecule fluorescent probe and preparation method thereof |
| CN115947720A (en) * | 2022-12-07 | 2023-04-11 | 南京师范大学 | Design of beta 3 adrenergic receptor anchoring probe and preparation method and application thereof |
Citations (2)
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| WO2006032926A2 (en) * | 2004-09-24 | 2006-03-30 | The University Of Nottingham | Improvements in high content screening |
| CN1860364A (en) * | 2003-04-02 | 2006-11-08 | 诺丁汉大学 | Fluorescently tagged ligands |
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2011
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1860364A (en) * | 2003-04-02 | 2006-11-08 | 诺丁汉大学 | Fluorescently tagged ligands |
| WO2006032926A2 (en) * | 2004-09-24 | 2006-03-30 | The University Of Nottingham | Improvements in high content screening |
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|---|
| C. J. DALY等: "Cellular Localization and Pharmacological Characterization of Functioning Alpha-1 Adrenoceptors by Fluorescent Ligand Binding and Image Analysis Reveals Identical Binding Properties of Clustered and Diffuse Populations of Receptors", 《THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》, vol. 286, no. 2, 31 December 1998 (1998-12-31) * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105062465A (en) * | 2015-07-31 | 2015-11-18 | 山东大学 | Environment-sensitive alpha1-adrenergic receptor near infrared fluorescence ligands and application thereof |
| CN109293673A (en) * | 2018-10-10 | 2019-02-01 | 中国药科大学 | A kind of prolyl hydroxylase small-molecule fluorescent probe and preparation method thereof |
| CN115947720A (en) * | 2022-12-07 | 2023-04-11 | 南京师范大学 | Design of beta 3 adrenergic receptor anchoring probe and preparation method and application thereof |
| CN115947720B (en) * | 2022-12-07 | 2024-03-29 | 南京师范大学 | Design, preparation and application of beta 3 adrenergic receptor anchoring probe |
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