CN108440601A - A kind of aromatic hydrocarbons-ruthenium complex and its preparation method and application - Google Patents
A kind of aromatic hydrocarbons-ruthenium complex and its preparation method and application Download PDFInfo
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- 125000003118 aryl group Chemical group 0.000 title claims abstract description 40
- 239000012327 Ruthenium complex Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 206010021143 Hypoxia Diseases 0.000 claims abstract description 15
- 230000001146 hypoxic effect Effects 0.000 claims abstract description 11
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000001424 substituent group Chemical group 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 28
- 206010028980 Neoplasm Diseases 0.000 claims description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 26
- 239000003446 ligand Substances 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 15
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 claims description 15
- 238000000926 separation method Methods 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 238000004440 column chromatography Methods 0.000 claims description 9
- 238000003786 synthesis reaction Methods 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000003480 eluent Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 5
- 239000007821 HATU Substances 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 229940014800 succinic anhydride Drugs 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 2
- 239000012964 benzotriazole Substances 0.000 claims description 2
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 claims description 2
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 claims description 2
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 2
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims 1
- 150000003851 azoles Chemical class 0.000 claims 1
- 201000002313 intestinal cancer Diseases 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 9
- 239000001301 oxygen Substances 0.000 abstract description 9
- 229910052760 oxygen Inorganic materials 0.000 abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 abstract description 7
- 230000003013 cytotoxicity Effects 0.000 abstract description 7
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 6
- 239000003112 inhibitor Substances 0.000 abstract description 5
- 230000001225 therapeutic effect Effects 0.000 abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 230000001093 anti-cancer Effects 0.000 abstract description 2
- 230000007246 mechanism Effects 0.000 abstract description 2
- 210000004881 tumor cell Anatomy 0.000 abstract 3
- 230000001472 cytotoxic effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 8
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 8
- 229910052697 platinum Inorganic materials 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 230000000118 anti-neoplastic effect Effects 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 4
- 206010002660 Anoxia Diseases 0.000 description 4
- 241000976983 Anoxia Species 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 4
- 230000007953 anoxia Effects 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 208000029742 colonic neoplasm Diseases 0.000 description 4
- 150000003057 platinum Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 102000002177 Hypoxia-inducible factor-1 alpha Human genes 0.000 description 2
- 108050009527 Hypoxia-inducible factor-1 alpha Proteins 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003303 ruthenium Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
Classifications
-
- 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
- C07F15/0046—Ruthenium compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
Abstract
The present invention relates to a kind of Aromatic ruthenium complex and its preparation method and application, the structure of the complex is shown in formula I：Wherein R indicates 06 substituent groups, is independently selected from H or C1‑6Alkyl；X, Y indicates halogen respectively.By introducing 1 alpha inhibitor YC 1 of HIF in ruthenium complex, biologically active ruthenium (II) and 1 alpha inhibitor YC 1 of HIF can be delivered to hypoxic tumor cell simultaneously, to wish to show its active anticancer by number of mechanisms, to improve the therapeutic effect of chemotherapeutics；By cytotoxic activity research shows that such Aromatic ruthenium complex has preferable antitumor activity, there is the cytotoxicity for being substantially better than normal oxygen tumour cell particularly with hypoxic tumor cell, can apply in the preparation of antitumor drugs.
Description
Technical field
The present invention relates to field of antineoplastic medicaments, and in particular to a kind of aromatic hydrocarbons-ruthenium complex and its preparation method and application.
Background technology
Anoxic is the mark of most of tumours, it influences many aspects of oncobiology.Oxygen content drops in tumor tissues
The low accumulation for leading to hypoxia-inducible factor-1 alpha (hypoxia inducible factor-1 α, HIF-1 α) albumen.Pass through adjusting
With tumor metabolic, angiogenesis, transfer is proliferated and breaks up the expression of relevant various genes, HIF-1 α are in tumour generating process
In play a significant role, HIF-1 α have become treatment Tumor Angiongesis and cancer important target.1- benzyls -3- (5- hydroxyl first
Base -2- furyls) indazole (YC-1) is a kind of effective HIF-1 alpha inhibitors, it is developing as targeting HIF-1 and tumour blood
The new type anticancer agent that pipe generates.
Tumour, which belongs to, endangers one of major disease of human health, and early period is the platinum series antineoplastic medicament of representative with cis-platinum etc.
Highly important effect is played in tumor disease therapeutic, as research is deeply more and more the study found that non-platinum class
Antitumoral compounds can also show good therapeutic effect, and alleviate some for even avoiding platinum series antineoplastic medicament and bringing
Side effect overcomes drug resistance caused by platinum series antineoplastic medicament, and ruthenium series antineoplastic medicament is considered most potential and replaces
Instead of one.Wherein, ruthenium (II)-aromatic hydrocarbons organometallic complex is most striking research direction in recent years, is shown
Huge treatment of cancer potentiality.In addition, the ligand being coordinated in aromatic hydrocarbons-ruthenium (II) complex can provide and more adjust its pharmacology
The possibility of property (such as lipophilicity and kinetic property).
And new type antineoplastic medicine is developed, especially high activity is always to chase after with certain specific antitumor drug
The target asked.
Invention content
Technical problem：The object of the present invention is to provide a new class of aromatic hydrocarbons-ruthenium complexes and preparation method thereof to be used for it
The purposes of antitumor drug is prepared, the ruthenium (II) of bioactivity and HIF-1 alpha inhibitors YC-1 can be delivered to hypoxic tumor by it
Cell, to show its active anticancer by number of mechanisms, to improve the therapeutic effect of chemotherapeutics.
Technical solution：A kind of aromatic hydrocarbons-ruthenium complex structure of the present invention is shown in formula I：
Wherein R indicates 0-6 substituent group, is independently selected from H or C1-6Alkyl；X, Y indicates halogen respectively.
Wherein,
The R is independently selected from H, methyl, isopropyl, and the halogen is F, Cl, Br or I.
Aromatic hydrocarbons-the ruthenium complex is complex 1,2 or 3, and the structural formula of complex 1-3 is as follows：
The preparation method of aromatic hydrocarbons-ruthenium complex of the present invention includes the following steps：
Step 1: producing YC-2 first：With N,N-dimethylformamide DMF by 1- benzyls -3- (5- methylol -2- furans
Base) indazole YC-1 and succinic anhydride be dissolved in flask, and triethylamine TEA is added, is reacted 4-6 hours at 40-60 DEG C, liquid cooling to be reacted
But after, revolving removes DMF, and after water and dichloromethane DCM extractions is added, organic phase is dried with anhydrous sodium sulfate, and filtering removes molten
Agent obtains YC-2, and structural formula is as follows：
Step 2: synthetic ligands L1 again：By the YC-2 and 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethyls
Urea hexafluorophosphoric acid ester HATU is dissolved with DMF, addition TEA, and under nitrogen protection, amino -1 5- is added after 1-2 hours in stirring at normal temperature,
10- ferrosins are warming up to 60-70 DEG C, and reaction overnight, after reaction is cooled to room temperature, is spin-dried for removing DMF, silica gel mixed sample, column layer
Analysis separation, obtains ligand L 1, the structural formula of ligand L 1 is as follows：
Step 3: ligand L 1 is dissolved in flask with organic solvent, add dihalo- (aryl) ruthenium (II) dimer thereto,
Stirring at normal temperature 4-6 hours, after after raw material, the reaction was complete, column chromatography for separation obtains aromatic hydrocarbons-ruthenium complex shown in Formulas I.
Wherein,
The column chromatography for separation, eluant, eluent used are the mixture of dichloromethane DCM and methanol MeOH, by volume DCM:
MeOH=80:1.
The ligand L 1, organic solvent is dichloromethane or methanol in synthesis step.
Dihalo- (aryl) ruthenium (II) dimer is [(arene) RuCl2]2、[(C6H6)RuCl2]2Or [(C6Me6)
RuCl2]2。
Aromatic hydrocarbons-ruthenium complex of the present invention is applied to prepare antitumor drug.
The tumour is hypoxic tumor.
The hypoxic tumor is anoxic colon cancer or anoxic lung cancer.
Advantageous effect：Advantages of the present invention and effect：The present invention will smoothly introduce HIF-1 alpha inhibitors for the first time by designing
YC-1 is introduced into ruthenium complex；Designed aromatic hydrocarbons-ruthenium complex synthetic method is simple, and product is stablized；Aromatic hydrocarbons-ruthenium of the present invention
Complex has preferable antitumor activity, has better inhibition particularly with hypoxic tumor, i.e., has to hypoxic tumor
There are a specificity, especially complex 3, the IC under anoxic in HCT116 cells and A549 cells50Value is 12.7 ± 0.6 Hes respectively
15.7 ± 0.6, half or so only under normoxic condition, more it is worth noting that, two values are below the 19.9 ± 1.3 of cis-platinum
With 20.9 ± 1.3, the cytotoxicity for being better than cis-platinum under anoxia condition is shown.
Specific implementation mode
The present invention provides a kind of aromatic hydrocarbons-ruthenium complex, shown in structure such as formula (I)：
Wherein R indicates 0-6 substituent group, is independently selected from H or C1-6Alkyl；Wherein R is preferably H, methyl, different
Propyl, R can be 0,1,2,3,4,5 or 6；
X, Y indicates halogen, wherein halogen preferred F, Cl, Br, I, more preferably Cl respectively.
Aromatic hydrocarbons-ruthenium complex of Formulas I is more preferably specific complex 1,2 or 3；The structural formula I of complex 1-3 is as follows：
The preparation method of aromatic hydrocarbons-ruthenium complex shown in a kind of formula (I) of present invention offer：Including being incited somebody to action with suitable organic solvent
Ligand L 1 is dissolved in flask, and thereto plus dihalo- (aryl) ruthenium (II) dimer (is preferably [(arene) RuCl2]2、
[(C6H6)RuCl2]2、[(C6Me6)RuCl2]2), stirring at normal temperature 4 hours, after after raw material, the reaction was complete, column chromatography for separation, eluant, eluent
For DCM:MeOH=80:1) aromatic hydrocarbons-ruthenium complex shown in formula (I), is obtained.Organic solvent is preferably DCM or methanol.
The preparation method of aromatic hydrocarbons-ruthenium complex shown in the formula (I) can also include the synthesis step of YC-2 and/or ligand L 1
Suddenly；
The synthesis step of YC-2 includes：YC-1 and succinic anhydride are dissolved in flask with DMF, TEA is added, is reacted at 50 DEG C
4 hours.After reaction solution cooling, revolving removes DMF, and after suitable quantity of water and DCM extractions is added, organic phase is dry with anhydrous sodium sulfate
Dry, filtering removes solvent and obtains YC-2.
The synthesis step of ligand L 1 includes：YC-2 and HATU are dissolved with DMF, addition TEA, under nitrogen protection, room temperature stirs
After mixing 1-2 hours, 5- amino -1,10- ferrosins are added, are warming up to 60 DEG C, reaction is overnight.After reaction is cooled to room temperature, rotation
It is dry to remove DMF, silica gel mixed sample, column chromatography for separation (eluant, eluent DCM:MeOH=40:1) ligand L 1, is obtained.
The synthesis equation of specific complex 1-3 is as follows：
A) succinic anhydride, triethylamine, DMF, 50 DEG C, 4h；B) 5- amino -1,10- ferrosin, triethylamine, HATU, DMF, 60
℃,12h；c)[(arene)RuCl2]2、[(C6H6)RuCl2]2、[(C6Me6)RuCl2]2, DCM, rt, 4h.
Aromatic hydrocarbons-ruthenium complex of the present invention can be used for preparing antitumor drug, the tumour be preferably colon cancer, lung cancer or
The tumour is preferably hypoxic tumor, and the hypoxic tumor is more preferably anoxic colon cancer, anoxic lung cancer.
Embodiment 1：The synthesis of YC-2
YC-1 (0.8406g, 2.763mmol) and succinic anhydride (0.5539g, 5.535mmol) are dissolved in the DMF of 10mL
In 50mL flasks, TEA (0.5600g, 5.535mmol) is added, is reacted 4 hours at 50 DEG C.After reaction solution cooling, revolving removes
DMF, after suitable quantity of water and DCM extractions is added, organic phase is dried with anhydrous sodium sulfate, filtering, is removed solvent and is obtained faint yellow solid
1.04g, yield 93.3%.White solid.Calcd (%) for C23H20N2O5:C 68.31,H 4.98,N 6.93.Found:C
68.20,H 4.91,N 6.79；1H NMR(600MHz,DMSO)δ2.50-2.52(m,2H),2.57-2.59(m,2H),5.19
(s, 2H), 5.73 (s, 2H), 6.71-6.72 (d, 1H, J=3.4Hz), 7.02-7.03 (d, 1H, J=3.4Hz), 7.24-7.28
(m, 4H), 7.30-7.33 (m, 2H), 7.45-7.47 (m, 1H), 7.76-7.77 (d, 1H, J=8.5Hz), 8.10-8.12 (d,
1H, J=8.2Hz), 12.24 (s, 1H) ppm.
Embodiment 2：The synthesis of ligand L 1
YC-2 (0.5000g, 1.236mmol) and HATU (0.5091g, the 1.339mmol) DMF of 7.5mL are dissolved, are added
Enter TEA (0.1355g, 1.339mmol), under nitrogen protection, 5- amino -1,10- ferrosins are added after 1-2 hours in stirring at normal temperature
(0.2010g, 1.030mmol) is warming up to 60 DEG C, and reaction is overnight.After reaction is cooled to room temperature, it is spin-dried for removing DMF, silica gel is mixed
Sample, column chromatography for separation (eluant, eluent DCM:MeOH=40:1) yellow solid 0.3235g, yield 54%, are obtained.It is light yellow solid
Body .Anal.Calcd (%) for C35H27N5O4:C 72.28,H 4.68,N 12.04.Found:C 72.20,H 4.81,N
11.96；1H NMR(600MHz,DMSO)δ2.77-2.79(m,2H),2.88-2.90(m,2H),5.24(s,2H),5.70(s,
2H), 6.74-6.75 (d, 1H, J=3.4Hz), 7.01-7.02 (d, 1H, J=3.3Hz), 7.18-7.26 (m, 4H), 7.29-
7.31 (m, 2H), 7.39-7.42 (m, 1H), 7.72-7.74 (d, 1H, J=8.2Hz), 7.75-7.77 (q, 1H, J=4.4Hz),
7.84-7.86 (q, 1H, J=4.4Hz), 8.08-8.09 (d, 1H, J=8.2Hz), 8.18 (s, 1H), 8.45-8.47 (1H, d-
D, J=8.1,1.4Hz), 8.69-8.70 (d, 1H, J=7.4Hz), 9.01 (m, 1H), 9.03-9.04 (1H, d-d, J=4.3,
1.6Hz), 9.12-9.13 (1H, d-d, J=4.2,1.5Hz), 10.27 (m, 1H) ppm.
Embodiment 3：The synthesis of aromatic hydrocarbons-ruthenium complex 1-3
L1 (0.2000g, 0.3441mmol) is dissolved in flask with suitable DCM, adds [(arene) respectively thereto
RuCl2]2、[(C6H6)RuCl2]2、[(C6Me6)RuCl2]2(0.3441mmol), stirring at normal temperature 4 hours.Waiting for raw material, the reaction was complete
Afterwards, silica gel mixed sample, column chromatography for separation (eluant, eluent DCM:MeOH=80:1) aromatic hydrocarbons-ruthenium complex 1-3, is respectively obtained.
Compound 1：Yield:0.23g (61.3%) yellow greenish powders .Anal.Calcd (%) for
C45H41Cl2N5O4Ru:C 60.88,H 4.65,N 7.89.Found:C 60.73,H 4.54,N 7.96；ESI-MS:m/z[M-
Cl]+=852.2；1H NMR (600MHz, DMSO) δ 0.89-0.91 (t, 6H, J=6.6Hz), 2.18 (s, 3H), 2.62 (m,
1H),2.75-2.77(m,2H),2.97-2.99(m,2H),5.22(s,2H),5.70(s,2H),6.15-6.17(m,2H),
6.39 (m, 2H), 6.73-6.74 (d, 1H, J=3.1Hz), 7.00-7.01 (d, 1H, J=3.1Hz), 7.18-7.32 (m, 5H),
7.38-7.41 (m, 1H), 7.72-7.74 (d, 1H, J=8.5Hz), 8.06 (m, 1H), 8.08-8.10 (d, 1H, J=8.1Hz),
8.18 (s, 1H), 8.47 (s, 1H), 8.79-8.80 (d, 1H, J=8.0Hz), 9.27-9.28 (d, 1H, J=8.0Hz), 9.89
(m,1H),10.02(m,1H),11.12(m,1H)ppm；13C NMR(150MHz,DMSO-d6)δ18.69,22.12,22.14,
29.17,30.86,31.23,52.44,58.31,84.23,84.39,86.42,86.57,103.23,104.48,108.41,
110.75,113.28,120.73,121.50,122.14,126.05,126.45,126.85,127.37,127.73,128.05,
129.08,130.12,133.95,135.48,135.65,137.76,138.50,140.77,143.18,145.87,149.06,
149.59,155.35,156.60,172.02,172.61ppm.
Compound 2：Yield:0.21g (59.6%) yellow greenish powders .Anal.Calcd (%) for
C41H33Cl2N5O4Ru:C 59.21,H 4.00,N 8.42.Found:C 59.33,H 4.04,N 8.30；ESI-MS:m/z[M-
Cl]+=796.2；1H NMR(600MHz,DMSO)δ2.82-2.84(m,2H),3.04(m,2H),5.28(s,2H),5.76(s,
2H), 6.40 (s, 6H), 6.79-6.80 (d, 1H, J=3.1Hz), 7.06-7.07 (d, 1H, J=3.1Hz), 7.22-7.25 (d,
1H, J=7.5Hz), 7.29-7.38 (m, 5H), 7.44-7.46 (m, 1H), 7.78-7.80 (d, 1H, J=8.5Hz), 8.11 (m,
1H), 8.13-8.15 (d, 1H, J=8.2Hz), 8.23 (m, 1H), 8.50 (s, 1H), 8.82-8.83 (d, 1H, J=8.0Hz),
9.30-9.31 (d, 1H, J=8.2Hz), 10.03 (m, 1H), 10.17 (m, 1H), 11.18 (m, 1H) ppm；13C NMR
(150MHz,DMSO-d6)δ29.19,31.32,52.41,58.29,87.11,108.38.110.71,113.29,120.69,
121.49,122.11,125.85,126.56,126.65,127.35,127.73,128.04,129.07,130.12,133.92,
135.46,135.77,137.76,138.46,140.73,143.33,146.02,149.06,149.57,155.56,156.82,
172.03,172.61ppm.
Compound 3：Yield:0.25g (65.2%) yellow greenish powders .Anal.Calcd (%) for
C47H45Cl2N5O4Ru:C 61.64,H 4.95,N 7.65.Found:C 61.58,H 4.90,N 7.73；ESI-MS:m/z[M-
Cl]+=880.3；1H NMR(600MHz,DMSO)δ2.10(s,18H),2.75-2.77(m,2H),2.98-3.00(m,2H),
5.21 (s, 2H), 5.69 (s, 2H), 6.72-6.73 (d, 1H, J=2.9Hz), 7.00-7.01 (d, 1H, J=2.9Hz), 7.18-
7.25 (m, 4H), 7.28-7.31 (m, 2H), 7.38-7.40 (m, 1H), 7.72-7.73 (d, 1H, J=8.4Hz), 8.08-8.09
(m, 2H), 8.16 (m, 1H), 8.45 (s, 1H), 8.73-8.75 (d, 1H, J=7.8Hz), 9.24-9.27 (m, 2H), 9.37-
9.38(m,1H),11.16(m,1H)ppm；13C NMR(150MHz,DMSO-d6)δ15.75,29.19,31.23,52.42,
58.29,95.81,108.41.110.75,113.28,120.71,121.50,122.14,126.24,126.27,127.06,
127.36,127.73,128.05,129.07,129.87,134.05,135.36,135.46,137.75,138.05,140.74,
143.23,145.92,149.04,149.58,153.05,154.24,172.06,172.62ppm.
Cytotoxicity test in vitro：
The present invention tests complex 1-3 and ligand L 1 under normal oxygen and anoxia condition, to colon cancer cell HCT116 and
The cytotoxicity of Non-small cell lung carcinoma cell A549, while cis-platinum is as positive controls.
Test result is as shown above, and under normoxic condition, ligand L 1 shows the cell toxicant faint to two kinds of cell line
Property, and the inhibitory activity of complex 1-3 is obvious, IC50For value between 22.8-76.3, the activity of wherein complex 3 is best,
Close to cis-platinum.
Under anoxic conditions, the cytotoxicity of ligand L 1 will be slightly better than normal oxygen situation, in the IC of two kinds of cell line50Value difference
It is 53.7 ± 4.5 and 63.8 ± 2.3, this is because inhibition of the YC-1 for HIF-1 α itself.Cis-platinum is in normal oxygen and anoxia condition
Under cytotoxicity it is similar.The activity of complex 1-3 under anoxic conditions is all than high under normal oxygen, especially complex
3, the IC under anoxic in HCT116 cells and A549 cells50Value is 12.7 ± 0.6 and 15.7 ± 0.6, only normal oxygen item respectively
Half or so under part, more it is worth noting that, two values are below the 19.9 ± 1.3 and 20.9 ± 1.3 of cis-platinum, performance is fallen vacant
It is better than the cytotoxicity of cis-platinum under the conditions of oxygen.
In short, these results indicate that three kinds of complexs have visibly different cytotoxicity under normal oxygen and anoxia condition,
Especially complex 3 is shown to anoxic cancer cell selectivity, significant antiproliferative activity.
Aromatic hydrocarbons-ruthenium complex of the present invention can be used as potential antitumor drug, and for inhibiting anoxic cancer cell to have one
Fixed selectivity.
Claims (10)
1. a kind of aromatic hydrocarbons-ruthenium complex, it is characterised in that the structure of the complex is shown in formula I：
Wherein R indicates 0-6 substituent group, is independently selected from H or C1-6Alkyl；X, Y indicates halogen respectively.
2. aromatic hydrocarbons-ruthenium complex as described in claim 1, it is characterised in that the R is independently selected from H, methyl, different
Propyl, the halogen are F, Cl, Br or I.
3. aromatic hydrocarbons-ruthenium complex as claimed in claim 1 or 2, it is characterised in that the aromatic hydrocarbons-ruthenium complex be complex 1,
2 or 3, the structural formula of complex 1-3 is as follows：
4. a kind of preparation method of aromatic hydrocarbons-ruthenium complex as claimed in claim 3, it is characterised in that this method includes following step
Suddenly：
Step 1: producing YC-2 first：With N,N-dimethylformamide DMF by 1- benzyls -3- (5- methylol -2- furyls) Yin
Azoles YC-1 and succinic anhydride are dissolved in flask, and triethylamine TEA is added, react 4-6 hours at 40-60 DEG C, after reaction solution cools down,
Revolving removes DMF, and after water and dichloromethane DCM extractions is added, organic phase is dried with anhydrous sodium sulfate, filtering, is removed solvent and is obtained
YC-2, structural formula are as follows：
Step 2: synthetic ligands L1：By the YC-2 and 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluoros
Phosphate HATU is dissolved with DMF, addition TEA, and under nitrogen protection, 5- amino -1,10- phenanthrene hello is added after 1-2 hours in stirring at normal temperature
Quinoline, is warming up to 60-70 DEG C, and reaction overnight, after reaction is cooled to room temperature, is spin-dried for removing DMF, silica gel mixed sample, column chromatography for separation,
Ligand L 1 is obtained, the structural formula of ligand L 1 is as follows：
Step 3: ligand L 1 is dissolved in flask with organic solvent, add dihalo- (aryl) ruthenium (II) dimer, room temperature thereto
Stirring 4-6 hours, after after raw material, the reaction was complete, column chromatography for separation obtains aromatic hydrocarbons-ruthenium complex shown in Formulas I.
5. the preparation method of aromatic hydrocarbons-ruthenium complex as claimed in claim 4, it is characterised in that the column chromatography for separation, it is used
Eluant, eluent is the mixture of dichloromethane DCM and methanol MeOH, by volume DCM:MeOH=80:1.
6. the preparation method of aromatic hydrocarbons-ruthenium complex as claimed in claim 4, it is characterised in that the ligand L 1, synthesis step
Organic solvent is dichloromethane or methanol in rapid.
7. the preparation method of aromatic hydrocarbons-ruthenium complex as claimed in claim 4, it is characterised in that dihalo- (aryl) ruthenium (II)
Dimer is [(arene) RuCl2]2、[(C6H6)RuCl2]2Or [(C6Me6)RuCl2]2。
8. a kind of application of aromatic hydrocarbons-ruthenium complex as described in claim 1, it is characterised in that the complex is used to prepare anti-swollen
Tumor medicine.
9. the application of aromatic hydrocarbons-ruthenium complex as claimed in claim 8, it is characterised in that the tumour is hypoxic tumor.
10. the application of aromatic hydrocarbons-ruthenium complex as claimed in claim 9, it is characterised in that the hypoxic tumor is anoxic knot
Intestinal cancer or anoxic lung cancer.
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| CN109232547A (en) * | 2018-10-14 | 2019-01-18 | 苏州华珍医药科技有限公司 | Quinazoline compound and its biomedical uses of the one kind based on YC-1 |
| CN115141148A (en) * | 2021-03-15 | 2022-10-04 | 江苏师范大学 | Bisimidazole ligand, ruthenium supermolecule self-assembly compound with imidazole ligands with different alkoxy chains, preparation method and application |
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| CN109232547A (en) * | 2018-10-14 | 2019-01-18 | 苏州华珍医药科技有限公司 | Quinazoline compound and its biomedical uses of the one kind based on YC-1 |
| CN115141148A (en) * | 2021-03-15 | 2022-10-04 | 江苏师范大学 | Bisimidazole ligand, ruthenium supermolecule self-assembly compound with imidazole ligands with different alkoxy chains, preparation method and application |
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