CN110305166A - It is a kind of using curcumin derivate as ruthenium (II) complex of ligand and its preparation method and application - Google Patents
It is a kind of using curcumin derivate as ruthenium (II) complex of ligand and its preparation method and application Download PDFInfo
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- CN110305166A CN110305166A CN201910496257.3A CN201910496257A CN110305166A CN 110305166 A CN110305166 A CN 110305166A CN 201910496257 A CN201910496257 A CN 201910496257A CN 110305166 A CN110305166 A CN 110305166A
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- ruthenium
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- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound 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 122
- 235000012754 curcumin Nutrition 0.000 title claims abstract description 61
- 229940109262 curcumin Drugs 0.000 title claims abstract description 61
- 239000004148 curcumin Substances 0.000 title claims abstract description 61
- 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 title claims abstract description 61
- 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 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000012453 solvate Substances 0.000 claims abstract description 7
- 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
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229910052707 ruthenium Inorganic materials 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000005110 aryl thio group Chemical group 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000002243 precursor Substances 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims description 4
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims description 3
- 230000001093 anti-cancer Effects 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 239000000470 constituent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims 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 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 12
- 229910052697 platinum Inorganic materials 0.000 abstract description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 6
- 238000012360 testing method Methods 0.000 abstract description 6
- 230000001988 toxicity Effects 0.000 abstract description 4
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 210000004881 tumor cell Anatomy 0.000 abstract description 4
- 125000005594 diketone group Chemical group 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- -1 methoxyl group Chemical group 0.000 description 14
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 206010017758 gastric cancer Diseases 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 125000003367 polycyclic group Chemical group 0.000 description 4
- 201000011549 stomach cancer Diseases 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 244000163122 Curcuma domestica Species 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 235000003373 curcuma longa Nutrition 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 2
- 235000003392 Curcuma domestica Nutrition 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 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
- 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 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
- 150000002460 imidazoles Chemical class 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 229910052740 iodine Inorganic materials 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
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([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
- 125000001544 thienyl group Chemical group 0.000 description 2
- 235000013976 turmeric Nutrition 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 241000551547 Dione <red algae> Species 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
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000012327 Ruthenium complex 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
- 230000003698 anagen phase Effects 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 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
- 239000000523 sample Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 229910001868 water Inorganic materials 0.000 description 1
Classifications
-
- 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
Landscapes
- 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 kind of using curcumin derivate as ruthenium (II) complex of ligand and its preparation method and application, this is using curcumin derivate as ruthenium (II) complex of ligand, its pharmaceutically acceptable salt and solvate, structure are shown in formula I；The present invention is for the first time using the curcumin derivate with diketone structure as ligand, a series of rutheniums (II) complex is synthesized, the present invention is combined curcumin derivate with ruthenium (II) coordination, obtained ruthenium (II) complex significantly improves the hydrolytic stability of curcumin, while showing significant toxicity to several tumour cells；Active testing shows that it, with preferable anti-tumor activity, has potential antitumor application thereof prospect；Ruthenium (II) complex of the invention has higher anti-tumor activity compared with curcumin, cis-platinum etc.；
Description
Technical field
The invention belongs to antitumor ruthenium complex fields, and in particular to relate to a kind of using curcumin derivate as the ruthenium of ligand
(II) complex and preparation method thereof and anti-tumor drug is used to prepare by ruthenium (II) complex of ligand of curcumin derivate
Purposes.
Background technique
Curcumin (Curcumin) derives from herbaceous plant turmeric (Curcuma longa) as a kind of diones polyphenol
Rhizome, well-known because of its extensive medicinal property, curcumin has the bioactivity such as antibacterial, anti-inflammatory, anti-oxidant, antitumor.
In anti-tumor aspect, curcumin can be used as antiproliferative, and anti-rotation, which is moved with anti-angiogenic medicaments, inhibits canceration, and limits tumour
Growth, and extremely low toxicity is shown to normal cell.However, due to the unstability under its poorly water-soluble and physiological condition
Lead to extremely low cellular uptake and Tissue distribution, therefore clinical application is hindered.
In recent years, many research report ruthenium (II) multi-pyridine ligands have many important biological characteristics, such as excellent
Reactivity worth, imaging capability, coordinate bonding capability etc..The more pyridine derivate TLD1433 of ruthenium (II) have entered clinical research rank
Section.This kind of complex can be used as probe or inhibitor, and include DNA, and the important biomolecule molecule including protein and RNA is mutual
Effect, this interaction normally result in damage or toxicity to biological target.These performances make they become potentially examine
Disconnected and cancer treatment drugs.
But for ruthenium field of antineoplastic medicaments, need constantly to develop the new ruthenium cooperation with high anti-tumor activity
Object, to be used for antitumor field.
Summary of the invention
Goal of the invention: in view of the problems of the existing technology, the present invention provides a kind of using curcumin derivate as ligand
Ruthenium (II) complex, the present invention is completely new to live using curcumin derivate as ruthenium (II) complex of ligand with stronger cell toxicant
Property, compared with curcumin or cis-platinum etc., of the invention using curcumin derivate is ruthenium (II) complex of ligand to lung cancer, cream
The cancer cells such as gland cancer, gastric cancer all have better inhibitory activity, application with higher.
The present invention also provides a kind of using curcumin derivate as ruthenium (II) complex of ligand and its application.
Technical solution: to achieve the goals above, a kind of using curcumin derivate as the ruthenium of ligand as described herein
(II) complex, pharmaceutically acceptable salt and solvate, structure are shown in formula I:
Wherein X is C or N；Preferably C；
The substituent R, R1、R2、R3For H, halogen, alkyl, alkoxy, alkylthio group, hydroxyl, sulfydryl, amino, naphthenic base,
Aryl, aryloxy group, arylthio or heteroaryl；The substituent R, R1、R2、R3Two of middle arbitrary neighborhood can connect cyclization, company, institute
The ring being connected into is preferably carbocyclic ring or heterocycle；The X1Indicate periphery anion, preferably halogen, trifluoromethanesulfonic acid root, PF6-、B
(C6F5)3 -Deng.
Specific group definition is as follows:
The halogen is preferably F, Cl, Br or I；
The alkyl is preferably the alkyl of the linear chain or branched chain of C1-20, more preferably the alkyl of the linear chain or branched chain of C1-6,
More preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl etc.；
The alkoxy is preferably the alkoxy of the linear chain or branched chain of C1-20, more preferably the linear chain or branched chain of C1-6
Alkoxy, more preferably methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tert-butoxy etc.；
The naphthenic base is preferably the monocycle or polycyclic naphthene base of C3-C12, the more preferably monocycle of C3-C6 or polycyclic ring
Alkyl, the more preferably monocyclic cycloalkyl of C3-C6, concretely cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.；
The aryl is preferably the aryl of C3-C20, more preferably the aryl of C3-C10, concretely phenyl, naphthalene etc.；
The aryloxy group is preferably the aryloxy group of C3-C20, more preferably the aryloxy group of C3-C10, concretely phenoxy group,
Naphthoxy etc.；
The arylthio is preferably the arylthio of C3-C20, more preferably the arylthio of C3-C10, concretely thiophenyl,
Naphthalene sulfenyl etc.；
The heteroaryl is preferably the heteroaryl of C1-20, more preferably the heteroaryl of C1-C12, concretely pyridine, click
Azoles, quinoline, imidazoles, indoles etc.；
The substituent R1Preferably hydroxyl, the substituent R on same phenyl ring2In one be non-alkoxy, another is
Alkoxy, preferably methoxyl group.
Preferably, described using curcumin derivate as ruthenium (II) complex structure such as Formulas I -1, I-2, I-3 institute of ligand
Show:
The substituent R, R ', R2、R3For the linear chain or branched chain of H, halogen, the alkyl of the linear chain or branched chain of C1-6, C1-6
The aryl of alkoxy or C3-C10；Substituent R1For hydroxyl, the X1For halogen, trifluoromethanesulfonic acid root, PF6 -、B(C6F5)3 -；
Specific group definition is as follows:
The halogen is preferably F, Cl, Br or I；
The alkyl is preferably the alkyl of the linear chain or branched chain of C1-20, more preferably the alkyl of the linear chain or branched chain of C1-6,
More preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl etc.；
The alkoxy is preferably the alkoxy of the linear chain or branched chain of C1-20, more preferably the linear chain or branched chain of C1-6
Alkoxy, more preferably methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, tert-butoxy etc.；
The naphthenic base is preferably the monocycle or polycyclic naphthene base of C3-C12, the more preferably monocycle of C3-C6 or polycyclic ring
Alkyl, the more preferably monocyclic cycloalkyl of C3-C6, concretely cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.；
The aryl is preferably the aryl of C3-C20, more preferably the aryl of C3-C10, concretely phenyl, naphthalene etc.；
The aryloxy group is preferably the aryloxy group of C3-C20, more preferably the aryloxy group of C3-C10, concretely phenoxy group,
Naphthoxy etc.；
The arylthio is preferably the arylthio of C3-C20, more preferably the arylthio of C3-C10, concretely thiophenyl,
Naphthalene sulfenyl etc.；
The heteroaryl is preferably the heteroaryl of C1-20, more preferably the heteroaryl of C1-C12, concretely pyridine, click
Azoles, quinoline, imidazoles, indoles etc.；
The substituent R1Preferably hydroxyl, the substituent R on same phenyl ring2In one be H, another is alkoxy,
Preferably methoxyl group.
Preferably, described as follows using curcumin derivate as ruthenium (II) complex structure of ligand, respectively complex
1-3:
It is of the present invention using curcumin derivate as the preparation method of ruthenium (II) complex of ligand, including walk as follows
It is rapid:
Ruthenium precursor is mixed in a solvent with curcumin derivate, LiCl, is stirred at reflux reaction, removes solvent, column chromatography
Obtain ruthenium (II) complex using curcumin derivate as ligand.
Preferably, the ruthenium precursor is Cis- (bpy)2RuCl2、Cis-(phen)2RuCl2Or [Ru (bpy) (dppn)
Cl2]；The curcumin derivate is curcumin.
Preferably, the molar ratio of the ruthenium precursor and curcumin derivate is 1:1-20；More preferably 1:5-15 or 1:
8-12；Most preferably 1:10.
Preferably, the molar ratio of the curcumin derivate and LiCl are 1:1.
Wherein, the solvent is EtOH/H2O, volume ratio 3:1.
Further, described to be stirred at reflux the time as 12h-24；The column solvent system is DCM/MeOH, and volume ratio is
10:1。
It is of the present invention using curcumin derivate as ruthenium (II) complex and its pharmaceutically acceptable salt of ligand and
Solvate is preparing the application in anticancer drug.
Wherein, the cancer can be lung cancer, breast cancer, gastric cancer etc..
Pharmaceutical composition of the present invention for anticancer, wherein containing described using curcumin derivate as ligand
Ruthenium (II) complex or its pharmaceutically acceptable salt or solvate are as active constituent and pharmaceutically acceptable carrier.
The present invention using the curcumin derivate with diketone structure as ligand, has synthesized a series of rutheniums (II) cooperation for the first time
Object, the present invention are combined curcumin derivate with ruthenium (II) coordination, and obtained ruthenium (II) complex significantly improves curcumin
Hydrolytic stability, while significant toxicity is shown to several tumour cells.It is preferable antitumor that active testing shows that it has
Activity has potential antitumor application thereof prospect；Ruthenium (II) complex of the invention has higher compared with curcumin, cis-platinum etc.
Anti-tumor activity.
The utility model has the advantages that compared with prior art, the present invention has the advantage that
Curcumin derivate in conjunction with specific ruthenium structure, has been prepared a series of with curcumin derivate the present invention
For ruthenium (II) complex of ligand, preparation method is simple and convenient；Show through active testing using curcumin derivate as ligand
Ruthenium (II) complex activity with higher, compared with curcumin or cis-platinum etc., it is of the invention with curcumin derivate be with
Ruthenium (II) complex of body all has better inhibitory activity, application with higher to cancer cells such as lung cancer, breast cancer, gastric cancers
Prospect.
One kind of the invention is novel to have stronger antitumor effect by ruthenium (II) complex of ligand of curcumin derivate
Fruit；Preparation process simple process, technique are easily prepared；With potential clinical treatment effect.
Specific embodiment
Below with reference to embodiment, the present invention will be further explained.
Embodiment 1
The synthesis of complex 1:
By Cis- (bpy)2RuCl2(48.40mg, 0.10mmol), curcumin (368.4mg, 1.0mmol), LiCl
(42.0mg, 1.0mmol) is in EtOH/H2Mixing, is stirred at reflux 12h in O (30/10ml), obtains dark solution, removes solvent,
Column chromatography DCM:MeOH=10:1 obtains 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) δ 3.75 (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.
Embodiment 2
The synthesis of complex 2:
By Cis- (phen)2RuCl2(53.2mg, 0.10mmol), curcumin (368.4mg, 1.0mmol), LiCl
(42.0mg, 1.0mmol) is in EtOH/H2Mixing, is stirred at reflux 12h in O (30/10ml), obtains dark solution, removes solvent,
Column chromatography DCM:MeOH=15:1 obtains 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) δ 3.73 (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.
Embodiment 3
The synthesis of complex 3:
By [Ru (bpy) (dppn) Cl2] (66.1mg, 0.1mmol), curcumin (368.4mg, 1.0mmol), LiCl
(42.0mg, 1.0mmol) is in EtOH/H2Mixing, is stirred at reflux 12h in O (30/10ml), obtains dark solution, removes solvent,
Column chromatography DCM:MeOH=15:1 obtains dark brown powder.Yield:40.5%.Black-brown powder.Anal.Calcd
(%) for 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.
Embodiment 4
Anticancer activity test:
The tumor cell line of selection includes Non-small cell lung carcinoma cell line A549, MCF-7 cell strainHJ2mm, people's stomach
Cancer cell line SGC7901 is attached cell, using preparation-obtained complex 1-3 in mtt assay testing example 1-3 to 3
The toxicity of kind of tumour cell designs 5 drug concentration gradients using cis-platinum, curcumin as positive control, and parallel laboratory test 3 times.
Cell culture condition: cell culture medium is green containing 10% fetal calf serum, 100 μ g/mL streptomysins and 100 μ g/mL
The RPMI-1640 of mycin, condition of culture 5%CO2, 37 DEG C of sterile humidified incubators.
Mtt assay: the cell count of logarithmic growth phase is inoculated in 96 well culture plates, every 100 μ L cell suspension of hole, about
1000-10000 cell, edge hole are filled with PBS or ultrapure water, 5%CO2, 37 DEG C be incubated overnight, carried out after cell is adherent
Administration, sets administration group, positive controls and negative control group respectively.Complex to be measured according to dissolubility difference, with DMSO or
5% glucose solution is configured to reservoir, before use with cell culture medium at a series of concentration, the wherein final concentration of DMSO
No more than 5 ‰.Each concentration sets 3 multiple holes.It cultivates 48 hours after dosing, is observed under inverted microscope, add the 20 μ L concentration to be
The MTT solution of 5mg/mL, 37 DEG C are incubated for 4 hours, remove supernatant, and 150 μ LDMSO are added and sufficiently dissolve first a ceremonial jade-ladle, used in libation.Existed with microplate reader
The OD value in every hole is measured under 490nm wavelength, and calculates inhibiting rate, is done concentration-inhibiting rate curve using SPSS18 software and is calculated
IC50 value.
The cytotoxic activity IC of compound50Value
Active testing shows ruthenium (II) the complex activity with higher using curcumin derivate as ligand, with turmeric
Element or cis-platinum etc. are compared, and of the invention using curcumin derivate is ruthenium (II) complex of ligand to lung cancer, breast cancer, gastric cancer
Equal cancer cells all have better inhibitory activity, can be used for preparing anticancer drug；And in complex 1-3, the entirety of complex 3
Activity is optimal.
Claims (10)
1. it is a kind of using curcumin derivate as ruthenium (II) complex of ligand, pharmaceutically acceptable salt and solvate,
Structure is shown in formula I:
Wherein X is C or N；
The substituent R, R1、R2、R3For H, halogen, alkyl, alkoxy, alkylthio group, hydroxyl, sulfydryl, amino, naphthenic base, virtue
Base, aryloxy group, arylthio or heteroaryl；The substituent R, R1、R2、R3Two of middle arbitrary neighborhood can connect cyclization；The X1
Indicate periphery anion.
2. according to claim 1 using curcumin derivate as ruthenium (II) complex of ligand, which is characterized in that it is described with
Curcumin derivate is ruthenium (II) complex structure of ligand as shown in Formulas I -1, I-2, I-3:
The substituent R, R ', R2、R3For the alcoxyl of the linear chain or branched chain of H, halogen, the alkyl of the linear chain or branched chain of C1-6, C1-6
The aryl of base or C3-C10；Substituent R1For hydroxyl, the X1For halogen, trifluoromethanesulfonic acid root, PF6 -、B(C6F5)3 -。
3. according to claim 1 using curcumin derivate as ruthenium (II) complex of ligand, which is characterized in that it is described with
Curcumin derivate is that ruthenium (II) complex structure of ligand is as follows:
4. a kind of described in claim 1 using curcumin derivate as the preparation method of ruthenium (II) complex of ligand, feature
It is, includes the following steps:
Ruthenium precursor is mixed in a solvent with curcumin derivate, LiCl, is stirred at reflux reaction, removes solvent, column chromatographs to obtain
Using curcumin derivate as ruthenium (II) complex of ligand.
5. the preparation method according to claim 4, which is characterized in that the ruthenium precursor is preferably Cis- (bpy)2RuCl2、
Cis-(phen)2RuCl2Or [Ru (bpy) (dppn) Cl2]；The curcumin derivate is curcumin.
6. the preparation method according to claim 4, which is characterized in that the molar ratio of the ruthenium precursor and curcumin derivate
For 1:1-20；The molar ratio of curcumin derivate and LiCl are 1:1.
7. the preparation method according to claim 4, which is characterized in that the solvent is EtOH/H2O, volume ratio 3:1.
8. the preparation method according to claim 4, which is characterized in that described to be stirred at reflux the time as 12-24h；The column
Solvent system is DCM/MeOH, volume ratio 10:1.
9. a kind of described in claim 1 using curcumin derivate as ruthenium (II) complex of ligand and its pharmaceutically acceptable
Salt or solvate are preparing the application in anticancer drug.
10. a kind of pharmaceutical composition for anticancer, wherein matching containing described by the ruthenium (II) of ligand of curcumin derivate
Object or its pharmaceutically acceptable salt or solvate are closed as active constituent and pharmaceutically acceptable carrier.
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| CN111939124A (en) * | 2020-07-13 | 2020-11-17 | 东南大学 | Metal polymer, metal polymer nano micelle, and preparation method and application thereof |
| CN111939124B (en) * | 2020-07-13 | 2022-06-28 | 东南大学 | Metal polymer, metal polymer nano micelle, and preparation method and application thereof |
| CN111875643A (en) * | 2020-08-10 | 2020-11-03 | 重庆医科大学 | Novel ruthenium-arene complex, preparation method and anti-tumor application thereof |
| CN113845549A (en) * | 2021-09-26 | 2021-12-28 | 广州鲁比生物科技有限公司 | Formononetin derivative and preparation method and application thereof |
| CN113845549B (en) * | 2021-09-26 | 2023-09-19 | 广州鲁比生物科技有限公司 | Formononetin derivative and preparation method and application thereof |
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