CN111057094A - Tri (2-methyl-2-phenylpropyl) tin benzothiophene-2-formate complex and preparation method and application thereof - Google Patents
Tri (2-methyl-2-phenylpropyl) tin benzothiophene-2-formate complex and preparation method and application thereof Download PDFInfo
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- DYSJMQABFPKAQM-UHFFFAOYSA-N 1-benzothiophene-2-carboxylic acid Chemical compound C1=CC=C2SC(C(=O)O)=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-N 0.000 claims description 12
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 4
- 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 4
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- AYOHIQLKSOJJQH-UHFFFAOYSA-N dibutyltin Chemical compound CCCC[Sn]CCCC AYOHIQLKSOJJQH-UHFFFAOYSA-N 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- LOAUVZALPPNFOQ-UHFFFAOYSA-N quinaldic acid Chemical compound C1=CC=CC2=NC(C(=O)O)=CC=C21 LOAUVZALPPNFOQ-UHFFFAOYSA-N 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
- C07F7/2224—Compounds having one or more tin-oxygen linkages
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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 tri (2-methyl-2-phenylpropyl) stannyl benzothiophene-2-formate complex, a preparation method and an application thereof, and the complex is represented by the following structural formula (I)
Description
Technical Field
The invention relates to a tri (2-methyl-2-phenylpropyl) stannyl benzothiophene-2-formate complex, a preparation method thereof and application of the complex in preparing anti-tumor drugs.
Background
Since Brown first discovered that organotin carboxylates (CH3CO2SnPh3) have bioactivity in inhibiting mouse tumors, research on the synthesis, structure and bioactivity of organotin carboxylate complexes has received much attention from scientists. However, the known organotin compounds are generally highly toxic and thus have limited applications. Research has shown that the structure, reactivity and biological activity of organotin compounds are related both to the structure of the hydrocarbon group directly attached to the tin atom and to the nature of the ligand. The optimization of the structure of the organic tin complex through molecular design so as to adjust the balance between the toxicity and the biological activity of the organic tin complex is an important direction of research of people at present. The functional activation of alkyl or ligand can greatly change the coordination mode of tin atom, and further influence the bioactivity of organic tin complex. Research shows that the toxicity of the organic tin compound is related to the relative molecular mass of the organic tin compound, the smaller the relative molecular mass is, the greater the toxicity is, and the larger the relative molecular mass of the large steric hindrance alkyl tin. Therefore, the novel alkyl tin complex with large steric hindrance is synthesized, and the structure and the biological activity of the complex are researched, so that the method has important research significance.
As is well known, nitrogen heterocycles are important and common structural units of medicines, pesticides, functional materials and the like, and most of them are closely related to life systems, so that the research on the structure of organotin derivatives of such ligands can not only provide useful information for the revealed anticancer mechanism, but also provide a possible molecular design scheme for the development of novel drugs. Nitrogen-containing heteroatom carboxylic acid is an important carboxylic acid ligand, and the synthesis of novel nitrogen-containing heterocyclic organic tin carboxylate compounds and the research on the biological activity of the nitrogen-containing heterocyclic organic tin carboxylate compounds are very necessary. For example, Chinese patent CN101402650B discloses the application of a dibutyltin and quinolinecarboxylic acid complex in preparing medicines for treating gastric cancer, nasopharyngeal carcinoma, human liver cancer or leukemia.
Based on that the bis [ tri (2-methyl-2-phenylpropyl) ] tin oxide is a substance with better biological activity proved by experiments, and the 2-methyl-2-phenylpropyl has the characteristics of larger steric hindrance, larger molecular weight and the like, the invention selects the bis [ tri (2-methyl-2-phenylpropyl) ] tin oxide to react with a heterocyclic carboxylic acid ligand benzothiophene-2-formic acid under certain conditions to synthesize the complex with stronger inhibitory activity to A549 (human lung cancer cells), Hela (human cervical cancer cells) and HGC-27 (human gastric cancer cells), thereby providing a new way for developing anticancer drugs.
Disclosure of Invention
In view of the problems of the prior art, the first object of the present invention is to provide a tris (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-carboxylate complex.
The second object of the present invention is to provide a process for producing the above tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex.
The third purpose of the invention is to provide the application of the tri (2-methyl-2-phenylpropyl) tin benzothiophene-2-formate complex in preparing anticancer drugs.
A tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex as a first aspect of the present invention is a complex of the following structural formula (I):
(I)。
the results of the tris (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-formate complex of the present invention by elemental analysis, infrared spectroscopic analysis and nuclear magnetic resonance spectroscopy are as follows:
elemental analysis (C)39H44O2SSn): theoretical value: c, 67.35; h, 6.38. Measurement value: c, 67.32; h, 6.40.
IR (KBr, v/cm-1): 3734.19 (m), 3051.39 (w), 2956.87 (m), 2920.23 (m),2860.43 (w), 1645.28 (s), 1521.84 (m), 1456.26 (m), 1363.67 (m), 1336.67 (s),1319.31 (s), 1309.67 (m), 1294.24 (m), 1178.51 (m), 1155.36 (w), 1076.28 (w),1051.20 (w), 1029.99 (w), 864.11 (w),767.67 (s), 721.38 (m), 700.16 (m),669.30 (m), 586.36 (w), 557.43 (w), 457.13 (w)。
1HNMR (CDCl3, 500 MHz), δ (ppm): 7.87 (d,J=11Hz, 3H), 7.44- 7.38(m,2H), 7.30 (t,J=7.5Hz, 6H), 7.22(t,J=7Hz, 3H), 7.14(d,J=7.5Hz, 6H), 1.27(s, 24H)。
13C NMR (CDCl3, 125MHz)δ(ppm): 166.30, 150.77, 142.21, 139.23,137.82, 129.04, 128.37, 126.07, 125.86, 125.25, 125.13, 124.43, 122.67,37.69, 37.52, 32.71(t,J= 22 Hz)。
119Sn NMR(CDCl3, 186 MHz), δ(ppm): 103.99。
The tri (2-methyl-2-phenylpropyl) tin benzothiophene-2-formate complex has the structural characteristics that: the central tin in the molecule forms a distorted tetrahedral configuration with the coordinating atoms.
According to the second aspect of the invention, the preparation method of the tri (2-methyl-2-phenylpropyl) tin benzothiophene-2-formate complex comprises the steps of sequentially adding bis [ tri (2-methyl-2-phenylpropyl) ] tin oxide, benzothiophene-2-carboxylic acid and a solvent toluene into a 250 mL round-bottom flask, installing a Dean-Stark water separator, and carrying out heating reflux reaction at 112-120 ℃ for 6-12 hours. After the reaction is finished, filtering while the reaction is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tri (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-formic ether complex.
In a preferred embodiment of the invention, the mass ratio of the bis [ tri (2-methyl-2-phenylpropyl) ] tin oxide to the benzothiophene-2-carboxylic acid is 1.0 (2.0-2.2).
In a preferred embodiment of the invention, the solvent toluene is added in an amount of 25 to 35 ml per mmol of bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide.
The third aspect of the invention relates to the application of a tri (2-methyl-2-phenylpropyl) tin benzothiophene-2-formate complex in the preparation of anti-cancer drugs.
The applicant carries out in-vitro antitumor activity confirmation research on the complex, and confirms that the complex has certain antitumor biological activity, namely the application of the complex in preparing antitumor drugs, in particular in preparing anti-human lung cancer drugs, human cervical cancer drugs and human gastric cancer drugs.
The tri (2-methyl-2-phenylpropyl) tin benzothiophene-2-formate complex shows good anticancer activity on human lung cancer cells, human cervical cancer cells, human gastric cancer cells and the like, and can be used as a raw material for preparing anti-lung cancer, anti-cervical cancer and anti-gastric cancer drugs. Compared with the currently commonly used platinum anticancer drugs, the tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-formate complex has the characteristics of high anticancer activity, low cost, simple preparation method and the like, and provides a new way for developing anticancer drugs.
Drawings
FIG. 1 is an IR spectrum of a tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex.
FIG. 2 is a drawing showing a tris (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-carboxylate complex1H NMR spectrum.
FIG. 3 is a drawing showing a tris (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-carboxylate complex13C NMR spectrum.
FIG. 4 is a drawing of a tris (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-carboxylate complex119Sn NMR spectrum.
Detailed Description
The present invention is further illustrated in detail by the following examples, but it should be noted that the scope of the present invention is not limited by these examples at all.
Example 1:
preparation of tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex:
in a 250 mL round-bottom flask, 1.0535 g (1.0mmol) of bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide, 0.3566 g (2.0mmol) of benzothiophene-2-carboxylic acid and 25 mL of toluene solvent are sequentially added, a Dean-Stark water separator is installed, and the reaction is heated at 120 ℃ and refluxed for 6 hours. After the reaction is finished, filtering while the reaction is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tri (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-formic ether complex. Yield: 76%, melting point: 103-105 ℃.
Elemental analysis (C)39H44O2SSn): theoretical value: c, 67.35; h, 6.38. Measurement value: c, 67.32; h, 6.40.
IR (KBr, v/cm-1): 3734.19 (m), 3051.39 (w), 2956.87 (m), 2920.23 (m),2860.43 (w), 1645.28 (s), 1521.84 (m), 1456.26 (m), 1363.67 (m), 1336.67 (s),1319.31 (s), 1309.67 (m), 1294.24 (m), 1178.51 (m), 1155.36 (w), 1076.28 (w),1051.20 (w), 1029.99 (w), 864.11 (w),767.67 (s), 721.38 (m), 700.16 (m),669.30 (m), 586.36 (w), 557.43 (w), 457.13 (w)。
1H NMR (CDCl3, 500 MHz), δ (ppm): 7.87 (d,J=11Hz, 3H), 7.44- 7.38(m,2H), 7.30 (t,J=7.5Hz, 6H), 7.22(t,J=7Hz, 3H), 7.14(d,J=7.5Hz, 6H), 1.27(s, 24H)。
13C NMR (CDCl3, 125MHz)δ(ppm): 166.30, 150.77, 142.21, 139.23,137.82, 129.04, 128.37, 126.07, 125.86, 125.25, 125.13, 124.43, 122.67,37.69, 37.52, 32.71(t,J= 22 Hz)。
119Sn NMR(CDCl3, 186 MHz), δ(ppm): 103.99。
Example 2:
preparation of tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex:
in a 250 mL round-bottom flask, 1.0532 g (1.0mmol) of bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide, 0.3925 g (2.2 mmol) of benzothiophene-2-carboxylic acid and 25 mL of toluene solvent are sequentially added, a Dean-Stark water separator is installed, and the reaction is heated at 120 ℃ and refluxed for 8 hours. After the reaction is finished, filtering while the reaction is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tri (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-formic ether complex. Yield: 76%, melting point: 103-105 ℃.
Elemental analysis (C)39H44O2SSn): theoretical value: c, 67.35; h, 6.38. Measurement value: c, 67.32; h, 6.40.
IR (KBr, v/cm-1): 3734.19 (m), 3051.39 (w), 2956.87 (m), 2920.23 (m),2860.43 (w), 1645.28 (s), 1521.84 (m), 1456.26 (m), 1363.67 (m), 1336.67 (s),1319.31 (s), 1309.67 (m), 1294.24 (m), 1178.51 (m), 1155.36 (w), 1076.28 (w),1051.20 (w), 1029.99 (w), 864.11 (w),767.67 (s), 721.38 (m), 700.16 (m),669.30 (m), 586.36 (w), 557.43 (w), 457.13 (w)。
1H NMR (CDCl3, 500 MHz), δ (ppm): 7.87 (d,J=11Hz, 3H), 7.44- 7.38(m,2H), 7.30 (t,J=7.5Hz, 6H), 7.22(t,J=7Hz, 3H), 7.14(d,J=7.5Hz, 6H), 1.27(s, 24H)。
13C NMR (CDCl3, 125MHz)δ(ppm): 166.30, 150.77, 142.21, 139.23,137.82, 129.04, 128.37, 126.07, 125.86, 125.25, 125.13, 124.43, 122.67,37.69, 37.52, 32.71(t,J= 22 Hz)。
119Sn NMR(CDCl3, 186 MHz), δ(ppm): 103.99。
Example 3:
preparation of tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex:
in a 250 mL round-bottom flask, 1.0538 g (1.0mmol) of bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide, 0.3930 g (2.2 mmol) of benzothiophene-2-carboxylic acid and 35 mL of toluene solvent are sequentially added, a Dean-Stark water separator is installed, and the reaction is heated at 120 ℃ and refluxed for 8 hours. After the reaction is finished, filtering while the reaction is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tri (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-formic ether complex. Yield: 76%, melting point: 103-105 ℃.
Elemental analysis (C)39H44O2SSn): theoretical value: c, 67.35; h, 6.38. Measurement value: c, 67.32; h, 6.40.
IR (KBr, v/cm-1): 3734.19 (m), 3051.39 (w), 2956.87 (m), 2920.23 (m),2860.43 (w), 1645.28 (s), 1521.84 (m), 1456.26 (m), 1363.67 (m), 1336.67 (s),1319.31 (s), 1309.67 (m), 1294.24 (m), 1178.51 (m), 1155.36 (w), 1076.28 (w),1051.20 (w), 1029.99 (w), 864.11 (w),767.67 (s), 721.38 (m), 700.16 (m),669.30 (m), 586.36 (w), 557.43 (w), 457.13 (w)。
1H NMR (CDCl3, 500 MHz), δ (ppm): 7.87 (d,J=11Hz, 3H), 7.44- 7.38(m,2H), 7.30 (t,J=7.5Hz, 6H), 7.22(t,J=7Hz, 3H), 7.14(d,J=7.5Hz, 6H), 1.27(s, 24H)。
13C NMR (CDCl3, 125MHz)δ(ppm): 166.30, 150.77, 142.21, 139.23,137.82, 129.04, 128.37, 126.07, 125.86, 125.25, 125.13, 124.43, 122.67,37.69, 37.52, 32.71(t,J= 22 Hz)。
119Sn NMR(CDCl3, 186 MHz), δ(ppm): 103.99。
Example 4:
for the preparation of the tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex:
in a 250 mL round-bottom flask, bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide 2.1066(2.0mmol), benzothiophene-2-carboxylic acid 0.7495 g (4.2 mmol) and solvent toluene 50 mL are sequentially added, a Dean-Stark water separator is installed, and the reaction is heated at 120 ℃ and refluxed for 8 h. After the reaction is finished, filtering while the reaction is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tri (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-formic ether complex. Yield: 76%, melting point: 103-105 ℃.
Elemental analysis (C)39H44O2SSn): theoretical value: c, 67.35; h, 6.38. Measurement value: c, 67.32; h, 6.40.
IR (KBr, v/cm-1): 3734.19 (m), 3051.39 (w), 2956.87 (m), 2920.23 (m),2860.43 (w), 1645.28 (s), 1521.84 (m), 1456.26 (m), 1363.67 (m), 1336.67 (s),1319.31 (s), 1309.67 (m), 1294.24 (m), 1178.51 (m), 1155.36 (w), 1076.28 (w),1051.20 (w), 1029.99 (w), 864.11 (w),767.67 (s), 721.38 (m), 700.16 (m),669.30 (m), 586.36 (w), 557.43 (w), 457.13 (w)。
1H NMR (CDCl3, 500 MHz), δ (ppm): 7.87 (d,J=11Hz, 3H), 7.44- 7.38(m,2H), 7.30 (t,J=7.5Hz, 6H), 7.22(t,J=7Hz, 3H), 7.14(d,J=7.5Hz, 6H), 1.27(s, 24H)。
13C NMR (CDCl3, 125MHz)δ(ppm): 166.30, 150.77, 142.21, 139.23,137.82, 129.04, 128.37, 126.07, 125.86, 125.25, 125.13, 124.43, 122.67,37.69, 37.52, 32.71(t,J= 22 Hz)。
119Sn NMR(CDCl3, 186 MHz), δ(ppm): 103.99。
Example 5:
preparation of tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex:
in a 250 mL round-bottom flask, bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide 2.1066(2.0mmol), benzothiophene-2-carboxylic acid 0.7138 g (4.0 mmol) and toluene solvent 60 mL are sequentially added, a Dean-Stark trap is installed, and the reaction is heated at 120 ℃ for reflux reaction for 12 h. After the reaction is finished, filtering while the reaction is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tri (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-formic ether complex. Yield: 76%, melting point: 102-105 ℃.
Elemental analysis (C)39H44O2SSn): theoretical value: c, 67.35; h, 6.38. Measurement value: c, 67.32; h, 6.40.
IR (KBr, v/cm-1): 3734.19 (m), 3051.39 (w), 2956.87 (m), 2920.23 (m),2860.43 (w), 1645.28 (s), 1521.84 (m), 1456.26 (m), 1363.67 (m), 1336.67 (s),1319.31 (s), 1309.67 (m), 1294.24 (m), 1178.51 (m), 1155.36 (w), 1076.28 (w),1051.20 (w), 1029.99 (w), 864.11 (w),767.67 (s), 721.38 (m), 700.16 (m),669.30 (m), 586.36 (w), 557.43 (w), 457.13 (w)。
1H NMR (CDCl3, 500 MHz), δ (ppm): 7.87 (d,J=11Hz, 3H), 7.44- 7.38(m,2H), 7.30 (t,J=7.5Hz, 6H), 7.22(t,J=7Hz, 3H), 7.14(d,J=7.5Hz, 6H), 1.27(s, 24H)。
13C NMR (CDCl3, 125MHz)δ(ppm): 166.30, 150.77, 142.21, 139.23,137.82, 129.04, 128.37, 126.07, 125.86, 125.25, 125.13, 124.43, 122.67,37.69, 37.52, 32.71(t,J= 22 Hz)。
119Sn NMR(CDCl3, 186 MHz), δ(ppm): 103.99。
Example 6:
preparation of tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex:
in a 250 mL round-bottom flask, bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide 3.1593(3.0mmol), benzothiophene-2-carboxylic acid 1.0705 g (6.0 mmol) and solvent toluene 75 mL were added in this order, and the mixture was placed in a Dean-Stark trap and heated at 120 ℃ under reflux for 12 hours. After the reaction is finished, filtering while the reaction is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tri (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-formic ether complex. Yield: 76%, melting point: 102-105 ℃.
Elemental analysis (C)39H44O2SSn): theoretical value: c, 67.35; h, 6.38. Measurement value: c, 67.32; h, 6.40.
IR (KBr, v/cm-1): 3734.19 (m), 3051.39 (w), 2956.87 (m), 2920.23 (m),2860.43 (w), 1645.28 (s), 1521.84 (m), 1456.26 (m), 1363.67 (m), 1336.67 (s),1319.31 (s), 1309.67 (m), 1294.24 (m), 1178.51 (m), 1155.36 (w), 1076.28 (w),1051.20 (w), 1029.99 (w), 864.11 (w),767.67 (s), 721.38 (m), 700.16 (m),669.30 (m), 586.36 (w), 557.43 (w), 457.13 (w)。
1H NMR (CDCl3, 500 MHz), δ (ppm): 7.87 (d,J=11Hz, 3H), 7.44- 7.38(m,2H), 7.30 (t,J=7.5Hz, 6H), 7.22(t,J=7Hz, 3H), 7.14(d,J=7.5Hz, 6H), 1.27(s, 24H)。
13C NMR (CDCl3, 125MHz)δ(ppm): 166.30, 150.77, 142.21, 139.23,137.82, 129.04, 128.37, 126.07, 125.86, 125.25, 125.13, 124.43, 122.67,37.69, 37.52, 32.71(t,J= 22 Hz)。
119Sn NMR(CDCl3, 186 MHz), δ(ppm): 103.99。
Example 7:
preparation of tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex:
in a 250 mL round-bottom flask, bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide 3.1593(3.0mmol), benzothiophene-2-carboxylic acid 1.1783 g (6.6 mmol) and solvent toluene 90 mL are sequentially added, a Dean-Stark water separator is installed, and the reaction is heated at 120 ℃ and refluxed for 6 h. After the reaction is finished, filtering while the reaction is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tri (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-formic ether complex. Yield: 76%, melting point: 102-105 ℃.
Elemental analysis (C)39H44O2SSn): theoretical value: c, 67.35; h, 6.38. Measurement value: c, 67.32; h, 6.40.
IR (KBr, v/cm-1): 3734.19 (m), 3051.39 (w), 2956.87 (m), 2920.23 (m),2860.43 (w), 1645.28 (s), 1521.84 (m), 1456.26 (m), 1363.67 (m), 1336.67 (s),1319.31 (s), 1309.67 (m), 1294.24 (m), 1178.51 (m), 1155.36 (w), 1076.28 (w),1051.20 (w), 1029.99 (w), 864.11 (w),767.67 (s), 721.38 (m), 700.16 (m),669.30 (m), 586.36 (w), 557.43 (w), 457.13 (w)。
1H NMR (CDCl3, 500 MHz), δ (ppm): 7.87 (d,J=11Hz, 3H), 7.44- 7.38(m,2H), 7.30 (t,J=7.5Hz, 6H), 7.22(t,J=7Hz, 3H), 7.14(d,J=7.5Hz, 6H), 1.27(s, 24H)。
13C NMR (CDCl3, 125MHz)δ(ppm): 166.30, 150.77, 142.21, 139.23,137.82, 129.04, 128.37, 126.07, 125.86, 125.25, 125.13, 124.43, 122.67,37.69, 37.52, 32.71(t,J= 22 Hz)。
119Sn NMR(CDCl3, 186 MHz), δ(ppm): 103.99。
Test example:
the in vitro anticancer activity of the tri (2-methyl-2-phenylpropyl) tin benzothiophene-2-formate complex is measured by an MTT experimental method.
MTT assay:
based on the metabolic reduction of 3- (4, 5-dimethylthiozol-2-yl) -2, 5-diaryltetrazolium bromide. Succinate dehydrogenase in mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple crystalline Formazan (Formazan) and deposit in cells, while dead cells do not have this function. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and the optical density of characteristic wavelength is measured by enzyme labeling instrument, which can indirectly reflect the number of living cells.
The inhibitory activity of the tris (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-carboxylate complex prepared in example 1 on human lung cancer cells (a 549), human cervical cancer cells (Hela), and human gastric cancer cells (HGC-27) was measured by the MTT method.
Cell line and culture System: the A549, Hela and HGC-27 cell lines were obtained from the American tissue culture Bank (ATCC). Using RPMI1640 medium (GIBICO) containing 10% fetal bovine serum at 5% (volume fraction) CO2And culturing in vitro in a 37 ℃ saturated humidity incubator.
The testing process comprises the following steps: and respectively adding the test liquid medicine (0.0625-0.5 mu mol/L) into each hole according to the concentration gradient of the concentration, wherein each concentration is provided with 3 parallel holes. The experiment was divided into drug test group (with different concentrations of test drug added), control group (with culture medium and cells only, without test drug added) and blank group (with culture medium only, without cells and test drug added). Placing the medicated hole plate at 37 deg.C and 5% CO2Culturing in an incubator for 24 h. The activity of the control drug was determined as per the method of the test sample. In the well plate after 48 hours of incubation, 20uL of MTT (5 g/L in PBS) was added to each well. After standing at 37 ℃ for 4h, the supernatant was removed. Add 150uL DMSO to each well, shake for 10min to dissolve the Formazan crystals. Finally, the absorbance of each well was measured at a wavelength of 570nm using a BioTek multifunctional microplate reader.
Data processing: data processing Using GraAr Pad Prism version5.0 program, Complex IC50Fitting was done by a non-linear regression model with sigmoidal dose response in the program.
Analyzing human lung cancer cell (A549) cell line, human cervical cancer cell (Hela) cell line and human gastric cancer cell (HGC-27) cell line by MTT analysis method, and determining IC50The results are shown in table 1, with the conclusion that: as can be seen from the data in the table, the tri (2-methyl-2-phenylpropyl) tin benzothiophene-2-formate complex disclosed by the invention is high in anticancer activity on human lung cancer, human cervical cancer and human gastric cancer as an anticancer drug, and can be used as a candidate complex of the anticancer drug.
Table 1 data of in vitro activity test of tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex anticancer drugs.
| Human lung cancer cell | Human cervical cancer cell | Human gastric cancer cell | |
| Cell line | A549 | Hela | HGC-27 |
| IC50 μM | 0.5674 | 0.506 | 0.6312 |
The tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex prepared in the remaining examples was tested for anticancer activity against human lung cancer cells (a 549), human cervical cancer cells (Hela) and human gastric cancer cells (HGC-27) by MTT method in the same experimental examples, and the test results were substantially the same as in table 1.
Claims (7)
1. A tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex, which is a complex of the following structural formula (I):
(I)。
2. the composition of claim 1 containingTris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex, infrared spectral data for which: FT-IR (KBr, v/cm)-1) 3734.19 (m), 3051.39 (w), 2956.87 (m),2920.23 (m), 2860.43 (w), 1645.28(s), 1521.84 (m), 1456.26 (m), 1363.67 (m), 1336.67(s), 1319.31(s), 1309.67 (m), 1294.24 (m), 1178.51 (m), 1155.36 (w),1076.28 (w), 1051.20 (w), 1029.99 (w), 864.11 (w), 767.67(s), 721.38 (m),700.16 (m), 669.30 (m), 586.36 (w), 557.43 (w), 457.13 (w); nuclear magnetic spectrum data thereof:1HNMR (CDCl3, 500 MHz), δ (ppm): 7.87 (d,J=11Hz, 3H), 7.44- 7.38(m, 2H), 7.30(t,J=7.5Hz, 6H), 7.22(t,J=7Hz, 3H), 7.14(d,J=7.5Hz, 6H), 1.27(s, 24H);13C NMR (CDCl3, 125MHz)δ(ppm): 166.30, 150.77, 142.21, 139.23, 137.82,129.04, 128.37, 126.07, 125.86, 125.25, 125.13, 124.43, 122.67, 37.69, 37.52,32.71(t,J= 22 Hz);119Sn NMR (CDCl3, 186 MHz),δ(ppm): 103.99。
3. the method for preparing the tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex according to claim 1, characterized in that bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide, benzothiophene-2-carboxylic acid and toluene as a solvent are sequentially added in a 250 mL round-bottomed flask, a Dean-Stark water separator is installed, and the reaction is performed at 112-120 ℃ under heating and reflux for 6-12 hours; after the reaction is finished, filtering while the reaction is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tri (2-methyl-2-phenylpropyl) stannylbenzothiophene-2-formic ether complex.
4. The method according to claim 3, wherein the bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide and benzothiophene-2-carboxylic acid are used in an amount ratio of 1.0 (2.0 to 2.2).
5. The method according to claim 3, wherein the solvent toluene is used in an amount of 25 to 35 ml per mmol of bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide.
6. Use of the tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-carboxylate complex of claim 1 for the preparation of an anticancer drug.
7. The use of claim 6, wherein the cancer cell is lung cancer, cervical cancer, gastric cancer.
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