CN109694391B - Platinum complex taking 2-amino-5-chlorobenzophenone thiosemicarbazone as ligand and synthetic method and application thereof - Google Patents
Platinum complex taking 2-amino-5-chlorobenzophenone thiosemicarbazone as ligand and synthetic method and application thereof Download PDFInfo
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- CN109694391B CN109694391B CN201811567156.2A CN201811567156A CN109694391B CN 109694391 B CN109694391 B CN 109694391B CN 201811567156 A CN201811567156 A CN 201811567156A CN 109694391 B CN109694391 B CN 109694391B
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims abstract description 51
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- 239000003446 ligand Substances 0.000 title claims abstract description 12
- AQKPBQCYVYASJK-UHFFFAOYSA-N [[(2-amino-5-chlorophenyl)-phenylmethylidene]amino]thiourea Chemical compound C=1C(Cl)=CC=C(N)C=1C(=NNC(=S)N)C1=CC=CC=C1 AQKPBQCYVYASJK-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000010189 synthetic method Methods 0.000 title abstract description 4
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- 239000013078 crystal Substances 0.000 claims abstract description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 21
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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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- 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
- C07F15/0086—Platinum compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses a platinum complex taking 2-amino-5-chlorobenzophenone thiosemicarbazone as a ligand, a synthetic method and application thereof, wherein the synthetic method of the platinum complex comprises the following steps: 1) dissolving 2-amino-5-chlorobenzophenone in ethanol, adding thiosemicarbazide, uniformly mixing, dropwise adding 3-4 drops of concentrated sulfuric acid, refluxing, filtering, volatilizing filtrate at room temperature to separate out light yellow crystals, filtering the crystals, and washing with absolute ethanol for 2-3 times to obtain a compound; 2) taking the compound obtained in the step 1) and Pt (DMSO)2Cl2Placing the mixture into a glass tube with one sealed end, dropwise adding methanol into the glass tube to dissolve the methanol, sealing the glass tube in vacuum, and placing the glass tube in a 60 ℃ forced air drying oven for standing for 72 hours to obtain the target complex. The complex has novel structure, greatly improved activity, more excellent neuroblastoma inhibiting activity, contribution to the penetration of BBB and certain overcoming of drug resistanceAnd (4) sex.
Description
Technical Field
The invention relates to synthesis of a metal complex, in particular to a platinum complex taking 2-amino-5-chlorobenzophenone thiosemicarbazone as a ligand, a synthesis method and application thereof.
Background
The Blood Brain Barrier (BBB) is a dynamic interface for the separation of the central nervous system from the circulatory system. It maintains homeostasis and normal neural function by regulating the exchange of substances between the central nervous system and the circulatory system. Studies have reported that less than 3% of cns drugs pass through the BBB for therapeutic purposes and are essentially small molecule drugs. Therefore, the risk of developing new brain disease drugs is very high for drug research and development enterprises, which greatly limits the development of brain drugs. In particular, treatment of brain tumors remains limited by the BBB. The compound must enter the brain tissue through the BBB, which has become a primary problem in the development of compounds for the treatment of brain tumors. By referring to the neural drug micromolecules which appear on the market for many years, the invention provides a new idea for the design of the brain tumor inhibiting compound due to the good BBB penetrating capability of the neural drug micromolecules. In order to realize the dual effects of good inhibitory activity to brain tumors in vivo and in vitro and the ability of fat-soluble nerve drug small group enhancing compounds to penetrate BBB, benzodiazepine sedative hypnotic drugs are used as special structural fragments (2-amino-5-chlorobenzophenone) of nerve drug small molecules. Whereas the key fragment, 2-amino-5-chlorobenzophenone, through the BBB, is metabolized by the liver mainly as a non-toxic product. However, 2-amino-5-chlorobenzophenone has no significant antitumor activity. Fortunately, the special structure of the compound can be condensed with thiosemicarbazide to form Schiff base, so that the related metal complex can be synthesized, the antitumor activity can be enhanced, and the targeting property of the compound can be improved.
Thiosemicarbazides have been used as antitumor agents for over half a century with major mechanisms including direct induction of DNA damage and inhibition of topoisomerase ii. Over the past half century, thiosemicarbazides have been studied for a number of anti-tumor properties. Since the discovery by Rosenberg that cisplatin (cis- [ PtCl2(NH3)2]) has anti-tumor activity, the study of metal-organic ligand complexes has risen to a hot trend. The platinum drugs mainly cause cross-linking by combining with DNA, thereby destroying the function of the DNA and inhibiting the growth of tumor cells. Studies have shown that metal-organic ligand complexes have higher biological activity than the ligand alone, particularly in terms of antitumor activity and reduced toxicity of the metal.
Thus, to achieve a compound that not only inhibits neuroma cells, but also facilitates BBB penetration. The invention synthesizes a series of brand-new 2-amino-5-chlorobenzophenone thiosemicarbazone platinum metal complexes and researches the neuroma inhibiting activity of the complexes.
Disclosure of Invention
The invention aims to provide a platinum complex taking 2-amino-5-chlorobenzophenone thiosemicarbazone as a ligand, a synthesis method and application thereof.
The technical scheme for realizing the purpose of the invention is as follows:
a platinum complex taking 2-amino-5-chlorobenzophenone thiosemicarbazone as a ligand has a structural formula shown as C1-C4:
the synthetic route of the platinum complex shown in the formula C1-C4 is as follows:
the synthesis method of the platinum complex shown in the formula C1-C4 comprises the following steps:
1) dissolving 2-amino-5-chlorobenzophenone in ethanol, adding thiosemicarbazide, uniformly mixing, dropwise adding 3-4 drops of concentrated sulfuric acid, refluxing, filtering, volatilizing filtrate at room temperature to separate out light yellow crystals, filtering the crystals, and washing with absolute ethanol for 2-3 times to obtain a compound;
2) taking the compound obtained in the step 1) and Pt (DMSO)2Cl2Placing the mixture into a glass tube with one sealed end, dropwise adding methanol into the glass tube to dissolve the methanol, sealing the glass tube in vacuum, and placing the glass tube in a 60 ℃ forced air drying oven for standing for 72 hours to obtain the target complex.
In the step 1), the mass ratio of the thiosemicarbazide to the 2-amino-5-chlorobenzophenone is 1: 1; the mass ratio of thiosemicarbazide to ethanol was 3: 3500.
the thiosemicarbazide is one of 4-methyl-3-thiosemicarbazide, (2-methylphenyl) -3-thiosemicarbazide, thiosemicarbazide and 4- (N, N-tetrahydropyrrole) -3-thiosemicarbazide.
In the step 1), refluxing is carried out at the refluxing temperature of 65 ℃ for 4 h.
In step 2), the compound is reacted with Pt (DMSO)2Cl2The ratio of the amounts of substances (1): 1; the mass ratio of compound to methanol was 1: 0.9-1.
The invention further comprises an anti-tumor medicine prepared by taking the platinum complex C1-C4 as an active ingredient.
Has the advantages that: compared with the prior art, the platinum complex taking the 2-amino-5-chlorobenzophenone thiosemicarbazone as the ligand has the advantages of novel structure, greatly improved activity, more excellent neuroma inhibiting activity, contribution to penetrating BBB and overcoming drug resistance to a certain extent.
Drawings
FIG. 1 is a single crystal structural diagram of the C1 complex synthesized in example 1;
FIG. 2 is a single crystal structural diagram of the C2 complex synthesized in example 2;
FIG. 3 is a single crystal structural diagram of the C3 complex synthesized in example 3;
FIG. 4 is a single crystal structural diagram of the C4 complex synthesized in example 4.
Detailed Description
The invention is further illustrated but not limited by the following figures and examples.
Example 1:
the synthesis method of the C1 complex comprises the following steps:
1) dissolving 3mmol (693mg) of 2-amino-5-chlorobenzophenone in 20mL of ethanol, adding 3mmol (315mg) of 4-methyl-3-thiosemicarbazide, uniformly mixing, dropwise adding 3-4 drops of concentrated sulfuric acid, refluxing, filtering, volatilizing the filtrate at room temperature, separating out light yellow crystals, filtering the crystals, and washing with absolute ethanol for 2-3 times to obtain a compound 1;
Yield:0.75g,78.6％,light yellow solid；Rf＝0.414(Petroleum ether:EtOAc＝1:1).M.p.133-135℃.1H NMR(400MHz,DMSO-d6)δ8.79(q,J＝4.5Hz,1H),8.70(s,1H),7.72-7.69(m,2H),7.42-7.37(m,3H),7.29(dd,J＝8.8,2.5Hz,1H),6.92-6.90(m,2H),5.28(s,2H),3.06(d,J＝4.6Hz,3H).13C NMR(100MHz,DMSO-d6)δ177.72,145.97,144.55,135.86,130.55,129.54,128.25,127.55,119.68,117.44,116.18,31.30.ESI+m/z:calcd for C15H16ClN4S，317[M-H]+。
2) take 0.05mmol (15.9mg) of Compound 1 obtained in step 1) and 23mg of Pt (DMSO)2Cl2Placing the mixture into a glass tube with one sealed end, and dropwise adding 2mL of CH3And (3) after OH is dissolved in the glass tube, sealing the glass tube in vacuum, and placing the glass tube in a 60 ℃ forced air drying oven for standing for 72 hours to obtain the target complex C1, wherein the single crystal structure of the target complex is shown in figure 1.
Yield：0.04g,71.5％,IR,cm-1:IR,cm-1:3434(s,amide),2926(m,aromatic hydrogen),1616(s),1524(s,-C＝C-),1384(s),1262(s,thioamide),1186(s),823(s),743(s,ph-H).ESI+m/z:calcd for C30H26Cl6N8Pt2S2,558[M+H]+。
Example 2:
the synthesis method of the C2 complex comprises the following steps:
1) dissolving 3mmol (693mg) of 2-amino-5-chlorobenzophenone in 20mL of ethanol, adding 3mmol (543mg) of 4- (2-methylphenyl) -3-thiosemicarbazide, uniformly mixing, dropwise adding 3-4 drops of concentrated sulfuric acid, refluxing, filtering, volatilizing the filtrate at room temperature, separating out light yellow crystals, filtering the crystals, and washing with absolute ethanol for 2-3 times to obtain a compound 2;
Yield:0.71g,60.0％,light yellow solid；Rf＝0.421(Petroleum ether:EtOAc＝2:1).M.p.140-142℃.1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),9.04(s,1H),7.82-7.79(m,2H),7.43-7.37(m,3H),7.33-7.29(m,3H),7.25-7.22(m,2H),6.99-6.93(m,2H),5.39(s,2H),2.27(s,3H).13C NMR(100MHz,DMSO-d6)δ176.99,146.83,144.63,137.91,135.82,135.24,130.63,130.08,129.68,128.40,128.29,128.23,127.88,126.83,125.93,119.76,117.56,116.40,17.75.ESI+m/z:calcd for C21H18ClN4S，393[M-H]+。
2) 0.05mmol (15.2mg) of Compound 2 obtained in step 1) and 23mg of Pt (DMSO)2Cl2Placing the mixture into a glass tube with one sealed end, and dropwise adding 2mL of a mixture with the volume ratio of 1: 1 of DMF and CH3And (3) dissolving the OH mixed solution in a glass tube, sealing the glass tube in vacuum, and placing the glass tube in a 60 ℃ forced air drying oven for standing for 72 hours to obtain the target complex C2, wherein the single crystal structure of the target complex is shown in figure 2.
IR,cm-1：3422(s,amide),1619(s),1571(s,-C＝C-),1521(s,-C＝C-),1488(s,-C＝C-),1248(m,thioamide),1155(s),866(s),816(s,ph-H),771(s,ph-H),736(s,ph-H).ESI+m/z:calcd for C42H35Cl6N8Pt2S2，1314[M+H]+。
Example 3:
the synthesis method of the C3 complex comprises the following steps:
1) dissolving 3mmol (693mg) of 2-amino-5-chlorobenzophenone in 20mL of ethanol, adding 3mmol (273mg) of thiosemicarbazide, uniformly mixing, dropwise adding 3-4 drops of concentrated sulfuric acid, refluxing, filtering, volatilizing filtrate at room temperature, separating out light yellow crystals, filtering the crystals, and washing with absolute ethanol for 2-3 times to obtain a compound 3;
Yield:0.76g,83.3％,light yellow solid；Rf＝0.321(Petroleum ether:EtOAc＝1:1).M.p.158-160℃.1H NMR(400MHz,DMSO-d6)δ8.61(s,2H),8.28(s,1H),7.72-7.69(m,2H),7.41-7.35(m,3H),7.28(dd,J＝8.8,2.6Hz,1H),6.92-6.90(m,2H),5.29(s,2H).13C NMR(100MHz,DMSO-d6)δ178.09,146.40,144.57,135.80,130.57,129.60,128.27,127.63,119.68,117.45,116.12.ESI+m/z:calcd for C14H14ClN4S，303[M-H]+。
2) take 0.05mmol (17.9mg) of Compound 3 obtained in step 1) and 23mg of Pt (DMSO)2Cl2Placing the mixture into a glass tube with one sealed end, and dropwise adding 2mL of a mixture with the volume ratio of 1: 1 of DMF and CH2Cl2After the mixed solution is dissolved in a glass tube, the glass tube is sealed in vacuum, and the glass tube is placed in a 60 ℃ forced air drying oven to stand for 72 hours, so that the target complex C3 is obtained, and the single crystal structure of the target complex is shown in figure 4.
IR,cm-1：3439(s,amide),1630(s),1549(s,-C＝C-),1517(s,-C＝C-),1452(s,-C＝C-),1268(m,thioamide),1150(s),820(s),775(s,ph-H),756(s,ph-H),735(s,ph-H).ESI+m/z:calcd for C16H18ClN4OPtS2，576[1/4M+DMSO+H]+。
Example 4:
the synthesis method of the C4 complex comprises the following steps:
1) dissolving 3mmol (693mg) of 2-amino-5-chlorobenzophenone in 20mL of ethanol, adding 3mmol (435mg) of 4- (N, N-tetrahydropyrrole) -3-thiosemicarbazide, uniformly mixing, dropwise adding 3-4 drops of concentrated sulfuric acid, refluxing, filtering, volatilizing the filtrate at room temperature to separate out light yellow crystals, filtering the crystals, and washing with absolute ethanol for 2-3 times to obtain a compound 4;
Yield:0.65g,60.5％,light yellow solid；Rf＝0.35(Petroleum ether:EtOAc＝1:1).M.p.135-137℃.1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),7.71-7.69(m,2H),7.42-7.38(m,3H),7.307.27(m,1H),6.92-6.90(m,2H),5.29(s,2H),3.59(q,J＝6.8Hz,2H),1.64-1.56(m,2H),1.38-1.29(s,2H),0.94-0.90(m,2H).13C NMR(100MHz,DMSO-d6)δ176.91,146.05,144.56,135.85,130.55,129.54,128.26,127.56,119.68,117.44,116.22,43.77,30.82.ESI+m/z:calcd for C18H18ClN4S，357[M-H]+。
2) 0.05mmol (19.7mg) of Compound 4 obtained in step 1) and 23mg of Pt (DMSO)2Cl2Placing the mixture into a glass tube with one sealed end, and dropwise adding 2mL of a mixture with the volume ratio of 1: 1 of DMF and CH3And (3) dissolving the OH mixed solution in a glass tube, sealing the glass tube in vacuum, and placing the glass tube in a 60 ℃ forced air drying oven for standing for 72 hours to obtain the target complex C4, wherein the single crystal structure of the target complex is shown in figure 4.
IR,cm-1：3452(s,amide),1628(s),1536(s,-C＝C-),1517(s,-C＝C-),1452(s,-C＝C-),1260(m,thioamide),1161(s),813(s),769(s,ph-H),734(s,ph-H).ESI+m/z:calcd for C20H24ClN4OPtS2，630[1/4M+DMSO+H]+。
In vitro Activity assay
In vitro proliferation inhibition activity experiments were performed:
1. cell lines and cell cultures
The activity of the experiment is researched by selecting a human neuroma cell strain (SK-N-MC), a human non-small lung cancer cell (A549), a human gastric cancer cell (MGC-803) and a human normal hepatocyte (HL-7702).
All cell lines were cultured in RPMI-1640/DMEM medium containing 10% calf serum and 100U/mL streptomycin at 37 ℃ with 5% CO by volume2Culturing in an incubator.
2. Preparation of test Compounds
The purity of the used test drug is more than or equal to 95 percent, the DMSO stock solution is diluted by physiological buffer solution to be prepared into 5mmol/L final solution, wherein the concentration of the cosolvent DMSO is less than or equal to 1 percent, and the degree of inhibition of the compound on the growth of various tumor cells under the concentration is tested.
3. Cell growth inhibition assay (MTT method)
(1) Taking tumor cells in a logarithmic growth phase, digesting the tumor cells by trypsin, preparing a cell suspension with the concentration of 5000/mL by using a culture solution containing 10% calf serum, inoculating 180 mu L of the cell suspension in a 96-well culture plate in a non-well manner, and enabling the concentration of the cells to be detected to be 1000-10000/well per well (filling a marginal well with sterile PBS);
(2)5％CO2incubating for 24h at 37 ℃ until a cell monolayer is paved on the bottom of the hole, adding 20 mu L of medicine with a certain concentration gradient into each hole, and arranging 5 compound holes in each concentration gradient;
(3)5％CO2incubating at 37 ℃ for 48h until the observation is carried out under an inverted microscope;
(4) adding 10 μ L of MTT solution (5mg/mL PBS, i.e. 0.5% MTT) into each well, and culturing for 4-6 h;
(5) terminating the culture, carefully removing the culture solution in the wells, adding 100. mu.L of DMSO into each well to sufficiently dissolve formazan precipitate, mixing uniformly by using an oscillator, and measuring the optical density of each well by using an microplate reader at a wavelength of 570nm and a reference wavelength of 450 nm;
(6) 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:
tumor cell growth inhibition (%) [ (1-mean OD of experimental group)/(mean OD of control group) ] ×%;
IC50and (3) determination: by using the method, each compound is required to be provided with a concentration gradient which comprises a plurality of (generally 5-8) concentrations, each concentration is also required to be provided with 3-5 secondary holes, the inhibition rate of each different concentration is obtained through experiments, and then the IC of the compound is calculated in SPSS software50The value is obtained.
TABLE 1 IC of the Compounds on different cell lines50Value (μ M)
In Table 1, IC50Lower values (μ M) indicate better compound inhibitory activity. The experimental research result shows that the series of 2-amino-5-chlorobenzophenone thiosemicarbazone platinum complexes synthesized for a plurality of tumor cell strains to be tested have high specificity to human neuroma cells and show good inhibitory activity, and the platinum complexes have no obvious toxicity to normal human hepatocytes.
Claims (5)
1. A platinum complex taking 2-amino-5-chlorobenzophenone thiosemicarbazone as a ligand is characterized in that the structural formula of the platinum complex is as follows:
the synthetic route of the platinum complex is as follows:
the synthesis method of the platinum complex shown by C1-C2 and C4 comprises the following steps:
1) dissolving 2-amino-5-chlorobenzophenone in ethanol, adding thiosemicarbazide, uniformly mixing, dropwise adding 3-4 drops of concentrated sulfuric acid, refluxing, filtering, volatilizing filtrate at room temperature to separate out light yellow crystals, filtering the crystals, and washing with absolute ethanol for 2-3 times to obtain a compound;
2) taking the compound obtained in the step 1) and Pt (DMSO)2Cl2Placing in a glass tube with one sealed end, and dropwise adding methanol or DMF and CH3After OH is dissolved in the glass tube, the glass tube is sealed in vacuum, and is placed in a 60 ℃ forced air drying oven to stand for 72 hours to obtain a target complex;
in the step 1), the mass ratio of the thiosemicarbazide to the 2-amino-5-chlorobenzophenone is 1: 1; the mass ratio of thiosemicarbazide to ethanol was 3: 3500.
2. the platinum complex with 2-amino-5-chlorobenzophenone thiosemicarbazone as a ligand according to claim 1, wherein the thiosemicarbazone is one of 4-methyl-3-thiosemicarbazone, (2-methylphenyl) -3-thiosemicarbazone, thiosemicarbazone and 4- (N, N-tetrahydropyrrole) -3-thiosemicarbazone.
3. The platinum complex with 2-amino-5-chlorobenzophenone thiosemicarbazone as a ligand according to claim 1, wherein the refluxing in step 1) is carried out at 65 ℃ for 4 h.
4. The platinum complex with 2-amino-5-chlorobenzophenone thiosemicarbazone as ligand according to claim 1, wherein in step 2), the compound is reacted with Pt (DMSO)2Cl2The ratio of the amounts of substances (1): 1; compounds with methanol or DMF and CH3The ratio of the amount of OH species is 1: 0.9-1.
5. The use of a platinum complex as claimed in claim 1 as active ingredient in the preparation of an anti-tumor medicament.
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