CN109265488B - Iridium anticancer complex containing phosphinimine bidentate chelating ligand and preparation method and application thereof - Google Patents
Iridium anticancer complex containing phosphinimine bidentate chelating ligand and preparation method and application thereof Download PDFInfo
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- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 22
- 239000003446 ligand Substances 0.000 title claims abstract description 22
- 229910052741 iridium Inorganic materials 0.000 title claims abstract description 20
- QLNAVQRIWDRPHA-UHFFFAOYSA-N iminophosphane Chemical compound P=N QLNAVQRIWDRPHA-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims description 6
- 229910052751 metal Inorganic materials 0.000 claims abstract description 10
- 239000002184 metal Substances 0.000 claims abstract description 10
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 8
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 8
- 239000013522 chelant Substances 0.000 claims abstract description 7
- 208000009956 adenocarcinoma Diseases 0.000 claims abstract description 5
- 239000000460 chlorine Substances 0.000 claims description 47
- -1 2- (diphenylphosphino) phenyl Chemical group 0.000 claims description 39
- 239000007787 solid Substances 0.000 claims description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 32
- 239000002904 solvent Substances 0.000 claims description 26
- 229910021135 KPF6 Inorganic materials 0.000 claims description 24
- 239000003153 chemical reaction reagent Substances 0.000 claims description 24
- 238000009792 diffusion process Methods 0.000 claims description 24
- 238000009987 spinning Methods 0.000 claims description 23
- 238000001914 filtration Methods 0.000 claims description 18
- 150000002503 iridium Chemical class 0.000 claims description 18
- 239000012265 solid product Substances 0.000 claims description 18
- 150000002466 imines Chemical class 0.000 claims description 16
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- 239000004305 biphenyl Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 4
- UNEATYXSUBPPKP-UHFFFAOYSA-N 1,3-Diisopropylbenzene Chemical compound CC(C)C1=CC=CC(C(C)C)=C1 UNEATYXSUBPPKP-UHFFFAOYSA-N 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 claims description 3
- 229910017717 NH4X Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 6
- 238000001035 drying Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 238000012986 modification Methods 0.000 abstract description 6
- 230000004048 modification Effects 0.000 abstract description 6
- 210000002919 epithelial cell Anatomy 0.000 abstract description 4
- 230000012010 growth Effects 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 238000001228 spectrum Methods 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052698 phosphorus Inorganic materials 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000004679 31P NMR spectroscopy Methods 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 8
- 239000011574 phosphorus Substances 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 229910052697 platinum Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- 150000004696 coordination complex Chemical class 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 2
- 229910000071 diazene Inorganic materials 0.000 description 2
- 230000005764 inhibitory process Effects 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
- 229910000073 phosphorus hydride Inorganic materials 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
- 239000011550 stock solution Substances 0.000 description 2
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YUWBVKYVJWNVLE-UHFFFAOYSA-N [N].[P] Chemical group [N].[P] YUWBVKYVJWNVLE-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 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
- 230000000295 complement effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000003106 haloaryl group Chemical group 0.000 description 1
- 125000005347 halocycloalkyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910021432 inorganic complex Inorganic materials 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000002097 pentamethylcyclopentadienyl group Chemical group 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic System
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- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention discloses an organic metal iridium anticancer complex containing phosphinimine bidentate chelate ligand,
(ii) a The prepared complex has an inhibiting effect on the growth of adenocarcinoma human alveolar basal epithelial cells (A549), and the in vitro anticancer activity of the complex is proved to be good. The iridium complex can be subjected to substituent modification at multiple positions, has good anticancer activity, and is a new class of potential anticancer drugs.
Description
Technical Field
The invention relates to a metal complex, in particular to an iridium anti-cancer complex containing a phosphinimine bidentate chelating ligand, a preparation method and application thereof, belonging to the field of chemical pharmacy.
Background
Cancer has become one of the medical problems that people have to overcome. Chemotherapy is currently the main strategy for the treatment of cancer. The first kind of metal-based anticancer medicine for clinical use represents cisplatin (PtCl)2(NH3)2Cissplatin) limits its further clinical use due to its high toxic side effects, susceptibility to drug resistance, and ineffectiveness in some tumor therapies. Therefore, the search for high-efficiency, low-toxicity and broad-spectrum anticancer drugs becomes a hotspot of research in the fields of chemistry, biology, medicine and the like. Although the new generation of synthetic bivalent platinum complex reduces some toxic and side effects, the toxic and side effects are still remainedThere is also a problem of drug resistance. The desire for better development from chemotherapy in the treatment of tumors has continued to be a need for the development of new metal anti-cancer drugs with different mechanisms of action to improve or complement the performance of existing platinum-based drugs. Among the compounds, the organic metal complex fills the gap between the traditional inorganic complex anticancer drugs and organic anticancer drugs because the structure of the organic metal complex is easy to modify, and shows higher activity and drug resistance. Among them, the half sandwich type hexa-coordinated iridium organometallic complex containing cyclopentadienyl has attracted attention due to the structural diversity and the anticancer mechanism different from that of platinum drugs. At present, researchers have synthesized the diimine ligand and pentamethylcyclopentadienyl Ir of bidentate phosphine ligandIIIAn organometallic complex (a)Inorg. Chem，2018, 57 (11) :6669-6685)、(Inorg. Chem，2018, 57 (4) :1705-1716) Exhibits good antitumor activity and has multiple anticancer mechanisms different from platinum drugs.
The phosphinimine (P ^ N) ligand is used as an asymmetric ligand with obvious antiposition effect and is mainly used for synthesizing metal catalysts and catalyzing organic reaction and polymerization. Compared with a diimine ligand and a bidentate phosphine ligand, the coordination center atom of the ligand is in an electronic asymmetric structure, and the phosphorus atom is a very strong sigma-electron donor and can stabilize metal; the relatively weak coordination capacity of the nitrogen atom in the imine can provide variability in the chemical and biological activity of the complex.
Disclosure of Invention
In order to solve the problems, the invention selects P ^ N as a neutral ligand chelated by two teeth to synthesize a novel iridium complex with high anticancer activity, which is hopeful to become a new class of potential anticancer drugs.
The invention is realized by the following technical scheme:
an iridium anticancer complex containing a phosphinimine bidentate chelate ligand, wherein the organic metal iridium complex is a complex of phosphorus nitrogen atoms and metal iridium in coordination, has anticancer activity and has a structural formula shown as a formula (I):
in the formula (I), R1Is hydrogen, aryl, alkyl, cycloalkyl, halogen; r2、R3Independently of one another, cycloalkyl or C7～C30Substituted aryl of (a); r4Is C1～C15Alkyl or C6～C30Aryl of (a); x is Cl-、PF6 -、BF4 -、BPh4 -、SbF6 -、
。
Preferably, said R is1The substituent on the aryl group of (A) is C1～C12Alkyl group of (1).
The aryl, alkyl and cycloalkyl groups may be haloalkyl, halocycloalkyl and haloaryl groups.
The structure of the specific compound of formula (I) provided by the invention is as follows:
the preparation method of the organic metal iridium anticancer complex comprises the following steps:
adding an iridium dimer, a P ^ N bidentate ligand and AX into dichloromethane serving as a solvent to react to form a cyclopentadienyl ring containing a substituent, a P ^ N bidentate chelate ligand and a hexacoordinate iridium complex with a chlorine atom coordinated with metal iridium; AX is NaX,KX, AgX or NH4X。
The synthesis method of the eight complexes 1-8 comprises the following specific steps:
(1) 39.8 mg of iridium dimer (R)1Methyl), 1- (2- (diphenylphosphino) phenyl) -N-phenylimine (36.5mg, 0.10 mmol) was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering to a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall, layering, and recrystallizing by a diffusion method to obtain a yellow solid product.
(2) 39.8 mg of iridium dimer (R)1Methyl), N- (2, 6-dimethylphenyl) -1- (2- (diphenylphosphino) phenyl) imine (39.3mg, 0.10 mmol) was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering to a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall, layering, and recrystallizing by a diffusion method to obtain a yellow solid product.
(3) 39.8 mg of iridium dimer (R)1Methyl), N- (2, 6-diisopropylbenzene) -1- (2- (diphenylphosphino) phenyl) imine (45.0 mg, 0.10 mmol) was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering to a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall, layering, and recrystallizing by a diffusion method to obtain a yellow solid product.
(4) 39.8 mg of iridium dimer (R)1Methyl), N-cyclohexyl-1- (2- (diphenylphosphino) phenyl) imine (37.1 mg, 0.10 mmol) was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering to a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall, layering, and recrystallizing by a diffusion method to obtain a yellow solid product.
(5) 39.8 mg of iridium dimer (R)1Methyl), N-benzyl-1- (2- (diphenylphosphino) phenyl) imine (38.0 mg, 0.10 mmol) was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering to a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall, layering, and recrystallizing by a diffusion method to obtain a yellow solid product.
(6) 39.8 mg of iridium dimer (R)1Methyl), 1- (2- (diphenylphosphino) phenyl-N-phenethylimine (39.3mg, 0.10 mmol) was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering to a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall, layering, and recrystallizing by a diffusion method to obtain a yellow solid product.
(7) 53.7 mg of iridium dimer (R)1Biphenyl), N-cyclohexyl-1- (2- (diphenylphosphino) phenyl) imine (37.1 mg, 0.10 mmol) was placed in a 50 mL round-bottom flask, and 20mL CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering to a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall, layering, and recrystallizing by a diffusion method to obtain a yellow solid product.
(8) 53.7 mg of iridium dimer (R)1As biphenyl), 1- (2- (diphenylphosphino) phenyl) -N-phenethylimine (39.3mg, 0.10 mmol) was placed in a 50 mL round bottom flask, and 20mL CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering to a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall, layering, and recrystallizing by a diffusion method to obtain a yellow solid product.
Advantageous effects
Experiments show that the prepared coordination compound 1-8 has an inhibiting effect on the growth of adenocarcinoma human alveolar basal epithelial cells (A549), and the coordination compound 1-8 has good in-vitro anticancer activity. The iridium complex can be subjected to substituent modification at multiple positions, has good anticancer activity, and is a new class of potential anticancer drugs.
Drawings
FIG. 1 shows the single crystal structure of complex 4 prepared in example 4 of the present invention.
FIG. 2 shows the nuclear magnetic hydrogen spectrum of complex 1 prepared in example 1 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 is a nuclear magnetic hydrogen spectrum of complex 3 prepared in example 3 of the present invention.
FIG. 5 is a nuclear magnetic hydrogen spectrum of complex 4 prepared in example 4 of the present invention.
FIG. 6 is a nuclear magnetic hydrogen spectrum of complex 5 prepared in example 5 of the present invention.
FIG. 7 is a nuclear magnetic hydrogen spectrum of complex 6 prepared in example 6 of the present invention.
FIG. 8 is a nuclear magnetic hydrogen spectrum of complex 7 prepared in example 7 of the present invention.
FIG. 9 is a nuclear magnetic hydrogen spectrum of complex 8 prepared in example 8 of the present invention.
FIG. 10 is a phosphorus spectrum of complex 1 prepared in example 1 of the present invention.
FIG. 11 is a phosphorus spectrum of complex 2 prepared in example 2 of the present invention.
FIG. 12 is a phosphorus spectrum of complex 3 prepared in example 3 of the present invention.
FIG. 13 is a phosphorus spectrum of complex 4 prepared in example 4 of the present invention.
FIG. 14 is a phosphorus spectrum of complex 5 prepared in example 5 of the present invention.
FIG. 15 is a phosphorus spectrum of complex 6 prepared in example 6 of the present invention.
FIG. 16 is a phosphorus spectrum of complex 7 prepared in example 7 of the present invention.
FIG. 17 is a phosphorus spectrum of complex 8 prepared in example 8 of the present invention.
FIG. 18 is a mass spectrum of complex 1 prepared in example 1 of the present invention.
FIG. 19 is a mass spectrum of complex 2 prepared in example 2 of the present invention.
FIG. 20 is a mass spectrum of complex 3 prepared in example 3 of the present invention.
FIG. 21 is a mass spectrum of complex 4 prepared in example 4 of the present invention.
FIG. 22 is a mass spectrum of complex 5 prepared in example 5 of the present invention.
FIG. 23 is a mass spectrum of complex 6 prepared in example 6 of the present invention.
FIG. 24 is a mass spectrum of complex 7 prepared in example 7 of the present invention.
FIG. 25 is a mass spectrum of complex 8 prepared in example 8 of the present invention.
Detailed Description
The following examples are given for the detailed implementation and specific operation of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
39.8 mg of iridium dimer (R)1Methyl), 1- (2- (diphenylphosphino) phenyl) -N-phenylimine (36.5mg, 0.10 mmol) was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering into a reagent bottle, and slowly moving along the bottle wall20mL of n-hexane was added to separate layers, and recrystallization was performed by diffusion to obtain 47 mg (yield, 54%) of a yellow solid product.1H NMR (500 MHz, DMSO) δ 8.62 (d, J = 2.4 Hz, 1H, HC = N), 7.87-7.80 (m, 3H, aryl-H), 7.72 (ddt, J11H, aryl- = 18.3, 15.9, 7.8 HzH), 7.62 (t, J= 7.6 Hz, 1H, aryl-H), 7.49 (dd, J1H, aryl- = 10.6, 7.8 Hz-H), 7.41 (t, J= 7.5 Hz, 1H, aryl-H), 7.12 (d, J= 7.7 Hz, 2H, aryl-H), 1.02 (d, J = 2.3 Hz, 15H, Cp*-H). 31P NMR (202 MHz, DMSO) δ 11.41 (P(Ph)2), -133.65 (PF6), -137.17 (PF6), -140.68 (PF6), -144.19 (PF6), -147.71 (PF6), -151.22 (PF6), -154.73 (PF6). MALDI-TOF-MS (m/z): C35H35ClIrPN theoretical value of 728.1825, 728.1370M-PF is actually measured6]+.
Example 2
39.8 mg of iridium dimer (R)1Methyl), N- (2, 6-dimethylphenyl) -1- (2- (diphenylphosphino) phenyl) imine (39.3mg, 0.10 mmol) was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2The solid was dissolved, filtered into a reagent bottle, and 20mL of n-hexane was slowly added along the wall of the bottle to separate layers, which were recrystallized by diffusion to give 63 mg (yield, 70%) of the product as a yellow solid.1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 3.2 Hz, 1H, HC = N), 7.72-7.65 (m, 4H, aryl-H) 7.64-7.58 (m, 5H, aryl-H) 7.54 (td, J = 8.0, 2.8 Hz, 2H, aryl-H) 7.28 (d, J = 3.8 Hz, 1H, aryl-H) 7.23 (s, 1H, aryl-)H) 7.18 (d, J = 6.9 Hz, 1H, aryl-H) 7.07-7.00 (m, 3H, aryl-H), 2.27 (s, 3H, o-aniline-CH 3), 1.37 (s, 3H, o-aniline-CH 3), 1.16 (d, J = 2.4 Hz, 15H, Cp*-H). 31P NMR (202 MHz, CDCl3) δ 6.64 (P(Ph)2), -133.94 (PF6), -137.46 (PF6), -140.98 (PF6), -144.50 (PF6), -148.02 (PF6), -151.53 (PF6), -155.05 (PF6). MALDI-TOF-MS (m/z): C37H39ClIrPN theoretical value of 756.2138, 756.1720M-PF is actually measured6]+.
Example 3
39.8 mg of iridium dimer (R)1Methyl), N- (2, 6-diisopropylbenzene) -1- (2- (diphenylphosphino) phenyl) imine (45.0 mg, 0.10 mmol) was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2The solid was dissolved, filtered into a reagent bottle, and 20mL of n-hexane was slowly added along the wall of the bottle to separate layers, which were recrystallized by diffusion to give 44 mg (yield, 46%) of the product as a yellow solid.1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 2.9 Hz, 1H, HC=N), 7.68 (tt, J= 14.9, 7.4 Hz, 5H, aryl-H) 7.63-7.59 (m, 1H, aryl-H), 7.51 (dd, J= 6.7, 4.6 Hz, 4H, aryl-H) 7.34-7.27 (m, 3H, aryl-H), 7.24 (d, J= 7.8 Hz, 2H, aryl-H) 7.16-7.03 (m, 2H, aryl-H), 3.46 – 3.43 (m, 1H, i Pr-CH), 2.19 – 2.12 (m, 1H, i Pr-CH), 1.38 (d, J = 6.8 Hz, 3H, i Pr-CH 3), 1.19 (d, J = 2.4 Hz, 15H, Cp*-H), 1.10 (d, J = 6.6 Hz, 3H, i Pr-CH 3), 1.06 (d, J = 6.7 Hz, 3H, i Pr-CH 3), 0.18 (d, J = 6.6 Hz, 3H, i Pr-CH 3). 31P NMR (202 MHz, CDCl3) δ 6.89 (P(Ph)2), -133.94 (PF6), -137.46 (PF6), -140.98 (PF6), -144.50 (PF6), -148.02 (PF6), -151.54 (PF6), 155.06 (PF6). MALDI-TOF-MS (m/z): C41H47ClIrPN theoretical value of 812.2764, 812.1550M-PF is actually measured6]+.
Example 4
39.8 mg of iridium dimer (R)1Methyl), N-cyclohexyl-1- (2- (diphenylphosphino) phenyl) imine (37.1 mg, 0.10 mmol) was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2The solid was dissolved, filtered into a reagent bottle, and 20mL of n-hexane was slowly added along the wall of the bottle to separate layers, which were recrystallized by diffusion to give 58 mg (yield, 66%) of the product as a yellow solid.1H NMR (500 MHz, DMSO) δ 8.64 (d, J = 2.5 Hz, 1H, HC=N), 7.82 (dd, J= 7.3, 3.8 Hz, 1H, aryl-H) 7.75-7.53 (m, 12H, aryl-H), 7.46 (dd, J= 10.0, 8.0 Hz, 1H, aryl-H), 4.03 (t, J = 11.8 Hz, 1H, Cy-H), 1.95 (t, J = 11.7 Hz, 2H, Cy-H), 1.84 (d, J = 13.3 Hz, 1H, Cy-H), 1.75 (t, J= 12.2 Hz, 2H, Cy-H), 1.68 (d, J = 12.5 Hz, 1H, Cy-H), 1.63 – 1.53 (m, 1H, Cy-H), 1.53 – 1.47 (m, 1H, Cy-H), 1.44 (d, J = 14.1 Hz, 1H, Cy-H), 1.40 (d, J= 2.1 Hz, 15H, Cp*-H), 1.23 (dd, J = 25.8, 12.8 Hz, 1H, Cy-H). 31P NMR (202 MHz, DMSO) δ 12.32 (P(Ph)2), -137.17 (PF6), -140.68 (PF6), -144.19 (PF6), -147.71 (PF6), -151.22 (PF6), -154.73 (PF6). MALDI-TOF-MS (m/z): C35H41ClIrPN theoretical value of 734.2294, measured in practice to be 734.1700 [, ]M-PF6]+.
Example 5
39.8 mg of iridium dimer (R)1Methyl), N-benzyl-1- (2- (diphenylphosphino) phenyl) imine (38.0 mg, 0.10 mmol) was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2The solid was dissolved, filtered into a reagent bottle, and 20mL of n-hexane was slowly added along the wall of the bottle to separate layers, which were recrystallized by diffusion to give 53 mg (yield, 60%) of the product as a yellow solid.1H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 1.7 Hz, 1H, HC=N), 7.63 (dd, J= 13.1, 7.3 Hz, 6H, aryl-H) 7.59-7.48 (m, 6H, aryl-H), 7.42 (td, J= 7.8, 2.7 Hz, 2H, aryl-H) 7.30-7.27 (m, 3H, aryl-H) 7.21-7.16 (m, 2H, aryl-H), 5.43 (d, J = 15.4 Hz, 1H, ArCH 2N), 5.30 (d, J = 15.4 Hz, 1H, ArCH 2N), 1.41 (s, 15H, Cp*-H). 31P NMR (202 MHz, CDCl3) δ 8.02 (P(Ph)2), -133.70 (PF6), -137.22 (PF6), -140.74 (PF6), -144.26 (PF6), -147.78 (PF6), -151.30 (PF6), -154.82 (PF6). MALDI-TOF-MS (m/z): C36H37ClIrPN theoretical value of 742.1981, 742.1977M-PF is actually measured6]+.
Example 6
39.8 mg of iridium dimer (R)1Methyl), 1- (2- (diphenylphosphino) phenyl-N-phenethylimine (39.3mg, 0.10 mmol) was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering into a reagent bottle, and slowly adding the solution along the bottle wallThe layers were separated by addition of 20mL of n-hexane and recrystallized by diffusion to give 70 mg (yield, 78%) of a yellow solid product.1H NMR (500 MHz, DMSO) δ 8.29 (d, J = 1.8 Hz, 1H, HC=N), 7.76 (t, J= 7.6 Hz, 1H, aryl-H) 7.73-7.61 (m, 6H, aryl-H), 7.57 (dt, J6H, aryl- = 8.9, 3.5 Hz-H), 7.48 (dd, J= 7.3, 3.7 Hz, 1H, aryl-H), 7.29 (dd, J= 11.1, 4.4 Hz, 2H, aryl-H), 7.24 (dd, J= 6.2, 3.9 Hz, 1H, aryl-H) 7.23-7.17 (m, 2H, aryl-H), 4.53 – 4.41 (m, 1H, ArCH2CH 2N), 4.28 – 4.17 (m, 1H, ArCH2CH 2N), 2.71 (ddd, J = 13.4, 8.3, 5.0 Hz, 1H, ArCH 2CH2N), 2.58 (dt, J= 13.7, 8.1 Hz, 1H, ArCH 2CH2N), 1.38 (s, 15H, Cp*-H). 31P NMR (202 MHz, DMSO) δ 8.09 (P(Ph)2), -133.65 (PF6), -137.16 (PF6), -140.68 (PF6), -144.19 (PF6), -147.70 (PF6), -151.22 (PF6), -154.73 (PF6). MALDI-TOF-MS (m/z): C37H39ClIrPN theoretical value of 756.2138, 756.2055M-PF is actually measured6]+.
Example 7
53.7 mg of iridium dimer (R)1Biphenyl), N-cyclohexyl-1- (2- (diphenylphosphino) phenyl) imine (37.1 mg, 0.10 mmol) was placed in a 50 mL round-bottom flask, and 20mL CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2The solid was dissolved, filtered into a reagent bottle, and 20mL of n-hexane was slowly added along the wall of the bottle to separate layers, which were recrystallized by diffusion to give 63 mg (yield, 62%) of the product as a yellow solid.1H NMR (500 MHz, DMSO) δ 8.61 (s, 1H, HC = N), 7.85-7.80 (m, 3H, aryl-H) 7.75-7.70 (m, 5H, aryl-H), 7.69-7.60 (m, 11H, aryl-H) 7.54-7.49 (m, 3H, aryl-H), 7.43 (t, J= 7.4 Hz, 1H, aryl-H), 3.66 (t, J= 11.7 Hz, 1H, Cy-H), 2.23 (s, 3H, Cpxbiph-CH 3), 1.98 (d, J = 11.7 Hz, 1H, Cy-H), 1.68 (s, 2H, Cy-H), 1.66 – 1.57 (m, 4H, Cy-H and Cpxbiph-CH 3), 1.54 (d, J = 1.7 Hz, 3H, Cpxbiph-CH 3), 1.45 (dt, J = 21.1, 7.3 Hz, 1H, Cy-H), 1.30 (d, J = 10.7 Hz, 2H, Cy-H), 1.03 – 0.93 (m, 2H, Cy-H), 0.30 (s, 3H, Cpxbiph-CH 3), -0.13 (dt, J = 22.1, 11.0 Hz, 1H, Cy-H). 31P NMR (202 MHz, DMSO) δ 12.29 (P(Ph)2), -133.65 (PF6), -137.16 (PF6), -140.68 (PF6), -144.19 (PF6), -147.70 (PF6), -151.22 (PF6), -154.73 (PF6). MALDI-TOF-MS (m/z): C46H47ClIrPN theoretical value of 872.2764, 872.2042M-PF is actually measured6]+.
Example 8
53.7 mg of iridium dimer (R)1Biphenyl), 1- (2- (diphenylphosphino) phenyl) -N-phenethylimine (39.3mg, 0.10 mmol) was placed in a 50 mL round-bottomed flask, and 20mL CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2The solid was dissolved, filtered into a reagent bottle, and 20mL of n-hexane was slowly added along the wall of the bottle to separate layers, which were recrystallized by diffusion to give 53 mg (yield, 51%) of the product as a yellow solid.1H NMR (500 MHz, DMSO) δ 8.79 (d, J = 1.9 Hz, 1H, HC = N), 7.94-7.70 (m, 9H, aryl-H) 7.65-7.29 (m, 14H, aryl-H) 7.24-7.11 (m, 3H, aryl-H) 6.96-6.88 (m, 2H, aryl-H), 4.30 (td, J = 11.6, 5.8 Hz, 1H, ArCH2CH 2N), 4.13 (td, J = 11.6, 4.8 Hz, 1H, ArCH2CH 2N), 3.20 (td, J = 12.0, 5.2 Hz, 1H, ArCH 2CH2N), 2.43 (td, J = 12.0, 4.2 Hz, 1H, ArCH 2CH2N), 1.93 (d, J= 1.7 Hz, 3H, Cpxbiph-CH 3), 1.70 (d, J = 3.9 Hz, 3H, Cpxbiph-CH 3), 1.49 (d, J = 3.0 Hz, 3H, Cpxbiph-CH 3), 0.53 (s, 3H, Cpxbiph-CH 3). 31P NMR (202 MHz, DMSO) δ 7.08 (P(Ph)2), -133.66 (PF6), -137.17 (PF6), -140.68 (PF6), -144.20 (PF6), -147.71 (PF6`), -151.22 (PF6), -154.73 (PF6). MALDI-TOF-MS (m/z): C48H45ClIrPN theoretical value of 894.2607, 894.2693M-PF is actually measured6]+.
Example 9
Experiment of proliferation inhibition activity of complexes 1-8 with anticancer activity on tumor cell strains:
(1) preparation of test compound: dissolving the solid complex in DMSO to prepare stock solution with a certain concentration, further diluting the stock solution with cell culture solution until the working concentration is reached, and culturing for 24 h;
(2) cell growth inhibition assay (MTT method):
1) 5000 adenocarcinoma human alveolar basal epithelial cells (A549) are prepared into cell suspension and inoculated into a 96-hole culture plate;
2) pre-culture of cells with drug-free Medium, 5% CO2Incubating for 24 hours at 310K, adding the 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 rate of the complexes 1-8 and cisplatin on the growth of adenocarcinoma human alveolar basal epithelial cells (A549) is shown in Table 1.
TABLE 1
As can be seen from example 9, the complexes 1-8 show very good anticancer activity, which is far superior to the activity of the commercialized cisplatin. In addition, the modification of the substituent on the phosphinimine ligand has little influence on the anticancer activity of the complex.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (5)
1. An iridium anticancer complex containing a phosphinimine bidentate chelating ligand is characterized in that the structure of the compound is as follows:
2. a method for preparing an iridium anticancer complex containing a phosphinimine bidentate chelate ligand according to claim 1, which comprises the following steps:
adding an iridium dimer, a P ^ N bidentate ligand and AX into dichloromethane serving as a solvent to react to form a cyclopentadienyl ring containing a substituent, a P ^ N bidentate chelate ligand and a hexacoordinate iridium complex with a chlorine atom coordinated with metal iridium; AX is NaX, KX, AgX or NH4X。
3. The production method according to claim 2: the preparation method is characterized in that when the complex is 1-8, the specific steps are as follows:
the complex 1: 39.8 mg of R1Iridium dimer as methyl, 36.5mg of 1- (2- (diphenylphosphino) phenyl) -N-phenylimine were placed in a 50 mL round-bottomed flask, and 20mL of CH were added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering the solid into a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall to stratify, and recrystallizing by using a diffusion method to obtain a yellow solid product;
and (2) the complex: 39.8 mg of R1Iridium dimer as methyl group, 39.3mg of N- (2, 6-dimethylphenyl) -1- (2- (diphenylphosphino) phenyl) imine were placed in a 50 mL round-bottomed flask, and 20mL of CH were added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering the solid into a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall to stratify, and recrystallizing by using a diffusion method to obtain a yellow solid product;
and (3) complex: 39.8 mg of R1Iridium dimer as methyl group, 45.0mg of N- (2, 6-diisopropylbenzene) -1- (2- (diphenylphosphino) phenyl) imine was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Is added and stirred for 2h, and is evaporated by rotary evaporationSpin-drying the solvent on the instrument with appropriate amount of CH2Cl2Dissolving the solid, filtering the solid into a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall to stratify, and recrystallizing by using a diffusion method to obtain a yellow solid product;
the complex 4: 39.8 mg of R1Iridium dimer as methyl group, 37.1mg of N-cyclohexyl-1- (2- (diphenylphosphino) phenyl) imine was placed in a 50 mL round-bottomed flask, and 20mL of CH was added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering the solid into a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall to stratify, and recrystallizing by using a diffusion method to obtain a yellow solid product;
and (3) a complex 5: 39.8 mg of R1Iridium dimer as methyl, 38.0mg of N-benzyl-1- (2- (diphenylphosphino) phenyl) imine were placed in a 50 mL round-bottomed flask, and 20mL of CH were added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering the solid into a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall to stratify, and recrystallizing by using a diffusion method to obtain a yellow solid product;
the complex 6: 39.8 mg of R1Iridium dimer as methyl, 39.3mg of 1- (2- (diphenylphosphino) phenyl-N-phenethylimine were placed in a 50 mL round bottom flask, and 20mL of CH were added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering the solid into a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall to stratify, and recrystallizing by using a diffusion method to obtain a yellow solid product;
the complex 7: 53.7 mg of R1Iridium dimer as biphenyl, 37.1mg of N-cyclohexyl-1- (2- (diphenylphosphino) phenyl) imine were placed in a 50 mL round-bottomed flask, and 20mL of CH were added2Cl2Stirring at room temperature24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering the solid into a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall to stratify, and recrystallizing by using a diffusion method to obtain a yellow solid product;
the complex 8: 53.7 mg of R1Iridium dimer as biphenyl, 39.3mg of 1- (2- (diphenylphosphino) phenyl) -N-phenethylimine were placed in a 50 mL round bottom flask, and 20mL of CH were added2Cl2Stirred at room temperature for 24 h, then 110.4 mg KPF6 Added and stirred for 2h, the solvent is dried by spinning on a rotary evaporator and the appropriate amount of CH is added2Cl2Dissolving the solid, filtering to a reagent bottle, slowly adding 20mL of normal hexane along the bottle wall, layering, and recrystallizing by a diffusion method to obtain a yellow solid product.
4. An application of the iridium anticancer complex containing the phosphinimine bidentate chelate ligand of claim 1 in preparing an anticancer drug.
5. An application of the iridium anticancer complex containing the phosphinimine bidentate chelate ligand of claim 1 in preparing an anti-adenocarcinoma drug.
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