CN111253418A - Novel white leaf vine zinc (II) complex and synthesis method and application thereof - Google Patents
Novel white leaf vine zinc (II) complex and synthesis method and application thereof Download PDFInfo
- Publication number
- CN111253418A CN111253418A CN202010055037.XA CN202010055037A CN111253418A CN 111253418 A CN111253418 A CN 111253418A CN 202010055037 A CN202010055037 A CN 202010055037A CN 111253418 A CN111253418 A CN 111253418A
- Authority
- CN
- China
- Prior art keywords
- zinc
- complex
- cryptolepine
- ligand
- synthesizing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- KURWKDDWCJELSV-UHFFFAOYSA-N cryptolepine Chemical class N1=C2C=CC=C[C]2C(N2C)=C1C=C1[C]2C=CC=C1 KURWKDDWCJELSV-UHFFFAOYSA-N 0.000 claims abstract description 52
- 239000003446 ligand Substances 0.000 claims abstract description 22
- 229960005503 cryptolepine Drugs 0.000 claims abstract description 19
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000011592 zinc chloride Substances 0.000 claims abstract description 8
- 235000005074 zinc chloride Nutrition 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 6
- 239000002798 polar solvent Substances 0.000 claims abstract description 5
- 239000000843 powder Substances 0.000 claims abstract description 4
- 239000007787 solid Substances 0.000 claims abstract description 4
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 3
- 239000011701 zinc Substances 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 206010006187 Breast cancer Diseases 0.000 claims description 11
- 208000026310 Breast neoplasm Diseases 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims 1
- 230000005918 in vitro anti-tumor Effects 0.000 abstract description 6
- 238000001727 in vivo Methods 0.000 abstract description 3
- 230000005917 in vivo anti-tumor Effects 0.000 abstract description 3
- 230000008685 targeting Effects 0.000 abstract description 3
- 210000004027 cell Anatomy 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 7
- 229960004316 cisplatin Drugs 0.000 description 6
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 230000001093 anti-cancer Effects 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 206010033128 Ovarian cancer Diseases 0.000 description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012216 screening Methods 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
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 241000219108 Bryonia dioica Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- MXTLAHSTUOXGQF-UHFFFAOYSA-O Jatrorrhizine Chemical class COC1=CC=C2C=C3C(C=C(C(=C4)O)OC)=C4CC[N+]3=CC2=C1OC MXTLAHSTUOXGQF-UHFFFAOYSA-O 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
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 238000000006 cell growth inhibition assay Methods 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002994 raw material Substances 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
- 150000003839 salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
Images
Classifications
-
- 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
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/003—Compounds containing elements of Groups 2 or 12 of the Periodic Table without C-Metal linkages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a novel white leaf vine zinc (II) complex and a synthesis method and application thereof. The chemical structural formula of the white leaf vine zinc (II) complex is
The synthesis method comprises the steps of reacting the cryptolepine derivative with 2-aminomethyl pyridine in the presence of a solvent to generate a yellow solid powder T2 ligand; and performing coordination reaction on the T2 ligand and zinc (II) chloride in equal amount in the presence of a polar solvent to obtain a yellow target product, namely the cryptolepine zinc (II) complex. The cryptolepine zinc (II) complex shows excellent in-vivo and in-vitro anti-tumor activity and targeting property, has potential medicinal value, and is expected to be used for preparing various anti-tumor medicaments.
Description
Technical Field
The invention relates to a complex, in particular to a novel zinc (II) complex of cryptolepine. Meanwhile, the invention also relates to a synthetic method and application of the complex.
Background
The clinical anticancer application of platinum drugs such as cisplatin, carboplatin and oxaliplatin makes the research of metal anticancer complexes one of the key points of the research of inorganic drugs, promotes the design, synthesis and screening of anticancer complexes to become a hot topic, and is very interested in inorganic anticancer compounds hopefully used in clinical medicine. However, the many limitations of cisplatin drugs make the synthesis of non-platinum metal complexes highly active as anti-cancer agents, with low toxic side effects and broad anti-cancer spectrum highly challenging.
In addition, the cryptolepine compounds have physiological activities of antibiosis, antivirus, hyperglycemia resistance and the like, and are important alkaloids. From the current reports, no metal complex reported by taking the cryptolepine and the derivative as ligands exists.
Disclosure of Invention
One of the purposes of the invention is to provide a novel white vine zinc (II) complex.
In particular to a novel white leaf vine zinc (II) complex with a chemical formula of [ Zn (T2) (H)2O)Cl2](T2-Zn) having the chemical formula:
the invention also aims to provide a method for synthesizing a novel white leaf vine zinc (II) complex.
Specifically, the synthesis method of the cryptolepine zinc (II) complex comprises the following steps:
(1) reacting the cryptolepine derivative (SM) with 2-aminomethyl pyridine in the presence of a solvent to generate a T2 ligand as yellow solid powder;
(2) the T2 ligand and zinc chloride (II) with the same amount of substance are subjected to coordination reaction in the presence of a polar solvent to obtain a yellow target product T2-Zn.
The synthetic route of the invention is as follows:
in the step (1), the molar ratio of the cryptolepine derivative (SM) to the 2-aminomethyl pyridine is 1: 1-1.2.
In the step (1), the byssurine derivative (SM) reacts with 2-aminomethyl pyridine at 45-60 ℃ for 15-18 hours.
In the step (2), the coordination reaction temperature is 27-100 ℃, and the reaction time is 4-80 h.
In the step (2), the polar solvent is any one solvent of methanol, ethanol, dichloromethane and chloroform or a mixed solution of two solvents, wherein the two solvents in the mixed solution are in any ratio.
The invention also aims to provide application of the cryptolepine zinc (II) complex. In particular to application of the cryptolepine zinc (II) complex in preparing antitumor drugs. More specifically, an application of the cryptolepine zinc (II) complex in preparation of a drug for targeted therapy of breast cancer is provided.
The invention has the beneficial effects that:
compared with the prior art, the novel jatrorrhizine derivative T2 active ligand is used as the ligand to synthesize the zinc complex [ Zn (T2) (H)2O)Cl2](T2-Zn). Through inspection, the human ovarian cancer resistant strain has the activities on human cervical cancer cells HeLa, human breast cancer cells (MCF-7 and MDA-MB-231), human ovarian cancer resistant strains SK-OV-3/DDP cells and human normal liver HL-7702 cellsSex and toxicity tests. MTT experimental results show that the complex T1-Zn selectively inhibits human breast cancer cells MCF-7, and the IC thereof50The value is 8.19 +/-0.52 mu M, and the in vitro anti-tumor activity of the compound is far greater than that of T2 ligand (30.89 +/-0.44 mu M) and a clinical classical metal-based anti-cancer drug cisplatin (11.24 +/-0.47 mu M); in addition, the toxicity of the complex T1-Zn to the normal cell HL-7702 is very small (IC)50More than 100 mu M), shows good target inhibition of human breast cancer proliferation. In a word, the complex T1-Zn shows excellent in-vivo and in-vitro anti-tumor activity and targeting property, has potential medicinal value and is expected to be used for preparing anti-breast cancer medicaments.
Drawings
FIG. 1 is a hydrogen nuclear magnetic resonance spectrum of T2 obtained in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of T2 obtained in example 1 of the present invention;
FIG. 3 is an electrospray mass spectrum of a complex T2-Zn prepared in example 1 of the present invention;
FIG. 4 is a NMR chart of T2-Zn prepared in example 1 of the present invention;
FIG. 5 shows the NMR spectrum of T2-Zn prepared in example 1 of the present invention.
Detailed Description
The present invention is further illustrated by the following specific examples, but the present invention is not limited to these examples.
The raw material of the cryptolepine derivative SM involved in the synthesis method of the present invention is prepared by referring to the existing literature (Gu, L. -Q.; et al.J.Med.chem.,2005,48: 7315-7321.).
Example 1
1. Synthesis and characterization of ligand T2:
in a 25.0mL round bottom flask, 1.0mol of the cryptolepine derivative SM and 1.10mol of 2-aminomethylpyridine were weighed and dissolved in a solution containing 5.0mL of phenol, and after reacting at 50.0 ℃ for 16.0 hours, a yellow solid powder of T2 ligand was obtained in a yield of 70.1%.
The resulting T2 was characterized:
(1) the NMR spectrum is shown in FIG. 1.
1H NMR(400MHz,CHCl3-d)δ8.68(d,J＝4.6Hz,1H),8.36(d,J＝7.7Hz,1H),8.24-8.06(m,2H),7.76-7.64(m,2H),7.59(d,J＝3.7Hz,2H),7.50(dt,J＝1.1,7.6Hz,1H),7.46-7.39(m,2H),7.26(s,1H),6.79(br s,1H),5.38(d,J＝4.9Hz,2H).
(2) NMR spectrum of carbon, as shown in FIG. 2.
13C NMR(101MHz,CHCl3-d)δ158.30,156.88,149.08,147.18(d,J＝15.4Hz,1C),136.76,134.06(d,J＝3.7Hz,1C),130.29-129.35(m,1C),127.92,124.27-123.23(m,1C),123.03,122.47,122.01(d,J＝24.9Hz,1C),120.51,118.28,111.88,49.48.
(3) The results of elemental analysis are shown in Table 1.
Table 1 elemental analysis results of Compounds T2 and T1-Zn in the examples
Thus, the yellow target product obtained was identified as compound T2, having the formula:
2. synthesizing and characterizing a complex T2-Zn:
weighing 1.0mmol of ligand T2 and 1.0mmol of zinc chloride (II), dissolving in 10mL of methanol and 1mL of dichloromethane solution, carrying out coordination reaction for 4h at 80 ℃, using 5.0mL of diethyl ether for 3 times, and drying in a vacuum drying oven at 40 ℃ to obtain a yellow target product T2-Zn. The yield was: 85.0 percent.
The obtained T1-Zn was identified:
(1) electrospray mass spectrometry, the spectrum of which is shown in FIG. 3.
ESI-MS m/z:460.1[M-H-(H2O)]+Wherein M is the molecular weight of the compound T2-Zn.
(2) NMR spectrum as shown in FIG. 4.
1H NMR(500MHz,DMSO-d6)δ8.58–8.52(m,2H),8.21(d,J＝7.7Hz,1H),8.02(d,J＝8.5Hz,1H),7.79(t,J＝7.8Hz,1H),7.74(td,J＝7.7,1.8Hz,1H),7.70–7.65(m,1H),7.65–7.57(m,2H),7.47(dq,J＝7.7,4.3Hz,2H),7.26(dd,J＝7.4,4.9Hz,1H),5.32(d,J＝6.3Hz,2H).
(2) NMR spectrum of carbon, as shown in FIG. 5.
13C NMR(126MHz,DMSO-d6)δ159.55,157.61,149.53,149.50,137.49,137.47,132.82,131.54,130.02,126.62,124.57,124.17,123.13,122.76,122.33,121.43,117.79,112.78,50.04,40.47,40.30,40.14,39.97,39.80,39.64,39.47.
(4) The results of elemental analysis are shown in Table 1.
Therefore, the obtained yellow target product can be determined to be complex T2-Zn, and the structural formula is as follows:
example 2
Weighing 1.0mmol of ligand T2 and 1.0mmol of zinc chloride (II), dissolving in 100mL of dichloromethane solution, carrying out coordination reaction for 80h at 30 ℃, using 5.0mL of diethyl ether for 3 times, and drying in a vacuum drying oven at 40 ℃ to obtain a yellow target product T2-Zn. The yield was: 60.2 percent.
Example 3
Weighing 1.0mmol of ligand T2 and 1.0mmol of zinc chloride (II), dissolving in 50mL of ethanol solution, carrying out coordination reaction for 80h at 100 ℃, using 5.0mL of diethyl ether for 3 times, and drying in a vacuum drying oven at 40 ℃ to obtain a yellow target product T2-Zn. The yield was: 75.0 percent.
Example 4
Weighing 1.0mmol of ligand T2 and 1.0mmol of zinc chloride (II), dissolving in 10mL of methanol and 10mL of ethanol solution, carrying out coordination reaction at 55 ℃ for 36h, using 5.0mL of diethyl ether for 3 times, and drying in a vacuum drying oven at 40 ℃ to obtain a yellow target product T2-Zn. The yield was: 69.9 percent.
To fully illustrate the utility of the novel cryptolepine zinc (II) complex T2-Zn in the pharmaceutical industry, the applicants have conducted in vitro anti-tumor activity assays.
Experiment on proliferation inhibition activity of novel cryptolepine zinc (II) complex T2-Zn on various human tumor cell strains
1. Cell lines and cell cultures
The experiment selects 5 human cell strains such as human cervical carcinoma HeLa cells, human ovarian cancer cisplatin drug-resistant SK-OV-3/DDP cells, human breast cancer cells (MCF-7 and MDA-MB-231) and human normal liver HL-7702 cells.
All human cell lines were cultured in RPMI-1640 medium containing 100U/mL penicillin, 10 wt% calf blood, and 100U/mL streptomycin, and placed at 37 deg.C with 5% CO by volume2Culturing in an incubator.
2. Preparation of test Compounds
The purity of the ligand T2 and the complex T2-Zn is more than or equal to 95 percent, the DMSO stock solutions of the ligand T2 and the complex T2-Zn are diluted into a final solution of 20 mu mol/L (the final concentration of DMSO is less than or equal to 1 percent) by using a physiological buffer solution, and the inhibition degree of each compound on the growth of normal cells or selected tumor cells under the concentration is tested.
3. Cell growth inhibition assay (MTT method)
(1) Taking normal cells or tumor cells in a logarithmic growth phase, digesting the cells or tumor cells by trypsin, preparing a cell suspension with the concentration of 5000/mL by using a culture solution containing 10% calf serum, inoculating 190 mu L of the cell suspension into a 96-hole culture plate, and enabling the density of cells to be detected to reach 1000-10000 holes (the edge holes are filled with sterile PBS);
(2)5％CO2incubating for 24h at 37 ℃ until a cell monolayer is paved on the bottom of each well, adding 10 mu L of medicine with a certain concentration gradient into each well, and arranging 4 compound wells in each concentration gradient;
(3)5％CO2incubating at 37 ℃ for 48 hours, and observing under an inverted microscope;
(4) add 10. mu.L of MTT solution (5mg/mL PBS, i.e., 0.5% MTT) to each well and continue culturing for 4 h;
(5) terminating the culture, carefully removing the culture solution in the wells, adding 150 μ L of DMSO into each well to sufficiently dissolve formazan precipitate, mixing uniformly with an oscillator, and measuring the optical density of each well with a microplate reader at a wavelength of 570nm and a reference wavelength of 450 nm;
(6) simultaneously, a zero setting hole (culture medium, MTT, DMSO) and a control hole (cells, culture solution, MTT, a drug dissolving medium with the same concentration, DMSO) are arranged.
(7) The number of living cells was judged from the measured optical density values (OD values), and the larger the OD value, the stronger the cell activity. Using the formula:
calculating the inhibition rate of each compound on the growth of the selected cells, and calculating the IC of each tested compound on each selected cell strain by a Bliss method50The value is obtained. The results are shown in table 2 below.
TABLE 2 IC of ligand T2 and Complex T2-Zn on various cell lines50Value (μ M)
Slave IC50According to the result of activity screening, the proliferation inhibition activity of the complex T2-Zn on 4 tested human tumor cell strains, namely human cervical cancer HeLa cells, human ovarian cancer cisplatin-resistant SK-OV-3/DDP cells, human breast cancer cells MCF-7 and human breast cancer cells MDA-MB-231 is obviously higher than that of metal salt ZnCl2And ligand 2, which embodies the synergistic effect of ligand T2 with the zinc central atom. Wherein the complex T2-Zn can target and inhibit human breast cancer cell MCF-7 and IC thereof50The value is 8.19 +/-0.52 mu M, and the in vitro anti-tumor activity of the compound is far greater than that of T2 ligand (30.89 +/-0.44 mu M) and clinical anti-cancer drug cisplatin (11.24 +/-0.47 mu M); in addition, the toxicity of the complex T2-Zn to the normal cell HL-7702 is very small (IC)50More than 100 mu M), shows good target inhibition of human breast cancer proliferation. In a word, the complex T2-Zn shows excellent in-vivo and in-vitro anti-tumor activity and targeting property, has potential medicinal value and is expected to be used for preparing anti-tumor medicaments.
Claims (9)
1. A novel cryptolepine zinc (II) complex is characterized in that the chemical formula is [ Zn (T2) (H)2O)Cl2]Chemical structure ofThe formula is shown as follows:
2. the method for synthesizing novel cryptolepine zinc (II) complex as claimed in claim 1, which comprises the following steps:
(1) reacting the cryptolepine derivative with 2-aminomethyl pyridine in the presence of a solvent to generate a yellow solid powder T2 ligand;
(2) the T2 ligand and zinc chloride (II) with equal amount of substance are subjected to coordination reaction in the presence of a polar solvent to obtain a yellow target product T2-Zn.
3. The method for synthesizing the cryptolepine zinc (II) complex as claimed in claim 2, wherein in the step (1), the molar ratio of cryptolepine derivative to 2-aminomethyl pyridine is 1: 1-1.2.
4. The method for synthesizing the cryptolepine zinc (II) complex according to claim 2 or 3, wherein in the step (1), the cryptolepine derivative is reacted with 2-aminomethylpyridine at 45-60 ℃ for 15-18 hours.
5. The method for synthesizing the cryptolepine zinc (II) complex according to claim 4, wherein in the step (1), the cryptolepine derivative is reacted with lutidine at 50 ℃ for 16 hours.
6. The method for synthesizing the cryptolepine zinc (II) complex as claimed in claim 2 or 3, wherein in the step (2), the coordination reaction temperature is 27-100 ℃ and the reaction time is 4-80 h.
7. The method for synthesizing the cryptolepine zinc (II) complex as claimed in claim 2 or 3, wherein in the step (2), the polar solvent is any one of methanol, ethanol, dichloromethane and chloroform or a mixed solution of two of the solvents; wherein, the two solvents in the mixed solution are in any ratio.
8. The use of the cryptolepine zinc (II) complex of claim 1 in the preparation of an anti-tumor medicament.
9. Use of the cryptolepine zinc (II) complex of claim 1 in the preparation of a medicament for the targeted treatment of breast cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010055037.XA CN111253418A (en) | 2020-01-17 | 2020-01-17 | Novel white leaf vine zinc (II) complex and synthesis method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010055037.XA CN111253418A (en) | 2020-01-17 | 2020-01-17 | Novel white leaf vine zinc (II) complex and synthesis method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111253418A true CN111253418A (en) | 2020-06-09 |
Family
ID=70923716
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010055037.XA Pending CN111253418A (en) | 2020-01-17 | 2020-01-17 | Novel white leaf vine zinc (II) complex and synthesis method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111253418A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114573598A (en) * | 2022-03-21 | 2022-06-03 | 玉林师范学院 | White leaf vine zinc (II) complex with high activity in vivo and in vitro and synthesis method and application thereof |
| CN115160347A (en) * | 2022-08-11 | 2022-10-11 | 玉林师范学院 | High-activity glycosyl solanum lyratum zinc (II) complex and application |
| CN115385940A (en) * | 2022-08-11 | 2022-11-25 | 玉林师范学院 | White leaf vine zinc (II) complex and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103224500A (en) * | 2013-03-26 | 2013-07-31 | 广东工业大学 | Annular secondary amino substitution cryptolepine ramification and preparation method thereof and application of annular substitution cryptolepine ramification being used as anti-cancer drug |
| CN104513240A (en) * | 2015-01-14 | 2015-04-15 | 中国药科大学 | Preparation method and use of iso-cryptolepine derivatives |
-
2020
- 2020-01-17 CN CN202010055037.XA patent/CN111253418A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103224500A (en) * | 2013-03-26 | 2013-07-31 | 广东工业大学 | Annular secondary amino substitution cryptolepine ramification and preparation method thereof and application of annular substitution cryptolepine ramification being used as anti-cancer drug |
| CN104513240A (en) * | 2015-01-14 | 2015-04-15 | 中国药科大学 | Preparation method and use of iso-cryptolepine derivatives |
Non-Patent Citations (8)
| Title |
|---|
| LI-QIN QIN，等: "Mitochondria-localizing curcumin-cryptolepine Zn(II) complexes and their antitumor activity", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| QI-PIN QIN，等: "Imaging and therapeutic applications of Zn(II)-cryptolepine-curcumin molecular probes in cell apoptosis detection and photodynamic therapy", 《CHEMICAL COMMUNICATIONS》 * |
| 张伟: "白叶藤碱类似物及其糖衍生物的合成", 《中国优秀博硕士学位论文全文数据库(硕士) 医药卫生科技辑》 * |
| 田富国，主编: "《乳腺癌的非手术治疗》", 30 April 2016, 华中科技大学出版社 * |
| 纪丽君: "部分天然产物单体组分抗菌抗肿瘤作用研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
| 陈临溪，等主编: "《细胞信号转导药理与临床》", 31 October 2014, 人民军医出版社 * |
| 顾运琼，等: "溴代色胺酮铁(Ⅱ)配合物的合成、晶体结构及与DNA的作用研究", 《化学世界》 * |
| 黄锁义，等主编: "《基础化学》", 31 August 2018, 华中科技大学出版社 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114573598A (en) * | 2022-03-21 | 2022-06-03 | 玉林师范学院 | White leaf vine zinc (II) complex with high activity in vivo and in vitro and synthesis method and application thereof |
| CN115160347A (en) * | 2022-08-11 | 2022-10-11 | 玉林师范学院 | High-activity glycosyl solanum lyratum zinc (II) complex and application |
| CN115385940A (en) * | 2022-08-11 | 2022-11-25 | 玉林师范学院 | White leaf vine zinc (II) complex and application thereof |
| CN115385940B (en) * | 2022-08-11 | 2023-09-12 | 玉林师范学院 | Zinc (II) complex of sinomenine and application thereof |
| CN115160347B (en) * | 2022-08-11 | 2023-09-12 | 玉林师范学院 | Glycosyl white vine zinc (II) complex and application |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107746418B (en) | Synthesis and application of 9-chloro-1, 2,3, 4-tetrahydroacridine-platinum (II) complex targeting liver cancer | |
| CN111187303B (en) | Platinum (II) complex with high antitumor activity of cryptolepine, and synthetic method and application thereof | |
| CN111253418A (en) | Novel white leaf vine zinc (II) complex and synthesis method and application thereof | |
| CN110950914B (en) | Iridium complex and synthesis method and application thereof | |
| CN111153916A (en) | White leaf vine zinc (II) complex and synthesis method and application thereof | |
| CN108774270B (en) | Sorafenib antitumor platinum (II) complex targeting drug-resistant cells of human lung cancer and preparation method and application thereof | |
| CN108774269B (en) | Novel targeted benzimidazole derivative antitumor platinum (II) and ruthenium (II) complex and preparation method and application thereof | |
| CN111039990B (en) | Low-toxicity iridium complex and synthesis method and application thereof | |
| CN111205311A (en) | Novel high-antitumor-activity white leaf vine zinc (II) complex and synthesis method and application thereof | |
| WO2013086804A1 (en) | 4-pyridyl porphyrin bridged crisscross quad-nuclear platinum complex, and preparation method and anti-tumor activity thereof | |
| CN110330534B (en) | Novel 2-phenylpyridine-platinum (IV) precursor anticancer complex and synthesis method and application thereof | |
| Du et al. | Organotin (IV) complexes derived from 1, 4-naphthalenedicarboxylic acid: synthesis, structure, in vitro cytostatic activity | |
| CN108558952B (en) | 2-phenylpyridine binuclear palladium (II) complex and preparation method and application thereof | |
| CN113683644B (en) | Bis-quinoline iridium complex for treating cisplatin-resistant cancer cells and preparation method and application thereof | |
| CN113527370A (en) | Quinoline iridium complex targeting lung cancer cisplatin drug-resistant cells and synthesis method and application thereof | |
| CN114539294B (en) | Cisplatin-resistant cell white rattan-phenanthrene Luo Linxin (II) complex for targeting human lung adenocarcinoma, synthesis method and application thereof | |
| CN114573598B (en) | White She Tengxin (II) complex with high in-vivo and in-vitro activity and synthesis method and application thereof | |
| CN107827934B (en) | Tetravalent platinum complex with anticancer activity, preparation method and application | |
| CN110172075B (en) | Novel coumarin-quinoline-platinum (II) complex and synthesis method and application thereof | |
| CN108997436B (en) | Rueglini antitumor platinum (II) complex and preparation method and application thereof | |
| CN110105402B (en) | Berberine antitumor platinum (II) complex and synthesis method and application thereof | |
| CN110156842B (en) | Coumarin-platinum (II) complex targeting lung cancer drug-resistant strain and synthesis method and application thereof | |
| CN115385940B (en) | Zinc (II) complex of sinomenine and application thereof | |
| CN108456231B (en) | Bis-halo coumarin-platinum (II) complex and synthesis method and application thereof | |
| CN115160347B (en) | Glycosyl white vine zinc (II) complex and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200609 |
|
| WD01 | Invention patent application deemed withdrawn after publication |