CN108250250B - Complex containing 1,1, 1-triphenyl-N- (1- (pyridine-2-) methylene) methylamine, preparation method and application - Google Patents
Complex containing 1,1, 1-triphenyl-N- (1- (pyridine-2-) methylene) methylamine, preparation method and application Download PDFInfo
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- CN108250250B CN108250250B CN201810070816.XA CN201810070816A CN108250250B CN 108250250 B CN108250250 B CN 108250250B CN 201810070816 A CN201810070816 A CN 201810070816A CN 108250250 B CN108250250 B CN 108250250B
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- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims description 8
- 230000001093 anti-cancer Effects 0.000 claims abstract description 20
- 239000000126 substance Substances 0.000 claims abstract description 9
- 238000003384 imaging method Methods 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 32
- 239000013078 crystal Substances 0.000 claims description 24
- 238000009792 diffusion process Methods 0.000 claims description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 19
- 229910052751 metal Inorganic materials 0.000 claims description 16
- 239000002184 metal Substances 0.000 claims description 16
- 229910021135 KPF6 Inorganic materials 0.000 claims description 15
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 15
- 229910052741 iridium Inorganic materials 0.000 claims description 14
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 14
- 150000003303 ruthenium Chemical class 0.000 claims description 13
- 229910052707 ruthenium Inorganic materials 0.000 claims description 13
- 150000002503 iridium Chemical class 0.000 claims description 9
- 239000004305 biphenyl Substances 0.000 claims description 4
- 229930007927 cymene Natural products 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000000352 p-cymenyl group Chemical group C1(=C(C=C(C=C1)C)*)C(C)C 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims 6
- 238000001914 filtration Methods 0.000 claims 6
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- 239000003446 ligand Substances 0.000 abstract description 6
- 238000011160 research Methods 0.000 abstract description 6
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- 150000001450 anions Chemical class 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 229910052739 hydrogen Inorganic materials 0.000 description 17
- 239000001257 hydrogen Substances 0.000 description 17
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 12
- 150000002431 hydrogen Chemical group 0.000 description 10
- 150000004696 coordination complex Chemical class 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 229940041181 antineoplastic drug Drugs 0.000 description 7
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 7
- 229960004316 cisplatin Drugs 0.000 description 6
- 230000005311 nuclear magnetism Effects 0.000 description 6
- 229910052697 platinum Inorganic materials 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000005909 Kieselgur Substances 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
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- 150000001875 compounds Chemical class 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- UGTJLJZQQFGTJD-UHFFFAOYSA-N Carbonylcyanide-3-chlorophenylhydrazone Chemical compound ClC1=CC=CC(NN=C(C#N)C#N)=C1 UGTJLJZQQFGTJD-UHFFFAOYSA-N 0.000 description 3
- 239000012327 Ruthenium complex Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 3
- 230000012202 endocytosis Effects 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
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- 230000004071 biological effect Effects 0.000 description 2
- 230000004700 cellular uptake Effects 0.000 description 2
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- 229960003677 chloroquine Drugs 0.000 description 2
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 2
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- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
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- 150000002739 metals Chemical class 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 125000002524 organometallic group Chemical group 0.000 description 2
- 125000002097 pentamethylcyclopentadienyl group Chemical group 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
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- 108010024636 Glutathione Proteins 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 150000004982 aromatic amines Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960004562 carboplatin Drugs 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
- 238000004113 cell culture Methods 0.000 description 1
- 238000000006 cell growth inhibition assay Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
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- 230000008045 co-localization Effects 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Chemical group 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical group [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
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- 206010013663 drug dependence Diseases 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005347 halocycloalkyl group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
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- 210000005061 intracellular organelle Anatomy 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000004020 luminiscence type Methods 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
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- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical group [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 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
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Chemical group 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical group [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
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- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
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- 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
- C07F15/0033—Iridium compounds
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- 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
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physics & Mathematics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
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- General Health & Medical Sciences (AREA)
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Abstract
The invention specifically relates to a complex containing 1,1, 1-triphenyl-N- (1- (pyridine-2-) methylene) methylamine, belonging to the field of chemical pharmacy. The molecular structural formula of the complex is as follows:
the complex prepared by the invention can endow the whole complex with high anti-cancer activity, mitochondrial targeting and nuclear targeting, has selectivity on cancer cells and has great significance on the research of drug targeting; the invention takes N ^ N as an anion ligand chelated by two teeth to synthesize a novel complex with higher anticancer activity, and the complex has good effect and high activity in anticancer and cell imaging; the method has the advantages of simple process, low cost, easy control of chemical components, good repeatability, high yield and the like.
Description
Technical Field
The invention relates to a metal complex, in particular to a complex containing 1,1, 1-triphenyl-N- (1- (pyridine-2-) methylene) methylamine, a preparation method and application thereof, belonging to the field of chemical pharmacy.
Background
In 1965, the synthesis of cisplatin drastically changed the current situation of cancer treatment by radiotherapy alone, and many cisplatin derivatives derived therefrom have also been biologically evaluated. With the continuous and intensive research, three platinum anticancer drugs of cisplatin, carboplatin and oxaliplatin become metal anticancer drugs approved worldwide and are the only metal-based anticancer drugs used in clinic worldwide. Metal complexes are used for about 50% of all tumors, but their use is often accompanied by toxic side effects such as nephrotoxicity and drug dependence, etc., and one of the most important limitations with platinum-based anticancer drugs is inactivation by small cellular molecules (in particular glutathione) and shedding of cells. In order to overcome the limitations of cisplatin in pharmaceutical research, new channels are continuously developed to become main strategies meeting the challenges, including seeking to use metal complexes except platinum and changing the basic framework structure of the complexes, and the iridium shows various good biological activities to make the complexes enter the public visual field. Based on the chemical differences between these metals, the spectral behavior of the molecular mechanism and the underlying indications can be greatly expanded, thereby maximizing the impact on cancer cells and minimizing the problem of their adverse side effects. Therefore, extensive research into transition metal drugs to combat malignant tumors is the current trend.
In recent years, the iridium (Ir) complex with antitumor activity is reported in succession, and the pentamethylcyclopentadienyl IrIII organometallic complex is discovered by Liuji, Peter J. Saler and the like to be used as a novel complex with anticancer activity and can be used as a potential anticancer drug. The pentamethyl cyclopentadienyl IrIII organometallic complex synthesized at present is mostly an iridium complex of an N ^ N, C ^ C or C ^ N ligand. The ruthenium complex is an internationally recognized anti-tumor drug with the most development potential, and is one of metals which are hopeful to become low in toxicity and high in activity after platinum is used. At present, hundreds of ruthenium complexes are synthesized. In 1987 Keppler synthesized ICR which gave good results in vivo. Alessio synthesized naffa in 1998, which was the 1 st clinically-entered ruthenium complex, followed by naffa by KP1019, which was the 2 nd clinically-entered nail complex. The anticancer activity of the complex prepared in the prior art still needs to be improved, and no research on imaging of self-luminescence of a half-sandwich structure in cells is available.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a complex containing 1,1, 1-triphenyl-N- (1- (pyridine-2-) methylene) methylamine, which is a semi-sandwich metal complex.
The invention also provides a preparation method of the complex containing 1,1, 1-triphenyl-N- (1- (pyridine-2-) methylene) methylamine.
The invention also provides application of the semi-sandwich metal complex.
The technical scheme adopted by the invention for realizing the purpose is as follows:
the invention provides a complex containing 1,1, 1-triphenyl-N- (1- (pyridine-2-) methylene) methylamine, wherein the molecular structural formula of the metal complex is as follows:
І
in the formula (І), R1 is aryl, arylamine, arylol, cymene or halogenated aryl, cyclopentadienyl, 1.2.3.4.5-pentamethyl cyclopentadienyl, and cyclopentadienyl substituted by halogenated cycloalkyl, halogenated aryl, aryl or halogen; r2 is hydrogen, alkyl, amino, alcoholic hydroxyl, halogen or haloalkyl, halocycloalkyl; m is a platinum group metal.
Further, M is iron, ruthenium, osmium, platinum, cobalt, rhodium and iridium.
Further, the optimized chemical structural formula of the synthesized complex is as follows:
the invention also provides a preparation method of the complex, which is characterized in that the complex shown in the formula (I) is obtained by reacting the iridium dimer shown in the formula (II) with the iridium dimer shown in the formula (III):
further, when the complex is a complex 1-6, the specific steps are as follows:
the complex 1: 50.0mg of iridium dimer (formula (I) R1 is 1.2.3.4.5-pentamethylcyclopentadienyl, R2 is hydrogen and M is metallic iridium), 46.3mg of 1,1, 1-triphenyl-N- (1- (pyridin-2-) methylene) methylamine are placed in a 250mL Schink (Schlenk) flask, evacuated, under nitrogen three times, 20mL of analytically pure ethanol are added with a needle, stirred at room temperature for 24h, 60 mg of KPF6 is added, spun dry with a rotary evaporator, dissolved with CH2Cl2, filtered over diatomaceous earth and recrystallized by diffusion to give red crystals.
And (2) the complex: 50.0mg of iridium dimer (formula (I) R1 is 4- (2.3.4.5-tetramethylcyclopentadienyl) -1' 1-biphenyl, R2 is hydrogen and M is metallic iridium), 43.6 mg of 1,1, 1-triphenyl-N- (1- (pyridin-2-yl) ethylene) methylamine are placed in a 250mL Schilek (Schlenk) flask, evacuated and stirred with nitrogen three times, 20mL of analytically pure ethanol is added via a needle, stirred at room temperature for 24h, 60 mg of KPF6 is added, spun dry using a rotary evaporator, then dissolved with CH2Cl2, filtered through celite, and recrystallized by diffusion to give red crystals.
And (3) complex: 50.0mg of ruthenium dimer (formula (III) R1 is phenyl, R2 is hydrogen, M is metallic ruthenium), 63.1mg of 1,1, 1-triphenyl-N- (1- (pyridin-2-yl) ethylene) methylamine are placed in a 250mL Schiek (Schlenk) flask, evacuated, mixed with nitrogen three times, 20mL of analytically pure ethanol are added via a needle, stirred at room temperature for 24h, 60 mg of KPF6 are added, spun dry on a rotary evaporator, dissolved in CH2Cl2, filtered through celite, and recrystallized by diffusion to give red crystals.
The complex 4: 50.0mg of ruthenium dimer (formula (III) R1 is cymene, R2 is hydrogen, M is metallic ruthenium), 57.5mg of 1,1, 1-triphenyl-N- (1- (pyridin-2-yl) ethylene) methylamine are placed in a 250mL Schiek (Schlenk) flask, evacuated, combined with nitrogen three times, 20mL of analytically pure ethanol is added with a needle, stirred at room temperature for 24h, 60 mg of KPF6 is added, spun dry with a rotary evaporator, dissolved with CH2Cl2, filtered through celite, and recrystallized by diffusion to give red crystals.
And (3) a complex 5: 50.0mg of ruthenium dimer (formula (III) R1 is 3- (1.4-cyclohexadiene) -propanol, R2 is hydrogen, M is metallic ruthenium), 60.0mg of 1,1, 1-triphenyl-N- (1- (pyridin-2-yl) ethylene) methylamine are placed in a 250mL Hirak (Schlenk) flask, evacuated with nitrogen three times, 20mL of analytically pure ethanol is added with a needle, stirred at room temperature for 24h, 60 mg of KPF6 is added, spun dry with a rotary evaporator, then dissolved with CH2Cl2, filtered through celite, and recrystallized by diffusion to give red crystals.
The complex 6: 50.0mg of ruthenium dimer (formula (III) 4- (1, 4-cyclohexadiene) -butanol, R2 hydrogen, M metallic ruthenium), 51.9mg of 1,1, 1-triphenyl-N- (1- (pyridin-2-yl) ethylene) methylamine in a 250mL Schlenk flask, evacuated in a vacuum with nitrogen three times, 20mL of analytically pure ethanol added via a needle, stirred at room temperature for 24h, 60 mg of KPF6 added, spun dry using a rotary evaporator, dissolved in CH2Cl2, filtered through celite, and recrystallized by diffusion to give red crystals.
The invention also provides application of the semi-sandwich metal complex in anti-cancer and cell imaging drugs.
The coordination center atom of the N ^ N ligand in the metal complex prepared by the invention is of an electronic asymmetric structure, and the nitrogen atom is a very strong sigma-electron donor and can stabilize metal; the phenyl group has a certain conjugation effect and can provide variability for the chemical and biological activity of the complex. Therefore, N ^ N is synthesized as a neutral ligand chelated by two teeth, and is a novel metal complex with high anticancer activity and capable of imaging in cells.
The invention has the beneficial effects that:
(1) the complex prepared by the invention can endow the whole complex with high anticancer activity, mitochondrial targeting and nuclear targeting, has selectivity on cancer cells and has great significance on the research of drug targeting.
(2) The invention takes N ^ N as an anion ligand chelated by two teeth to synthesize a novel complex with higher anticancer activity, and the complex has good effect and high activity in anticancer and cell imaging.
(3) The method has the advantages of simple process, low cost, easy control of chemical components, good repeatability, high yield and the like.
Drawings
FIG. 1 shows the nuclear magnetic hydrogen spectrum of complex 1 prepared in example 1 of the present invention.
FIG. 2 shows the single crystal structure of complex 2 prepared in example 2 of the present invention.
FIG. 3 is a nuclear magnetic hydrogen spectrum of complex 2 prepared in example 2 of the present invention.
FIG. 4 shows a single crystal structure of complex 3 prepared in example 3 of the present invention.
FIG. 5 is a nuclear magnetic hydrogen spectrum of complex 3 prepared in example 3 of the present invention.
FIG. 6 shows the single crystal structure of complex 4 prepared in example 4 of the present invention.
FIG. 7 shows the nuclear magnetic hydrogen spectrum of complex 4 prepared in example 4 of the present invention.
FIG. 8 is a nuclear magnetic phosphorus spectrum of complex 5 prepared in example 5 of the present invention.
FIG. 9 is a nuclear magnetic carbon spectrum of complex 6 prepared in example 6 of the present invention.
FIG. 10 is an image of a complex of the present invention targeting intracellular organelles.
FIG. 11 is a study of the intracellular uptake mechanism of the complex of the present invention.
Detailed Description
The invention is further illustrated by the following examples of some representative compounds, which are not intended to limit the invention.
The starting compounds used in the synthesis of the compounds are commercial products or can be prepared from known synthetic methods, all methods for the preparation of organic compounds are available from the literature and are fundamental and obvious to the synthetic chemist. The following description of the synthetic methods may therefore be considered in detail and specific.
Example 1
50.0mg of iridium dimer (formula (I) R1 is 1.2.3.4.5-pentamethylcyclopentadienyl, R2 is hydrogen and M is metallic iridium), 46.3mg of 1,1, 1-triphenyl-N- (1- (pyridin-2-) methylene) methylamine are placed in a 250mL Schink (Schlenk) flask, evacuated, admixed with nitrogen three times, with 20mL of analytically pure ethanol being added via a needle, stirred at room temperature for 24h, 60 mg of KPF6 are added, spun dry using a rotary evaporator, dissolved in CH2Cl2, filtered over kieselguhr and recrystallized by diffusion to give red crystals. Yield 52.48 mg (61.3%).
The nuclear magnetism was characterized as [ (η -Cp) Ir (N ^ N) Cl ] PF6 (1). 1H NMR (500 MHz, DMSO) delta 8.61 (d, J = 4.7 Hz,1H), 8.33 (d, J = 7.9 Hz,1H), 7.98 (t, J = 7.0Hz, 1H), 7.77 (s, 1H), 7.51 (ddd, J = 7.5, 4.8, 1.1 Hz,1H), 7.37 (t, J = 7.5, 6H), 7.31 (t, J = 7.3Hz, 3H), 7.24-7.21 (m, 6H), 1.75 (s, 15H), anal. Calcd. For [ (η -Cp) Ir (N ^ N) Cl ] PF (32, 19H ]: 6, 18H ], 3H ] (N ^ N): 17H ], 3H, 18H ]: 17H, 3H.
Example 2
50.0mg of iridium dimer (formula (I) R1 is 4- (2.3.4.5-tetramethylcyclopentadiene) -1' 1-biphenyl, R2 is hydrogen, M is metallic iridium), 43.6 mg of 1,1, 1-triphenyl-N- (1- (pyridin-2-yl) ethylene) methylamine are placed in a 250mL Schilek (Schlenk) flask, evacuated and nitrogen three times, 20mL of analytically pure ethanol is added through a needle, stirred at room temperature for 24h, 60 mg of KPF6 is added, spun dry with a rotary evaporator, dissolved with CH2Cl2, filtered through diatomaceous earth, and recrystallized by diffusion to give red crystals, and the single crystal structure of complex 2 is shown in FIG. 2. Yield 40.05mg (40.3%).
As shown in FIG. 3, the nuclear magnetism is characterized by [ (η -Cpxbiph) Ir (N ^ N) Cl ] PF6 (2); Yield: 40.05mg, 40.3%.1H NMR (500 MHz, DMSO) delta 13.59 (d, J = 9.6 Hz, 2H), 9.54 (d, J =9.7 Hz, 3H), 8.80 (d, J = 5.4Hz, 2H), 8.57-8.13 (m, 5H), 8.05-7.65 (m,8H), 7.64-7.23 (m,8H), 1.83 (dd, J = 33.5, 10.8 Hz, 12H), anal. Calcd. For [ (η -Cpxbiph) Ir (N ^ N) Cl ] PF6 (994.47) C, 55.56; 4.16, 82, 2. UN N.3H ] (2N) [ (26H): F, 5-Cp N): 2H) [ (3H): 389.3H, 18H ]: F, 2H, 3%: F, 3H, 5H, 3H, III [ (3H ]: F ]: C.
Example 3
50.0mg of ruthenium dimer (formula (III) R1 is phenyl, R2 is hydrogen, M is metallic ruthenium), 63.1mg of 1,1, 1-triphenyl-N- (1- (pyridin-2-yl) ethylene) methylamine are placed in a 250mL Schiek (Schlenk) flask, evacuated, mixed with nitrogen three times, 20mL of analytically pure ethanol is added through a needle, stirred at room temperature for 24h, 60 mg of KPF6 is added, spun dry with a rotary evaporator, then dissolved with CH2Cl2, filtered through celite, and recrystallized by diffusion to obtain red crystals, and the single crystal structure of complex 3 is shown in FIG. 4. Yield 45.43 mg (61.3%).
As shown in FIG. 5, the nuclear magnetism was characterized as [ (η -bz) Ru (N ^ N) Cl ] PF6 (3). 1H NMR (500 MHz, DMSO) delta 9.63 (d, J = 5.3 Hz,1H), 8.78 (s, 1H), 8.32 (d, J = 7.9 Hz,1H), 8.26 (t, J = 8.2 Hz,1H), 7.89-7.86 (m, 1H), 7.45 (ddd, J = 27.3, 19.4, 7.3Hz, 15H), 5.61 (s, 6H), anal. Calcd. For [ (η -bz) Ir (N ^ N) Cl ] PF6 (708.04): C,52.59; H, 3.70; N, 3.96; un: C, 50.20; H, 3.62; N, 3.86: 6. 389.86) < 6 > Ir ^ N > (5.6H) < 6H) ].
Example 4
50.0mg of ruthenium dimer (formula (III) R1 is cymene, R2 is hydrogen, M is metallic ruthenium), 57.5mg of 1,1, 1-triphenyl-N- (1- (pyridin-2-yl) ethylene) methylamine are placed in a 250mL Schiek (Schlenk) flask, evacuated, mixed with nitrogen three times, 20mL of analytically pure ethanol is added through a needle, stirred at room temperature for 24h, 60 mg of KPF6 is added, spun dry with a rotary evaporator, dissolved with CH2Cl2, filtered with diatomaceous earth, and recrystallized by diffusion to obtain red crystals, and the single crystal structure of complex 4 is shown in FIG. 6. Yield 55.31 mg, 72.4%.
As shown in FIG. 7, the nuclear magnetism was characterized as [ (η -p-cym) Ru (N ^ N) Cl ] PF6 (4). 1H NMR (500 MHz, CDCl3) delta 9.48 (s, 1H), 8.37 (s, 2H), 8.06 (s, 2H), 7.84 (d, J = 61.2 Hz, 3H),7.47 (dd, J = 46.9, 7.3Hz, 12H), 5.83 (s, 1H), 5.27 (s, 1H), 4.71 (s, 1H),4.48 (s, 1H), 2.43 (s, 1H), 2.17 (s, 3H), 1.00-0.76 (m, 6H), anal. cd.389 [ (5-p-cym) Ir (N ^ N) Cl ] PF 63, 48364, 5H, 6748H ], 5.75H, 3H ] (n.75-10H), N.75H ] (n.75H): 3648H 8H, 75H, 3H ] (75H), 5H, 75H, 3H): 3648H 8H, 3H, III.
Example 5
50.0mg of ruthenium dimer (formula (III) R1 is 3- (1.4-cyclohexadiene) -propanol, R2 is hydrogen, M is metallic ruthenium), 60.0mg of 1,1, 1-triphenyl-N- (1- (pyridin-2-yl) ethylene) methylamine are placed in a 250mL Hirak (Schlenk) flask, evacuated with nitrogen three times, 20mL of analytically pure ethanol is added with a needle, stirred at room temperature for 24h, 60 mg of KPF6 is added, spun dry with a rotary evaporator, then dissolved with CH2Cl2, filtered through celite, and recrystallized by diffusion to give red crystals. Yield 53.51 mg (69.8%).
As shown in FIG. 8, the nuclear magnetism is characterized by [ (η -bz-PA) Ru (N ^ N) Cl ] PF6 (5). 1H NMR (500 MHz, DMSO) delta 9.57 (d, J = 5.3 Hz,1H), 8.76 (s, 1H), 8.35-8.21 (m, 3H), 7.92-7.81 (m, 2H), 7.45 (ddd, J = 26.9, 15.6, 7.3Hz, 13H), 5.71 (t, J = 6.0 Hz,1H), 5.66 (d, J = 6.3 Hz,1H), 5.38 (t, J = 5.6 Hz,1H), 5.03-4.96 (m, 2H),4.55 (t, J = 5.0 Hz,1H), 2.45-2.38 (m, 2H), 1.65 (ddd = 5.9, 12, J = 5.9, 13H), 2H, 11H, 3H, 11H, 3H, 11H, 3.
Example 6
50.0mg of ruthenium dimer (formula (III) 4- (1, 4-cyclohexadiene) -butanol, R2 hydrogen, M metallic ruthenium), 51.9mg of 1,1, 1-triphenyl-N- (1- (pyridin-2-yl) ethylene) methylamine in a 250mL Schlenk flask, evacuated in a vacuum with nitrogen three times, 20mL of analytically pure ethanol added via a needle, stirred at room temperature for 24h, 60 mg of KPF6 added, spun dry using a rotary evaporator, dissolved in CH2Cl2, filtered through celite, and recrystallized by diffusion to give red crystals. Yield 50.72 mg (65.0%).
As shown in FIG. 9, the nuclear magnetism is characterized by [ (η -bz-BA) Ru (N ^ N) Cl ] PF6 (6). 1H NMR (500 MHz, DMSO) delta 9.56 (d, J = 5.4Hz, 1H), 8.76 (s, 1H), 8.31 (d, J =6.5 Hz,1H), 8.26 (t, J = 7.7 Hz,1H), 7.88 (t, J = 5.8 Hz,1H), 7.45 (ddd, J = 26.8,14.7, 7.3Hz, 13H), 5.73 (dd, J = 13.6, 7.7 Hz, 2H), 5.64 (d, J = 5.9 Hz,1H), 5.40 (t, J = 5.6 Hz,1H), 5.02 (t, J = 6.0, 1H), 4.96.96 =6, J = 5.9 Hz,1H), 5.3H [ (N ^ N, 7H, 1H ] (N, 26H): 19H, 3H, 19H, 3H, 2H, 3H.
Comparative example 1
Synthesis of Complex 7 [ (η 5-C5Me5) Ir (L1) Cl ] PF6 (7) 50.0mg of an iridium dimer (formula (I) R1 is 1.2.3.4.5-pentamethylcyclopentadienyl, formula L1, M is metallic iridium), 40.2 mg of L1 are placed in a 250mL Hilac (Schlenk) flask, evacuated, purged with nitrogen three times, 20mL of analytically pure ethanol are added via a needle, stirred at room temperature for 24h, 60 mg of KPF6 is added, spin-dried using a rotary evaporator, then dissolved with CH2Cl2, filtered through diatomaceous earth and recrystallized by diffusion to give a red crystal yield 37.5 mg, 52.2%.
1H NMR (500 MHz, DMSO-d6) δ 9.52 (s, 1H), 9.05 (d, J = 5.5 Hz, 1H),8.37 (dt, J = 15.2, 6.4 Hz, 2H), 8.00 – 7.97 (m, 1H), 7.38 – 7.35 (m, 1H),7.30 (dd, J = 8.0, 5.5 Hz, 2H), 2.29 (s, 3H), 2.09 (s, 3H), 1.42 (s, 15H).13C NMR (126 MHz, DMSO-d6) δ 174.30 (s), 155.37 (s), 152.99 (s), 147.10 (s),141.17 (s), 132.28 (s), 131.32 (s), 130.53 (d, J = 15.4 Hz), 129.72 (s),129.15 (s), 128.87 (s), 90.98 (s), 19.93 (s), 19.11 (s). Anal. Calcd. for [(η5-C5Me5)Ir(L1)Cl]PF6 (718.13): C, 40.14; H, 4.07; N, 3.90; Found: C, 40.02;H, 4.02; N, 3.83. MS: m/z 538.61 [(η5-C5Me5)Ir(L2) + H]+。
The complex 7 prepared in this comparative example had poor cell imaging effect.
Effects of the embodiment
(I) proliferation inhibition activity experiment of complexes 1-6 with anticancer activity on tumor cell strains:
(1) preparation of test compound:
respectively dissolving the solid complexes 1-5 in DMSO to prepare stock solutions with a certain concentration, further diluting the stock solutions with a cell culture solution until the working concentration is reached, and culturing for 24 hours;
(2) cell growth inhibition assay (MTT method):
1) 5000 cervical cancer cells (HeLa) or lung cancer cells (A549) are prepared into cell suspension and inoculated into a 96-hole culture plate;
2) pre-culturing cells by using a drug-free culture medium, incubating for 24 hours by using 5% CO2 and 310K, adding a prepared compound to be tested, and culturing for 24 hours;
3) after 15. mu.L of 5 mg/mL MTT solution was added to each well, the culture was continued for 4 hours to form formazan as a purple crystalline substance;
4) terminating the culture, carefully removing the culture solution in the wells, adding 100. mu.L of DMSO into each well to sufficiently dissolve formazan precipitate, uniformly mixing with an oscillator, and measuring the optical density of each well with a microplate reader at a wavelength of 570 nm;
5) each experiment was repeated three times, IC50= mean ± SEM
The inhibition rates of the complexes 1-6 and cisplatin on the growth of cervical cancer cells (HeLa) and lung cancer cells (A549) are shown in Table 1.
TABLE 1
As can be seen from the table 1, the changes of the 1-6 cyclopentadienyl ring R1 and the metal of the complex have great influence on two cancer cells, for A549 cells, the anticancer activity of the complexes 2 and 3 is basically equal to that of a commercial cis-platinum anticancer drug, the anticancer activity of the complex 5 is slightly weaker than that of cisplatin, and the anticancer activity of the complex 1 is about 4 times that of cisplatin. In addition, when M is metal iridium, R1 is changed from 4- (2.3.4.5-tetramethylcyclopentadiene) -1' 1-biphenyl to 1.2.3.4.5-pentamethylcyclopentadienyl, the anticancer activity is improved by about 5 times; when the 3- (1, 4-cyclohexadiene) -propanol at the R1 position is changed into 4- (1, 4-cyclohexadiene) -butanol when M is metallic ruthenium, the anticancer activity is reduced; compared with ruthenium and iridium, the anticancer activity of the metal iridium complex is obviously higher than that of the metal ruthenium complex. The anticancer activity of the metal complex containing the 1,1, 1-triphenyl-N- (1- (pyridine-2-) methylene) methylamine ligand is obviously superior to that of the complex 7, which shows that the modification of a substituent group has great influence on the anticancer activity.
(II) cell imaging experiment steps:
a549 cells were incubated in 6-well plates for 24 hours, added with MTDR (mitochondrial stain)/LTDR (lysosomal stain) at 100nM for 30 minutes at 37 deg.C, added with 1/310 μ M of the complex, incubated for 30 minutes, washed three times with cold PBS, and immediately observed under a two-photon laser confocal microscope.
The experimental results show that: as can be seen from FIG. 10, complex enters the nucleus in 130 minutes, complex 3 firstly has good co-localization with mitochondria and lysosome in cytoplasm and enters the nucleus after 8 hours, and compared with cytotoxic complex 1 IC50=6.5 + -0.6 complex 3 IC50=32.0 + -1.2, direct targeting of the nucleus is better for promoting cancer apoptosis, and the reason for this phenomenon is that the nucleus is the center for controlling all metabolic activities.
(III) cell uptake mechanism experiment
A549 cells are put in a 6-well plate to be incubated for 24 hours, added with chloroquine/CCCP 50 mu M respectively and incubated for 60 minutes, added with a complex 1/310 mu M and incubated for 30 minutes at 37 ℃, and washed with cold PBS three times after being incubated for 30 minutes at 4 ℃ and 37 ℃ in parallel, and immediately observed under a two-photon laser confocal microscope.
Chloroquine is an endocytosis inhibitor, CCCP is an energy inhibitor, the endocytosis can be obtained from figure 11, the cellular uptake is not obvious all the time, however, the cellular uptake is basically and completely inhibited when CCCP is added, which indicates that the complex enters the cell by means of energy, and the small molecules enter the cell mainly in an energy-dependent mode (active transportation, endocytosis) and are not in an energy-dependent mode (assisted diffusion, free diffusion), so that the complexes 1 and 3 are both in active transportation into the cell.
Claims (3)
1. A complex containing 1,1, 1-triphenyl-N- (1- (pyridine-2-) methylene) methylamine is characterized in that the specific chemical structural formula of the complex is as follows:
2. a method for preparing the complex as claimed in claim 1, wherein when the complex is a complex 1-6, the specific steps are as follows:
the complex 1: 50.0mg of iridium dimer formula II, wherein R11.2.3.4.5-pentamethylcyclopentadienyl, M metal iridium, 46.3mg of 1,1, 1-triphenyl-N- (1- (pyridin-2-) methylene) methylamine in a 250mL Hilenk (Schlenk) flask, evacuated, purged with nitrogen three times, spiked with 20mL of analytically pure ethanol, stirred at room temperature for 24h, charged with 60 mg of KPF6Spin-drying with rotary evaporator, and then using CH2Cl2Dissolving, filtering with diatomite, and recrystallizing with diffusion method to obtain red crystal;
and (2) the complex: 50.0mg of an iridium dimer of formula II, wherein R14- (2.3.4.5-Tetramethylcyclopentadienyl) -1', 1-biphenyl, M metal iridium, 43.6 mg1,1, 1-triphenyl-N- (1- (pyridin-2-) methylene) methylamine in a 250mL Hilenk flask, evacuated, purged with nitrogen three times, 20mL of analytical grade ethanol added via a needle, stirred at room temperature for 24h, 60 mg KPF was added6Spin-drying with rotary evaporator, and then using CH2Cl2Dissolving, filtering with diatomite, and recrystallizing with diffusion method to obtain red crystal;
and (3) complex: 50.0mg of ruthenium dimer formula II, wherein R1For phenyl, M is ruthenium metal, 63.1mg of 1,1, 1-triphenyl-N- (1- (pyridine-2-) methylene) methylamine are placed in a 250mL Hilenk (Schlenk) flask, evacuated, purged with nitrogen three times, added with 20mL of analytically pure ethanol through a needle, stirred at room temperature for 24h, added with 60 mg of KPF6Spin-drying with rotary evaporator, and then using CH2Cl2Dissolving, filtering with diatomite, and recrystallizing with diffusion method to obtain red crystal;
the complex 4: 50.0mg of ruthenium dimer formula II, wherein R1M is cymene, M is ruthenium metal, 57.5mg of 1,1, 1-triphenyl-N- (1- (pyridine-2-) methylene) methylamine is placed in a 250mL Hilenk (Schlenk) bottle, vacuum is pumped, nitrogen is introduced three times, 20mL of analytically pure ethanol is added through a needle, stirring is carried out at room temperature for 24h, 60 mg of KPF is added6Spin-drying with rotary evaporator, and then using CH2Cl2Dissolving, filtering with diatomite, and recrystallizing with diffusion method to obtain red crystal;
and (3) a complex 5: 50.0mg of ruthenium dimer formula II, wherein R13- (1, 4-cyclohexadiene) -propanol, M metal ruthenium, 60.0mg 1,1, 1-triphenyl-N- (1- (pyridine-2-) methylene) methylamine in a 250mL Hilenk flask, evacuated, purged with nitrogen three times, 20mL of analytically pure ethanol added via a needle, stirred at room temperature for 24h, 60 mg KPF added6Spin-drying with rotary evaporator, and then using CH2Cl2Dissolving, filtering with diatomite, and recrystallizing with diffusion method to obtain red crystal;
the complex 6: 50.0mg of ruthenium dimer formula II, wherein R14- (1.4-cyclohexadiene) -butanol, M metal ruthenium, 51.9mg 1,1, 1-triphenyl-N- (1- (pyridine-2-) methylene) methylamine in a 250mL Hilenk flask, evacuated, purged with nitrogen three times, 20mL of analytically pure ethanol added via a needle, stirred at room temperature for 24h, 60 mg KPF added6Spin-drying with rotary evaporator, and then using CH2Cl2Dissolving, filtering with diatomite, and recrystallizing with diffusion method to obtain red crystalA body;
the structural formula of the formula II is as follows:
3. use of a complex as claimed in claim 1 in the preparation of a medicament for anti-cancer and cellular imaging.
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