CN110305166B - Ruthenium (II) complex with curcumin derivative as ligand and preparation method and application thereof - Google Patents
Ruthenium (II) complex with curcumin derivative as ligand and preparation method and application thereof Download PDFInfo
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- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical class C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 title claims abstract description 67
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 239000003446 ligand Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 235000012754 curcumin Nutrition 0.000 claims abstract description 14
- 229940109262 curcumin Drugs 0.000 claims abstract description 14
- 239000004148 curcumin Substances 0.000 claims abstract description 14
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000012453 solvate Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 229910052707 ruthenium Inorganic materials 0.000 claims description 7
- 239000002243 precursor Substances 0.000 claims description 6
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- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 230000001093 anti-cancer Effects 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
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- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 8
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 abstract description 6
- 229960004316 cisplatin Drugs 0.000 abstract description 6
- 238000012360 testing method Methods 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 125000005594 diketone group Chemical group 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 125000003545 alkoxy group Chemical group 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- -1 diketone polyphenol Chemical class 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
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- 239000000843 powder Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 201000011549 stomach cancer Diseases 0.000 description 5
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
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- 208000020816 lung neoplasm Diseases 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 125000005110 aryl thio group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 125000001072 heteroaryl group Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 125000006653 (C1-C20) heteroaryl group Chemical group 0.000 description 2
- 244000163122 Curcuma domestica Species 0.000 description 2
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 235000003373 curcuma longa Nutrition 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003303 ruthenium Chemical class 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- OBAJXDYVZBHCGT-UHFFFAOYSA-N tris(pentafluorophenyl)borane Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1B(C=1C(=C(F)C(F)=C(F)C=1F)F)C1=C(F)C(F)=C(F)C(F)=C1F OBAJXDYVZBHCGT-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 229940125656 TLD-1433 Drugs 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002001 anti-metastasis Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000002257 antimetastatic agent Substances 0.000 description 1
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- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
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- 230000004700 cellular uptake Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 108010010165 curculin Proteins 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
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- 238000003384 imaging method Methods 0.000 description 1
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
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- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
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- 235000013824 polyphenols Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 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 1
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Classifications
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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
-
- 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
- C07F15/0053—Ruthenium compounds without a metal-carbon linkage
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a ruthenium (II) complex taking curcumin derivatives as ligands and a preparation method and application thereof, wherein the ruthenium (II) complex taking curcumin derivatives as ligands, pharmaceutically acceptable salts and solvates thereof have a structure shown in a formula I; according to the invention, the curcumin derivative with a diketone structure is used as a ligand for the first time, and a series of ruthenium (II) complexes are synthesized; the activity test shows that the compound has better anti-tumor activity and potential anti-tumor application prospect; compared with curcumin, cisplatin and the like, the ruthenium (II) complex has higher antitumor activity;
Description
Technical Field
The invention belongs to the field of anti-tumor ruthenium complexes, and particularly relates to a ruthenium (II) complex taking a curcumin derivative as a ligand, a preparation method thereof and application of the ruthenium (II) complex taking the curcumin derivative as the ligand in preparation of anti-tumor drugs.
Background
Curcumin (curculin), a diketone polyphenol, is derived from the rhizome of the herbal plant Curcuma longa (Curcuma longa), is known for its wide medicinal properties, and has biological activities such as antibacterial, anti-inflammatory, antioxidant, antitumor and the like. In the anti-tumor aspect, curcumin can be used as an anti-proliferative, anti-metastatic and anti-angiogenic drug to inhibit canceration and limit tumor growth, and has extremely low toxicity to normal cells. However, clinical use is hindered due to poor water solubility and instability under physiological conditions resulting in extremely low cellular uptake and tissue distribution.
In recent years, many studies have reported that ruthenium (II) polypyridine complexes have many important biological properties, such as excellent reactivity, imaging ability, coordination binding ability, and the like. The ruthenium (II) polypyridine derivative TLD1433 has entered the clinical study stage. Such complexes may act as probes or inhibitors, interacting with important biomolecules including DNA, proteins and RNA, which interaction often results in damage or toxicity to the biological target. These properties make them potential diagnostic and cancer therapeutic agents.
However, in the field of ruthenium antitumor drugs, new ruthenium complexes with high antitumor activity need to be continuously developed for the antitumor field.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the problems in the prior art, the invention provides the ruthenium (II) complex taking the curcumin derivative as the ligand, the brand-new ruthenium (II) complex taking the curcumin derivative as the ligand has stronger cytotoxic activity, and compared with curcumin or cisplatin and the like, the ruthenium (II) complex taking the curcumin derivative as the ligand has better inhibitory activity on cancer cells such as lung cancer, breast cancer, gastric cancer and the like, and has higher application.
The invention also provides a ruthenium (II) complex taking the curcumin derivative as a ligand and application thereof.
The technical scheme is as follows: in order to achieve the above purpose, the invention provides a ruthenium (II) complex with curcumin derivative as ligand, its pharmaceutically acceptable salt and solvate, and its structure is shown in formula I:
wherein X is C or N; preferably C;
said substituent R, R1、R2、R3Is H, halogen, alkyl, alkoxy, alkylthio, hydroxy, mercapto, amino, cycloalkyl, aryl, aryloxy, arylthio or heteroaryl; said substituent R, R1、R2、R3Any two adjacent of them may be linked to form a ring, and the linked ring is preferably a carbocyclic ring or a heterocyclic ring; said X1Denotes a peripheral anion, preferably halogen, triflate, PF6-、B(C6F5)3 -And the like.
Specific groups are defined as follows:
the halogen is preferably F, Cl, Br or I;
the alkyl is preferably C1-20 linear or branched chain alkyl, more preferably C1-6 linear or branched chain alkyl, more preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like;
the alkoxy group is preferably a C1-20 linear or branched alkoxy group, more preferably a C1-6 linear or branched alkoxy group, and still more preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, or the like;
the cycloalkyl is preferably C3-C12 monocyclic or polycyclic cycloalkyl, more preferably C3-C6 monocyclic or polycyclic cycloalkyl, more preferably C3-C6 monocyclic cycloalkyl, and specifically can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
the aryl is preferably C3-C20, more preferably C3-C10, and can be phenyl, naphthyl and the like;
the aryloxy is preferably C3-C20 aryloxy, more preferably C3-C10 aryloxy, and can be phenoxy, naphthoxy and the like;
the arylthio is preferably C3-C20, more preferably C3-C10, and can be concretely phenylthio, naphthylthio and the like;
the heteroaryl is preferably C1-20 heteroaryl, more preferably C1-C12 heteroaryl, and specifically can be pyridine, carbazole, quinoline, imidazole, indole and the like;
the substituent R1Preferably hydroxy, the substituent R on the same phenyl ring2One of which is a non-alkoxy group and the other is an alkoxy group, preferably a methoxy group.
Preferably, the structure of the ruthenium (II) complex taking the curcumin derivative as the ligand is shown as formulas I-1, I-2 and I-3:
the substituents R, R' and R2、R3Is H, halogen, C1-6 linear or branched alkyl, C1-6 linear or branched alkoxy, or C3-C10 aryl; substituent R1Is hydroxy, said X1Is halogen, trifluoromethanesulfonate, PF6 -、B(C6F5)3 -；
Specific groups are defined as follows:
the halogen is preferably F, Cl, Br or I;
the alkyl is preferably C1-20 linear or branched chain alkyl, more preferably C1-6 linear or branched chain alkyl, more preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like;
the alkoxy group is preferably a C1-20 linear or branched alkoxy group, more preferably a C1-6 linear or branched alkoxy group, and still more preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, or the like;
the cycloalkyl is preferably C3-C12 monocyclic or polycyclic cycloalkyl, more preferably C3-C6 monocyclic or polycyclic cycloalkyl, more preferably C3-C6 monocyclic cycloalkyl, and specifically can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
the aryl is preferably C3-C20, more preferably C3-C10, and can be phenyl, naphthyl and the like;
the aryloxy is preferably C3-C20 aryloxy, more preferably C3-C10 aryloxy, and can be phenoxy, naphthoxy and the like;
the arylthio is preferably C3-C20, more preferably C3-C10, and can be concretely phenylthio, naphthylthio and the like;
the heteroaryl is preferably C1-20 heteroaryl, more preferably C1-C12 heteroaryl, and specifically can be pyridine, carbazole, quinoline, imidazole, indole and the like;
the substituent R1Preferably hydroxy, the substituent R on the same phenyl ring2One of which is H and the other is an alkoxy group, preferably methoxy.
Preferably, the ruthenium (II) complex taking the curcumin derivative as the ligand has the following structure, namely complexes 1-3:
the preparation method of the ruthenium (II) complex with the curcumin derivative as the ligand comprises the following steps:
mixing the ruthenium precursor, the curcumin derivative and LiCl in a solvent, stirring and refluxing for reaction, removing the solvent, and carrying out column chromatography to obtain the ruthenium (II) complex taking the curcumin derivative as a ligand.
Preferably, the ruthenium precursor is Cis- (bpy)2RuCl2、Cis-(phen)2RuCl2Or [ Ru (bpy) ((dppn) Cl)2](ii) a The curcumin derivative is curcumin.
Preferably, the molar ratio of the ruthenium precursor to the curcumin derivative is 1: 1-20; more preferably 1:5-15 or 1: 8-12; most preferably 1: 10.
Preferably, the molar ratio of the curcumin derivative to the LiCl is 1: 1.
Wherein the solvent is EtOH/H2O, the volume ratio of which is 3: 1.
Further, the stirring reflux time is 12 h-24; the column chromatography solvent is DCM/MeOH, and the volume ratio is 10: 1.
The invention relates to a ruthenium (II) complex taking curcumin derivatives as ligands and application of pharmaceutically acceptable salts and solvates thereof in preparing anticancer drugs.
Wherein the cancer may be lung cancer, breast cancer, gastric cancer, etc.
The anti-cancer pharmaceutical composition contains the ruthenium (II) complex taking the curcumin derivative as the ligand or pharmaceutically acceptable salt or solvate thereof as an active ingredient and a pharmaceutically acceptable carrier.
The curcumin derivative with a diketone structure is used as a ligand for the first time to synthesize a series of ruthenium (II) complexes, and the curcumin derivative and ruthenium (II) are coordinated and combined to obtain the ruthenium (II) complex, so that the hydrolysis stability of curcumin is remarkably improved, and the ruthenium (II) complex has remarkable toxicity to a plurality of tumor cells. The activity test shows that the compound has better anti-tumor activity and potential anti-tumor application prospect; compared with curcumin, cisplatin and the like, the ruthenium (II) complex has higher antitumor activity.
Has the advantages that: compared with the prior art, the invention has the following advantages:
according to the invention, the curcumin derivative is combined with a specific ruthenium structure, a series of ruthenium (II) complexes taking the curcumin derivative as a ligand are prepared, and the preparation method is simple and convenient; the activity test shows that the ruthenium (II) complex taking the curcumin derivative as the ligand has higher activity, and compared with curcumin or cisplatin and the like, the ruthenium (II) complex taking the curcumin derivative as the ligand has better inhibitory activity on cancer cells such as lung cancer, breast cancer, gastric cancer and the like, and has higher application prospect.
The novel ruthenium (II) complex taking the curcumin derivative as the ligand has a strong anti-tumor effect; the preparation process is simple in process and easy to prepare; has potential clinical treatment effect.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1
Synthesis of complex 1:
will Cis- (bpy)2RuCl2(48.40mg, 0.10mmol), curcumin (368.4mg, 1.0mmol), LiCl (42.0mg, 1.0mmol) in EtOH/H2O (30/10ml), stirred under reflux for 12h to give a black solution, the solvent removed and column chromatographed DCM: MeOH 10:1 to give a dark brown powder.
Yield:52.0％。Black-brown powder.Anal.Calcd(％)for C41H35ClN4O6Ru:C60.33,H 4.32,N 6.86.Found:C 60.18,H 4.37,N 6.97；ESI-MS:m/z[M-Cl]+＝781.16；1H NMR(600MHz,DMSO-d6)δ3.75(s,6H),5.96(s,1H),6.58-6.61(d,2H,J＝15.8Hz),6.79-6.81(d,2H,J＝8.2Hz),6.88-6.90(m,2H),6.95-6.97(d,2H,J＝15.7Hz),7.11-7.12(m,2H),7.29-7.32(t,2H,J＝6.6Hz),7.76-7.80(m,4H),7.91-7.93(t,2H,J＝7.6Hz),8.16-8.19(t,2H,J＝7.6Hz),8.64-8.65(d,2H,J＝5.3Hz),8.74-8.76(d,2H,J＝8.0Hz),8.85-8.86(d,2H,J＝8.1Hz)；13C NMR(150MHz,DMSO-d6)δ56.02,101.87,110.68,116.08,122.42,123.97,124.02,126.26,126.39,126.93,127.31,135.44,136.47,137.04,148.39,148.77,149.81,153.23,157.88,159.24,178.20ppm.
Example 2
Synthesis of complex 2:
cis- (phen)2RuCl2(53.2mg,0.10mmol), curcumin (368.4mg, 1.0mmol), LiCl (42.0mg, 1.0mmol) in EtOH/H2O (30/10ml), stirred under reflux for 12h to give a black solution, the solvent removed and column chromatographed DCM: MeOH 15:1 to give a dark brown powder.
Yield:48.6％.Black-brown powder.Anal.Calcd(％)for C45H35ClN4O6Ru:C62.53,H 4.08,N 6.48.Found:C 62.38,H 4.27,N 6.69；ESI-MS:m/z[M-Cl]+＝829.16；1H NMR(600MHz,DMSO-d6)δ3.73(s,6H),6.05(s,1H),6.58-6.61(d,2H,J＝15.9Hz),6.77-6.79(d,2H,J＝8.2Hz),6.85-6.86(m,2H),6.93-6.95(d,2H,J＝15.8Hz),7.07(m,2H),7.53-7.55(m,2H),8.01-8.02(d,2H,J＝5.1Hz),8.20-8.22(m,2H),8.28-8.30(d,2H,J＝8.8Hz),8.37-8.38(d,2H,J＝8.9Hz),8.49-8.50(d,2H,J＝8.0Hz),8.84-8.85(d,2H,J＝8.1Hz),9.12-9.13(d,2H,J＝5.0Hz),9.66(m,2H)；13CNMR(150MHz,DMSO-d6)δ56.03,100.00,101.76,110.81,116.08,122.33,125.34,126.02,126.34,127.31,128.07,128.15,130.30,130.45,134.38,136.06,136.53,148.36,148.77,148.82,150.13,151.04,154.43,178.49ppm.
Example 3
Synthesis of complex 3:
reacting [ Ru (bpy) ((dppn) Cl)2](66.1mg, 0.1mmol), curcumin (368.4mg, 1.0mmol), LiCl (42.0mg, 1.0mmol) in EtOH/H2O (30/10ml), stirred under reflux for 12h to give a black solution, the solvent removed and column chromatographed DCM: MeOH 15:1 to give a dark brown powder. Yield 40.5%. Black-brown powderfor C53H39ClN6O6Ru:C 64.14,H 3.96,N 8.47.Found:C 63.98,H 4.13,N 8.69；ESI-MS:m/z[M-Cl]+＝957.21；1H NMR(600MHz,DMSO-d6)δ3.54(s,3H),3.79(s,3H),6.09(s,1H),6.60-6.61(d,1H,J＝8.3Hz),6.69-6.71(d,2H,J＝15.9Hz),6.78-6.82(m,2H),6.94-6.95(m,1H),6.99(m,1H),7.06-7.09(d,1H,J＝15.8Hz),7.15-7.17(m,2H),7.21-7.23(t,1H,J＝6.6Hz),7.63(m,2H),7.71-7.72(m,1H),7.83-7.84(d,1H,J＝5.6Hz),7.88-7.93(m,2H),8.09-8.10(m,1H),8.23-8.29(m,4H),8.75-8.77(d,1H,J＝8.2Hz),8.84-8.90(m,3H),8.96(m,1H),9.03-9.04(d,2H,J＝5.2Hz),9.26(m,1H),9.43(s,1H),9.57(s,1H)；13C NMR(150MHz,DMSO-d6)δ55.70,56.10,102.66,110.86,116.06,116.19,122.56,126.15,126.35,127.29,127.36,127.76,129.63,137.45,140.55,148.19,148.47,148.71,148.93,150.01,151.81,152.01,153.32,153.88,155.38,158.09,159.21,178.16,178.84ppm.
Example 4
And (3) testing the anticancer activity:
the selected tumor cell strains comprise a non-small cell lung cancer cell strain A549, a breast cancer cell strain MCF-7 and a gastric cancer cell strain SGC7901, which are adherent cells, the toxicity of the complexes 1-3 prepared in the examples 1-3 to 3 tumor cells is tested by adopting an MTT method, cisplatin and curcumin are used as positive controls, 5 drug concentration gradients are designed, and experiments are carried out for 3 times in parallel.
Cell culture conditions: the cell culture medium is RPMI-1640 containing 10% fetal calf serum, 100. mu.g/mL streptomycin and 100. mu.g/mL penicillin, and the culture condition is 5% CO2And a sterile humid incubator at 37 ℃.
MTT method: counting cells in logarithmic phase, inoculating into 96-well culture plate with 100 μ L cell suspension per well, about 1000-2And culturing overnight at 37 ℃, and after the cells adhere to the wall, administering, wherein an administration group, a positive control group and a negative control group are respectively arranged. The complex to be tested is prepared into stock solution by DMSO or 5% glucose solution according to different solubility, and is diluted into a series of concentrations by cell culture medium before use, wherein the final concentration of DMSO is not more than 5And (5) permillage. Each concentration was provided with 3 multiple wells. After addition of the reagent, the cells were cultured for 48 hours, observed under an inverted microscope, and 20. mu.L of a 5mg/mL MTT solution was added thereto, incubated at 37 ℃ for 4 hours, and then the supernatant was removed, and 150. mu.L of LDMSO was added thereto to sufficiently dissolve formazan. The OD value of each well is measured by a microplate reader at 490nm wavelength, the inhibition rate is calculated, and the IC50 value is calculated by using SPSS18 software as a concentration-inhibition rate curve.
Cytotoxic Activity of Compounds IC50Value of
The activity test shows that the ruthenium (II) complex taking the curcumin derivative as the ligand has higher activity, and compared with curcumin or cisplatin and the like, the ruthenium (II) complex taking the curcumin derivative as the ligand has better inhibitory activity on cancer cells such as lung cancer, breast cancer, gastric cancer and the like, and can be used for preparing anticancer drugs; whereas in complexes 1-3, the overall activity of complex 3 is optimal.
Claims (7)
1. A ruthenium (II) complex with curcumin derivatives as ligands or pharmaceutically acceptable salts thereof, wherein the structure of the ruthenium (II) complex is shown as the following formula:
2. a process for preparing a ruthenium (II) complex with a curcumin derivative as a ligand according to claim 1, comprising the steps of:
mixing a ruthenium precursor, a curcumin derivative and LiCl in a solvent, stirring, carrying out reflux reaction, removing the solvent, and carrying out column chromatography to obtain a ruthenium (II) complex taking the curcumin derivative as a ligand; the ruthenium precursor is [ Ru (bpy) ((dppn) Cl)2](ii) a The curcumin derivative is curcumin.
3. The production method according to claim 2, wherein the molar ratio of the ruthenium precursor to the curcumin derivative is 1:1 to 20; the molar ratio of curcumin derivative to LiCl is 1: 1.
4. The method of claim 2, wherein the solvent is EtOH/H2O, the volume ratio of which is 3: 1.
5. The preparation method according to claim 2, wherein the stirring reflux time is 12 to 24 hours; the column chromatography solvent is DCM/MeOH, and the volume ratio is 10: 1.
6. The use of the ruthenium (II) complex with curcumin derivative as ligand and its pharmaceutically acceptable salt or solvate in the preparation of anticancer drugs as claimed in claim 1.
7. A pharmaceutical composition for anticancer comprising the ruthenium (II) complex or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier.
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