CN107619425A - A kind of tail is connected to aryl ruthenium complex and its synthetic method and the application of machine guide molecule - Google Patents
A kind of tail is connected to aryl ruthenium complex and its synthetic method and the application of machine guide molecule Download PDFInfo
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- CN107619425A CN107619425A CN201710864836.XA CN201710864836A CN107619425A CN 107619425 A CN107619425 A CN 107619425A CN 201710864836 A CN201710864836 A CN 201710864836A CN 107619425 A CN107619425 A CN 107619425A
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- Prior art keywords
- tail
- aryl ruthenium
- ruthenium complex
- guide molecule
- machine guide
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- 239000012327 Ruthenium complex Substances 0.000 title claims abstract description 58
- 125000003118 aryl group Chemical group 0.000 title claims abstract description 56
- 238000010189 synthetic method Methods 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 21
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 19
- 229940079593 drug Drugs 0.000 claims abstract description 15
- 238000011275 oncology therapy Methods 0.000 claims abstract description 15
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 11
- 150000002894 organic compounds Chemical class 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 19
- 239000003446 ligand Substances 0.000 claims description 19
- -1 p-cymene aryl ruthenium dimer Chemical class 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 229960003720 enoxolone Drugs 0.000 claims description 11
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Natural products CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 238000005119 centrifugation Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 claims description 4
- 239000012298 atmosphere Substances 0.000 claims description 4
- WNIFXKPDILJURQ-UHFFFAOYSA-N stearyl glycyrrhizinate Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=O)OCCCCCCCCCCCCCCCCCC)(C)CC5C4=CC(=O)C3C21C WNIFXKPDILJURQ-UHFFFAOYSA-N 0.000 claims description 4
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
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- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
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- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 2
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- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
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- 239000005695 Ammonium acetate Substances 0.000 description 1
- GUEXVJSBMSLVSW-UHFFFAOYSA-N CC1=CC(=NC=C1)C1=NC=CC(=C1)C.CC1=CC(=NC=C1)C1=NC=CC(=C1)C Chemical group CC1=CC(=NC=C1)C1=NC=CC(=C1)C.CC1=CC(=NC=C1)C1=NC=CC(=C1)C GUEXVJSBMSLVSW-UHFFFAOYSA-N 0.000 description 1
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 101001031591 Mus musculus Heart- and neural crest derivatives-expressed protein 2 Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
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- 229910018162 SeO2 Inorganic materials 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
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- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
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- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 229960005542 ethidium bromide Drugs 0.000 description 1
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- 125000002168 glycyrrhetinic acid group Chemical group 0.000 description 1
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
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- 238000011534 incubation Methods 0.000 description 1
- 231100000405 induce cancer Toxicity 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
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- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General 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)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses the aryl ruthenium complex that a kind of tail is connected to machine guide molecule, the aryl ruthenium complex that tail connects 18 β enoxolones has good targeting and anticancer, antibacterial activity.The synthetic method of the aryl ruthenium complex of machine guide molecule is connected to the invention also discloses above-mentioned tail, this method technological process is simple, easily operated, and yield is high.The present invention finally discloses above-mentioned tail and is connected to application of the aryl ruthenium complex of machine guide molecule in terms of for preparing cancer therapy drug, cancer therapy drug component, antibacterials and antibacterials component.
Description
Technical field
The present invention relates to the aryl ruthenium complex that a kind of tail is connected to machine guide molecule, and in particular to a kind of with 18 β-radix glycyrrhizae time
Acid function group is the aryl ruthenium metal complex of organic guide molecule, further relates to the synthetic method of above-mentioned aryl ruthenium metal complex
And application.
Technical background
Metal Anticancer Drug is widely used in pharmaceutical chemical research due to its unique pharmacological action, wherein clinical
The use of more anti-tumor medicine thing is cis-platinum, carboplatin and oxaliplatin, but platinum medicine is present that efficiency is low, toxic side effect
Greatly, poor selectivity and the shortcomings of resistance, therefore, new and effective, the less toxic antineoplastic of research and development enjoys the world always
Attract attention.Since last century the seventies, aryl ruthenium compound has made substantial progress as the research of anti-cancer active matter, portion
Divide the active anticancer of aryl ruthenium compound suitable with the cis-platinum that current clinical therapeutic efficacy is best, and it is anticancer in following aryl ruthenium
In the structure design of compound, it is efficient that many scientists are considered to build up having the aryl ruthenium compound of Targeting Performance can assign its
The advantages of selective.In this respect, the Peter Sadler seminars of UNIVERSITY OF WARWICK of Britain are by the polypeptide containing receptor target
It is connected on aryl ruthenium complex, the complex after modification has the anticancer mechanism of double selectivity, and the result is published in
J.Am.Chem.Soc periodicals.As can be seen here, aryl ruthenium anticancer complex of the structure with targeting will turn into futuristic design metal
The important research strategy of cancer therapy drug.
The content of the invention
The technical problems to be solved by the invention are to provide the aryl ruthenium complex that a kind of tail is connected to machine guide molecule, the virtue
Base ruthenium complex tail is connected to 18 β-enoxolone functional group as guide molecule, so that its (aryl ruthenium complex) has well
Targeting.
The present invention also technical problems to be solved are to provide the conjunction that above-mentioned tail is connected to the aryl ruthenium complex of machine guide molecule
Into method, this method technological process is simple, easily operated, and yield is high.
Technical problems to be solved of the invention last, which are to provide above-mentioned tail and are connected to the aryl ruthenium complex of machine guide molecule, to exist
Application in terms of for preparing cancer therapy drug, cancer therapy drug component, antibacterials and antibacterials component.
In order to solve the above technical problems, the technical solution adopted in the present invention is：
A kind of tail is connected to the aryl ruthenium complex of machine guide molecule, has following structural formula：
Above-mentioned tail is connected to the synthetic method of the aryl ruthenium complex of machine guide molecule, comprises the following steps：
Step 1, with organic compound of the enoxolone synthesis with 18 β-enoxolone functional group；
Step 2, in an inert atmosphere, by the desired amount of p-cymene aryl ruthenium dimer (p-cymene ruthenous chloride two
Aggressiveness) with step 1 made from organic compound be dissolved in solvent, ether is added after heating response, finally centrifugation obtain needed for
Product.
Wherein, in step 1, the synthetic method with 18 β-enoxolone functional group organic compound is：
In an inert atmosphere, by the desired amount of 18 β-enoxolone and bridge ligand 2- (1- imidazole radicals) ethamine or 4- (4'-
Methyl -2,2'- bipyridyl)-methylamine is dissolved in organic solvent, a certain amount of 1- (3- dimethylaminos are also contained in organic solvent
Propyl group) -3- ethyl-carbodiimide hydrochlorides and I-hydroxybenzotriazole；After mixed material reacts a period of time under certain temperature
Crude product is obtained, crude product can be obtained organising with 18 β-enoxolone functional group after column chromatography isolates and purifies
Compound.
Wherein, in step 1, the structural formula with 18 β-enoxolone functional group organic compound is：
Wherein, in step 2, the reaction mol ratio of the p-cymene aryl ruthenium dimer and organic compound is 5:1~
1:20。
Wherein, in step 2, the solvent is dichloromethane, chloroform, methanol, ethanol or ethylene glycol；Reaction temperature be 2~
90℃。
Wherein, 18 β-enoxolone and bridge ligand 2- (1- imidazole radicals) ethamine or 4- (4'- methyl -2,2'- connection pyrroles
Pyridine)-methylamine reaction mol ratio be 5:1~1:10.In the method for anthropogenics, EDCI (1- (3- dimethylaminos third
Base) -3- ethyl-carbodiimide hydrochlorides) it is used for the activating reagent of carboxyl, HOBt (I-hydroxybenzotriazole) is used for condensation reaction
Catalyst.
Wherein, the organic solvent is DMF or other formamides, acetyl amine solvent；Reaction temperature
For -20~120 DEG C.
Above-mentioned tail is connected to the aryl ruthenium complex of machine guide molecule for preparing cancer therapy drug, cancer therapy drug component, resisting
Application in terms of bacterium medicine and antibacterials component.
Above-mentioned tail, which is connected in the synthetic method of the aryl ruthenium complex of machine guide molecule, has 18 β-enoxolone functional group
Application of the organic compound in terms of for preparing cancer therapy drug and cancer therapy drug component.
Tail of the present invention is connected in the synthetic method of aryl ruthenium complex of machine guide molecule, bridge ligand 2- (1- imidazole radicals)
The preparation method of ethamine is as follows：Step (1), by the desired amount of imidazoles, ethyl acrylate and FeCl3·6H2O is soluble in water, reaction
Extracted after 0.1~15h with dichloromethane, decompression boils off solvent, and crude product is isolated and purified by column chromatography, obtains light yellow liquid
Body；Step (2), hydrazine hydrate and ethanol mixed, the mixture of ethanol and step (1) product is added under heating condition, is heated back
Extracted after 0.2~9h of stream reaction with dichloromethane, decompression boils off solvent, and crude product is isolated and purified by column chromatography, obtains yellow
Grease；Step (3), product, water and the concentrated sulfuric acid in step (2) be added in three-necked bottle, be slowly added dropwise under cryogenic conditions
To containing NaNO2Solution in, 0.3~6h is reacted under heating condition after reacting 0.1~3h, is cooled to room temperature, is hydrogenated with oxygen
Change sodium water solution and adjust PH to 7~11, decompression boils off solvent, methanol is added into residue, filters, and filtrate boils off solvent, thick production
Thing is isolated and purified by column chromatography, and it is 2- (1- imidazole radicals) ethamine to obtain pale yellow oil.
Tail of the present invention is connected in the synthetic method of aryl ruthenium complex of machine guide molecule, bridge ligand 4- (4'- methyl-
2,2'- bipyridyls)-methylamine preparation method is as follows：Step (1), by SeO2(selenium dioxide), Isosorbide-5-Nitrae-dioxide (Isosorbide-5-Nitraes-dioxy
Six rings) and 4,4'-dimethyl-2,2'-bipyridyl (4,4'- dimethyl -2,2'- bipyridyl) be mixed in three-necked bottle,
0.4~15h of reaction is heated at reflux, is reacted after terminating, cold filtration, rotary evaporation of solvent, NaHCO is added in residue3Solution,
Revolving removes solvent after being extracted with dichloromethane, and certain density Na is added in residue2S2O5, filtering, filtrate tune PH to 8~
12, then extracted with dichloromethane, decompression boils off solvent, and product is solid powder；Step (2), by hydroxylamine hydrochloride, K2CO3And step
Suddenly the product of (1) is dissolved in the mixed solution of methanol and water, is reacted under heating condition a period of time, and reaction is cooled to room after terminating
Temperature, appropriate water is added, filter, obtain solid powder；Step (3), the product, ammonium acetate and ammoniacal liquor of step (2) be dissolved in second
In the mixed solution of alcohol and water, a period of time is heated at reflux, adds zinc powder, 0.2~4h is reacted, is cooled to room temperature, is filtered, revolving
Solvent is removed, strong base solution is added, is extracted using dichloromethane, decompression boils off solvent, and it is 4- (4'- first to obtain solid powder
Base -2,2'- bipyridyl)-methylamine.
The present invention have 18 β-enoxolone functional group organic compound through bridge ligand 2- (1- imidazole radicals) ethamine or
Tail, which can be obtained, after the modification of 4- (4'- methyl -2,2'- bipyridyl)-methylamine connects 18 β-virtue of the enoxolone functional group as guide molecule
Base ruthenium complex, the aryl ruthenium complex have good targeting and anticancer antibiotic activity, are coordinated by studying the aryl ruthenium
The anticancer antibiotic activity of thing finds that the activity of double coordination complex will be significantly larger than the activity of monodentate ligand complex.
The reaction chain that tail of the present invention is connected to the aryl ruthenium complex synthetic method of machine guide molecule is：
Compared with prior art, technical solution of the present invention have the advantage that for：
The aryl ruthenium complex that tail of the present invention is connected to machine guide molecule has good targeting and anticancer antibiotic activity, closes
Method technological process into the aryl ruthenium complex is simple, easily operated, and yield is high；Tail of the present invention is connected to machine guide molecule
Aryl ruthenium complex can be applied to prepare cancer therapy drug, cancer therapy drug component, antibacterials and antibacterials component.
Brief description of the drawings
Fig. 1 is the aryl ruthenium complex and the circular dichroism spectrogram of DNA interactions that the tail of embodiment 3 is connected to machine guide molecule；
Fig. 2 is the aryl ruthenium complex and the circular dichroism spectrogram of DNA interactions that the tail of embodiment 4 is connected to machine guide molecule；
Fig. 3 is the electrophoretogram for the aryl ruthenium complex that the tail of embodiment 3 is connected to machine guide molecule；
Fig. 4 is the electrophoretogram for the aryl ruthenium complex that the tail of embodiment 4 is connected to machine guide molecule；
Fig. 5 is that the tail of embodiment 4 is connected to the copolymerization that the aryl ruthenium complex of machine guide molecule promotes reactive oxygen species to generate
Burnt fluorescence imaging figure；
Fig. 6 is the cell streaming figure for the aryl ruthenium complex that the tail of embodiment 4 is connected to machine guide molecule.
Embodiment
Technical scheme is described further below in conjunction with the drawings and specific embodiments.
Embodiment 1
Under argon atmosphere, by 18 β-enoxolone (0.22g, 0.5mmol), EDCI (1.05g, 5.5mmol), HOBt
(0.61g, 4.5mmol) and bridge ligand 2- (1- imidazole radicals) ethamine (0.56g, 5.0mmol) are dissolved in DMF (N, N- diformazans
Base formamide) in, 5h is stirred at 20 DEG C, crude product is isolated and purified by column chromatography, is obtained after bridge ligand is modified
Organic compound L1, yield 58%.
Organic compound L1 structural formula is：
Elementary analysis：Theoretical value (%)：C35H53N3O3·(C3H8O):C 73.15,H 9.85,N 6.74；Experiment value:C
73.24,H 9.62,N 6.66。1H NMR(400Hz,CDCl3):δ7.44(s,1H,HIm),7.10(s,1H,HIm),6.94(s,
1H,HIm), 6.01(s,br,1H,CONH),5.61(s,1H,H18β-GA),4.14(m,2H,HIm),3.61(m,2H,HIm),3.23
(dd,1H, H18β-GA, J1=5.6, J2=10.8Hz), 2.79 (d, 1H, H18β-GA, J=13.6Hz), 2.33-0.69 (42H,
3CH,9CH2 and 7CH3of 18β-GA).ESI-MS(+):Theoretical value：M/z 564.41, experiment value：m/z 564.83.
Embodiment 2
Under argon atmosphere, by 18 β-enoxolone (0.22g, 0.5mmol), EDC (1.05g, 5.5mmol), HOBt
(0.61g, 4.5mmol) and bridge ligand 4- (4'- methyl -2,2'- bipyridyl)-methylamine (1.0g, 5.0mmol) is dissolved in
In DMF, 5h is stirred at 20 DEG C, crude product is isolated and purified by column chromatography, obtains organising after bridge ligand is modified
Compound L2, yield 65%.
Organic compound L2 structural formula is：
Elementary analysis：Theoretical value (%) C42H57N3O3·0.5(CH3OH):C 76.42, H 8.90, N 6.29, experiment value:
C 76.04, H 9.02,N 5.82。1H NMR(400Hz,CDCl3):MR(400Hz,CDClbpy, J=5.2Hz), 8.51 (d,
1H,Hbpy, J=4.8Hz), 8.34 (s, 1H, Hbpy),8.24(s,1H,Hbpy),7.23(d,1H,Hbpy, J=4.0Hz), 7.15
(d,1H,Hbpy, J=4.4Hz), 6.24 (s, br, 1H, CONH), 5.66 (s, 1H, H18β-GA),4.58(m,2H,Hbpy),3.23
(dd,1H,H18β-GA, J1=5.6, J2=10.8Hz), 2.79 (d, 1H, H18β-GA, J=13.2Hz), 2.45 (s, 3H, Hbpy),
2.33-0.69(42H,3 CH,9CH2and 7CH3of 18CH 0.ESI-MS(+):Theoretical value：M/z 652.44, experiment value：m/
z 652.83。
Embodiment 3
Under argon atmosphere, by organic compound L1 (0.07g, 0.1mmol) and p-cymene aryl ruthenium dimer (to umbrella
Flower hydrocarbon ruthenous chloride dimer) (0.31g, 0.5mmol) be dissolved in methanol, after reaction terminates (reaction temperature is 65 DEG C), add
Enter ether, centrifugation obtains the monodentate ligand aryl ruthenium complex 1 with organic guide molecule, yield 87%.
The structural formula of aryl ruthenium complex 1 is：
Elementary analysis：Theoretical value (%) C45H67Cl2N3O3Ru·2(H2O):C 60.86, H 7.76, N 4.83, experiment value:
C C 60.51,H 7.83,N 4.73。1H NMR(400Hz,CDCl3):δ8.22(s,1H,HIm),7.24(s,1H,HIm),6.91
(s, 1H,HIm),6.89(s,br,1H,CONH),5.73(s,1H,H18β-GA),5.41(m,2H,Hbz ofp-cymene),5.27
(d,2H, HbzOfp-cymene, J=6.0Hz), 3.80 (m, 2H, HIm),2.93(m,2H,HIm),3.22(s,1H,H18β-GA),
2.81(d, H18β-GA, J=13.6Hz), 2.46-0.71 (10H, 1CH and 3CH3ofp-cymene),2.34-0.69(m,
42H,3CH, 9CH2and 7CH3of 18β-GA).ESI-MS(+):Theoretical value：[1-Cl-]+m/z:834.36, experiment value：m/z
834.92。
Embodiment 4
Under argon atmosphere, by organic compound L2 (0.06g, 0.1mmol) and p-cymene aryl ruthenium dimer (to umbrella
Flower hydrocarbon ruthenous chloride dimer) (0.31g, 0.5mmol) is dissolved in methanol, and (reaction temperature is 65 DEG C) adds after reaction terminates
Ether, centrifugation obtain the double coordination aryl ruthenium complex 2 with organic guide molecule, yield 85%.
The structural formula of aryl ruthenium complex 2 is：
Elementary analysis：Theoretical value (%) C52H71Cl2N3O3Ru·3(H2O):C 61.71, H 7.67, N 4.15, experiment value:
C 61.29, H 7.58,N 4.36。1H NMR(400Hz,d6-DMSO):δ9.47(d,1H,Hbpy, J=5.6Hz), 9.37 (d,
1H,Hbpy, J=6.0Hz), 8.51 (s, 1H, Hbpy),8.40(s,1H,Hbpy),7.56(d,1H,Hbpy, J=5.6Hz), 7.51
(d,1H,Hbpy, J=6.4Hz), 8.49 (s, br, 1H, CONH), 6.20 (dd, 2H, Hbz ofp-cymene,J1=3.6Hz, J2
=6.4Hz), 5.95 (dd, 2H, Hbz ofp-cymene,J1=2.0Hz, J2=5.2Hz), 5.49 (d, 1H, H18β-GA, J=
13.2Hz),4.52(m, 2H,Hbpy),4.32(d,1H,H18β-GA),3.02(m,1H,H18β-GA),2.56(S,3H,Hbpy),
2.54–0.71(10H,1CH and 3CH3ofp-cymene),2.33-0.69(42H,3CH,9CH2and 7CH3of 18β-
GA).ESI-MS(+):Theoretical value：[2-Cl-]+m/z:923.42, experiment value：m/z 923.08.
There is the present invention organic compound of 18 β-enoxolone functional group and the aryl ruthenium containing organic guide molecule to match somebody with somebody
Research in terms of compound active anticancer：HeLa (cervical carcinoma), A2780 (ovarian cancer cell) and MCF-7 (breast cancer).
Method：MTT colorimetric methods, organic compound and tail of the measure with 18 β-enoxolone functional group are connected to machine guiding
The aryl ruthenium complex of molecule is to people source cancerous cell line (Hela (cervical carcinoma), MCF7 (breast cancer), A2780 (oophoroma)) in body
Outer active anticancer.By Hela, MCF7 and A2780 cells are placed in 10% hyclone and 1% Pen .- Strep solution
DMEM culture mediums in, 37 DEG C, 5%CO2Cultivated in cell culture incubator.Cell is inoculated with the initial density of 5000 cells/wells
Into 96 porocyte culture plates, culture medium is removed after 24 hours of incubation, makees 4 groups of contrast tests, and 4 groups of test groups are separately added into not
With the organic compound L1 (embodiment 1) of concentration, organic compound L2 (embodiment 2), complex 1 (embodiment 3) and complex 2
(embodiment 4), continue to be incubated 44h.Afterwards, 20 μ L MTT solution is added in each test group hole, continues to be incubated 4h, finally
Culture medium is removed, 150mL DMSO is added, shakes 10 minutes, and in ELIASA (Tecan Infinite M1000Pro) enzyme mark
The absorbance at 590nm is read on instrument.
Organic compound L1 made from embodiment 1~4, organic compound L2, metal complex 1 and metal complex 2
Active anticancer is as shown in the table.
Table 1 is 18 β-enoxolone (18 β-GA), organic compound L1, organic compound L2, metal complex 1, metal
The IC of complex 2 and cis-platinum (CDDP)50(μM) value：
As a result show, by N, compared to unmodified enoxolone, it lives the enoxolone after the modification of N- chelands
Property significantly improved, meanwhile, bidentate made from bidentate organic compound L2 made from embodiment 2 and embodiment 4
The activity of coordination aryl ruthenium complex 2 will be significantly larger than monodentate organic compound L1 made from embodiment 1 and embodiment 3 is made
Monodentate ligand aryl ruthenium complex 1, this be probably because double coordination complex stability it is preferable, its chemolysis performance
Preferably match with biotic environment, and the less stable of monodentate ligand complex, and imidazoles is preferably water-soluble in part
Also it have impact on its cellular uptake.
The present invention has application of organic guide molecule aryl ruthenium complex in antibiosis：
Method：Micro broth dilution method, external test have organic guide molecule aryl ruthenium complex to golden yellow grape
The minimum bactericidal concentration of coccus and Escherichia coli (MBC) and minimum inhibitory concentration (MIC).
The strain of exponential phase is inoculated in broth medium and by its concentration dilution to 5 × 105CFU/mL,
The constant gradient antibacterials diluted (0.125-256 μ g/mL) are added in 96 hole plates, then will in advance per the μ l of hole 100
The bacterium solution diluted is added in 96 hole plates, and the final volume per hole is 200 μ l, the ultimate density of antibacterials in such hole
For 0.125-256 μ g/mL, 96 hole plates are placed in and are lined with the pallet of wet absorbent cotton, 37 DEG C of cultures in the case of not shaking
18h.Minimum inhibitory concentration agrees to read the extinction at 600nm on Tecan multi-function microplate reader platform Spark 10M in Switzerland Supreme Being
Degree.Take the μ L culture transferrings of nutrient solution 5 of more than MIC terminals not long bacterium that agar plate is placed in into 37 DEG C on other agar plate
18h is cultivated in insulating box, then the medicine least concentration for cultivating asepsis growth on rear plate is minimum bactericidal concentration (MBC).
The antibacterial activity of aryl ruthenium metal complex 1,2 is as shown in table 2 made from embodiment 3~4.
Table 2 is the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) value of aryl ruthenium metal complex 1,2.
As a result show, be the monodentate ligand aryl ruthenium complex 1 of bridge ligand substantially without antibacterial activity using imidazole radicals, and with
Bipyridyl shows the significant antibacterial activity of comparison for the double coordination aryl ruthenium complex 2 of bridge ligand, and it is to gram
Positive bacterium S. aureus and Gram-negative bacteria Escherichia coli MIC/MBC scope are in 2.0-8.0 μ g/ml, cooperation
Thing 2 is probably due to introducing fat-soluble preferably bipyridyl so as to effectively improving its antibacterial activity.
Tail of the present invention is connected to aryl ruthenium complex and the application of DNA effects of machine guide molecule：
Method one：Circular dichroism detector.Complex 1,2 is studied in PBS cushioning liquid (5mM, pH=7.2) by CD spectrum
With CT-DNA interaction.Prepare a series of (r of different mol ratiosi=[complex]/[CT-DNA], riValue is respectively 0,
0.05,0.1,0.2 sample, wherein, CT-DNA base-pair concentration is set as 100 μM, and it is small to hatch 24 in 37 DEG C of insulating boxs
When.CD spectrum are recorded in the cuvette of 1cm width, scanning range is arranged to 200-600nm, and sweep speed is 100 nm
min-1, slit width 1nm.Tail made from embodiment 3~4 is connected to aryl ruthenium complex 1, the 2 and DNA's of machine guide molecule
Effect is as shown in Fig. 1~2.
As a result show：With the increase of [complex]/[CT-DNA] mol ratios, CT-DNA two positive and negative signal intensity of circle is equal
Gradually weaken, wherein, peak intensity, which weakens, shows that complex shows sedimentation, negative peak remitted its fury occurs with DNA base
Complex makes duplex DNA generating unit decompose rotation by inserting base-pair pattern.This explanation complex 1,2 may be matched somebody with somebody by hydrolysis
Position and embedded intercalation model change DNA secondary structure.
Method two：Agarose gel electrophoresis method.Complex 1,2 and supercoiled plasmid DNA are studied by gel electrophoresis
PBR322 interaction.A series of different mol ratios are prepared in 50mM Tris-HCl (PH=7.4) cushioning liquid
(ri=[complex]/[CT-DNA], riValue is respectively 0,1,2,3,4,5) sample, wherein, CT-DNA base-pair concentration is set as
10 μM, after hatching 24 hours in 37 DEG C of insulating boxs, inwardly add terminate liquid (0.05% bromophenol blue, 50% glycerine and
2mM Na2H2Edta), by the sample point sample prepared in the good hole slot containing 0.8% Ago-Gel paved in advance,
Electrophoresis in TAE (40mM Tris-Acetate, 1mM EDTA, PH=8.3) solution, voltage are set to 70mV, time 120min,
After terminating electrophoresis, using 10mg/ μ l ethidium bromide staining 20min, the gel after dyeing is placed in Bio-Rad molecular imagings Gel
It is imaged under the uviol lamp of Doc XR systems, electrophoretic image needed for acquisition, as shown in figs. 34.
As a result show：Closed circular form plasmid DNA can change its superhelix density after being combined with medicine, so as to change it in gel electricity
Migration rate in swimming.With the increase of the concentration of complex 1,2, supercoil cyclic DNA band gradually decreases, and at loading wells
DNA amount gradually increases, and this explanation complex can induce DNA to polymerize, due to its huge molecular weight and complicated knot
Structure influences mobilities of the DNA in electrophoresis so as to which migration can not occur.Complex 2 and PBR322 interaction result shows
Show, when r value is 3.0, polymerism takes place in DNA, and when r value is 5.0, DNA then occurs to polymerize completely.Complex
1 is similar to complex 2 to PBR322 exercising result, but polymerization of the complex 1 to DNA is more obvious, when r value is
When 3.0, supercoil cyclic DNA band disappears, and there occurs complete polymerism by DNA.Result above shows that complex 1,2 can lure
Lead DNA and polymerism occurs, but the effect of complex 1 becomes apparent, and this is probably because the hydrophily of imidazoles is better than bipyridyl
Hydrophily.
Tail of the present invention is connected to the application that the aryl ruthenium complex 2 of machine guide molecule generates to inducing reactive oxygen species：
Method 1：ROS in flow cytometer monitoring living cells.50 μM of complex 2 is added to cultured in advance
In Hela cells, in 37 DEG C, 5%CO2Hatch 1h in cell culture incubator, then inwardly add 10 μM of DCFHDA continuation lucifuges and incubate
Change 30min.Hatching uses the method for centrifugation to obtain cell after terminating, and the culture medium washing cell for using serum-free is three times, removes
Go to be introduced into intracellular DCFHD.Last flow cytometer (FlowJo 7.6software (Tree Star, OR, USA))
Detect reactive oxygen species.Excitation wavelength is set to 488nm, and wavelength of transmitted light is set to 530 ± 30nm.
Method 2：Laser Scanning Confocal Microscope monitors intracellular ROS.50 μM of complex 2 is added to cultured in advance
In Hela cells, in 37 DEG C, 5%CO2Hatch 2h in cell culture incubator, then inwardly add 10 μM of DCFHDA continuation lucifuges and incubate
Change 30min.Hatching uses the culture medium washing cell of serum-free three times after terminating, removing is introduced into intracellular DCFHD.Then
Confocal microscopy cell fluorescence intensity is used to monitor reactive oxygen species at once.Excitation wavelength is set to 488
Nm, wavelength of transmitted light are set to 530 ± 30nm.
As a result show：Complex 2 substantially can effectively induce the rise of intracellular reactive oxygen content, add under Laser Scanning Confocal Microscope
The fluorescence intensity of medicine is 2 times of non-dosing or so, and this illustrates that such aryl ruthenium for containing the organic guide molecule of enoxolone is matched somebody with somebody
Compound may cause cancer cell that apoptosis occurs by inducing reactive oxygen species generation.
The bridge ligand of the present invention has the functional group of uniquely energy and amino reaction, meanwhile, in the building-up process of complex
In only exist unique coordination site, this brings convenience for follow-up synthesis separation, is easy to improve the yield of reaction product；Obtained tool
The aryl ruthenium complex of organic guide molecule can be used for subsequent analysis research have different structure complex with it is antitumor/resist
Structure-activity relationship between bacterium selectivity.Found in the research to the further anticancer mechanism of aryl ruthenium complex of the present invention, this hair
Bright aryl ruthenium complex can change DNA secondary structure and polymerize DNA, while can also induce reactive oxygen species generation
So as to induce cancer cell that apoptosis occurs, so as to provide preferable reference value as the development for preparing antineoplastic for it.
Claims (10)
1. a kind of tail is connected to the aryl ruthenium complex of machine guide molecule, it is characterised in that has following structural formula：
2. tail described in claim 1 is connected to the synthetic method of the aryl ruthenium complex of machine guide molecule, it is characterised in that including such as
Lower step：
Step 1, with organic compound of the enoxolone synthesis with 18 β-enoxolone functional group；
Step 2, in an inert atmosphere, by organic compound made from the desired amount of p-cymene aryl ruthenium dimer and step 1
It is dissolved in solvent, ether is added after heating response, finally centrifugation obtains required product.
3. tail is connected to the synthetic method of the aryl ruthenium complex of machine guide molecule according to claim 2, it is characterised in that：Step
In rapid 1, the synthetic method with 18 β-enoxolone functional group organic compound is：
In an inert atmosphere, by the desired amount of 18 β-enoxolone and bridge ligand 2- (1- imidazole radicals) ethamine or 4- (4 '-first
Base -2,2 '-bipyridyl)-methylamine is dissolved in organic solvent, a certain amount of 1- (3- dimethylaminos third are also contained in organic solvent
Base) -3- ethyl-carbodiimide hydrochlorides and I-hydroxybenzotriazole；Mixed material obtains after a period of time is reacted under certain temperature
To crude product, crude product can be obtained after column chromatography isolates and purifies to have 18 β-enoxolone functional group organic compound
Thing.
4. tail is connected to the synthetic method of the aryl ruthenium complex of machine guide molecule according to claim 2, it is characterised in that：Step
In rapid 1, the structural formula with 18 β-enoxolone functional group organic compound is：
5. tail is connected to the synthetic method of the aryl ruthenium complex of machine guide molecule according to claim 2, it is characterised in that：Step
In rapid 2, the reaction mol ratio of the p-cymene aryl ruthenium dimer and organic compound is 5: 1~1: 20.
6. tail is connected to the synthetic method of the aryl ruthenium complex of machine guide molecule according to claim 2, it is characterised in that：Step
In rapid 2, the solvent is dichloromethane, chloroform, methanol, ethanol or ethylene glycol.
7. tail is connected to the synthetic method of the aryl ruthenium complex of machine guide molecule according to claim 3, it is characterised in that：Institute
State the reaction of 18 β-enoxolone and bridge ligand 2- (1- imidazole radicals) ethamine or 4- (4 '-methyl -2,2 '-bipyridyl)-methylamine
Mol ratio is 5: 1~1: 10.
8. tail is connected to the synthetic method of the aryl ruthenium complex of machine guide molecule according to claim 3, it is characterised in that：Institute
It is DMF to state organic solvent.
9. tail described in claim 1 is connected to the aryl ruthenium complex of machine guide molecule for preparing cancer therapy drug, cancer therapy drug
Application in terms of component, antibacterials and antibacterials component.
10. tail described in claim 4, which is connected in the synthetic method of the aryl ruthenium complex of machine guide molecule, has 18 β-radix glycyrrhizae time
Application of acid function group's organic compound in terms of for preparing cancer therapy drug and cancer therapy drug component.
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| CN108530343A (en) * | 2018-04-08 | 2018-09-14 | 南京师范大学 | A kind of organic compound of Rhein special groups modification, its metal aryl complex, and its preparation method and application |
| WO2021139395A1 (en) * | 2020-01-08 | 2021-07-15 | 南京师范大学 | High-efficiency low-toxicity anti-cancer compound synthesized by autocatalysis in cells and living bodies and synthesis method for anti-cancer compound |
| CN113336797A (en) * | 2021-04-06 | 2021-09-03 | 江西科技师范大学 | Ruthenium polypyridine complex with triphenylphosphine structure and preparation method and application thereof |
| CN116375788A (en) * | 2023-03-20 | 2023-07-04 | 南京中医药大学 | Anti-carbapenem acinetobacter baumannii glycyrrhetinic acid-gold complex and preparation method and application thereof |
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| CN113072611B (en) * | 2021-04-06 | 2024-02-06 | 江西科技师范大学 | Preparation method of glycyrrhetinic acid modified polypyridine ruthenium complex antibacterial agent |
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| CN100488979C (en) * | 2005-10-14 | 2009-05-20 | 天津药物研究院 | Glycyrrhetinic acid-30-acylamide derivatives and its use |
| CN105315321B (en) * | 2014-07-01 | 2018-10-16 | 思路迪（北京）医药科技有限公司 | Compound and its preparation method and application with antitumor action |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108530343A (en) * | 2018-04-08 | 2018-09-14 | 南京师范大学 | A kind of organic compound of Rhein special groups modification, its metal aryl complex, and its preparation method and application |
| CN108530343B (en) * | 2018-04-08 | 2021-07-27 | 南京师范大学 | Rhein specific group modified organic compound, aryl metal complex thereof, preparation method and application thereof |
| WO2021139395A1 (en) * | 2020-01-08 | 2021-07-15 | 南京师范大学 | High-efficiency low-toxicity anti-cancer compound synthesized by autocatalysis in cells and living bodies and synthesis method for anti-cancer compound |
| CN113336797A (en) * | 2021-04-06 | 2021-09-03 | 江西科技师范大学 | Ruthenium polypyridine complex with triphenylphosphine structure and preparation method and application thereof |
| CN113336797B (en) * | 2021-04-06 | 2022-09-27 | 江西科技师范大学 | Ruthenium polypyridine complex with triphenylphosphine structure and preparation method and application thereof |
| CN116375788A (en) * | 2023-03-20 | 2023-07-04 | 南京中医药大学 | Anti-carbapenem acinetobacter baumannii glycyrrhetinic acid-gold complex and preparation method and application thereof |
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| CN108929360B (en) | 2020-11-20 |
| CN108929360A (en) | 2018-12-04 |
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