CN111057091B - Preparation method and application of bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex - Google Patents
Preparation method and application of bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex Download PDFInfo
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- -1 5-amino isophthalic acid ester Chemical class 0.000 title claims abstract description 52
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- NBDAHKQJXVLAID-UHFFFAOYSA-N 5-nitroisophthalic acid Chemical compound OC(=O)C1=CC(C(O)=O)=CC([N+]([O-])=O)=C1 NBDAHKQJXVLAID-UHFFFAOYSA-N 0.000 description 1
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- 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 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- HOXINJBQVZWYGZ-UHFFFAOYSA-N fenbutatin oxide Chemical compound C=1C=CC=CC=1C(C)(C)C[Sn](O[Sn](CC(C)(C)C=1C=CC=CC=1)(CC(C)(C)C=1C=CC=CC=1)CC(C)(C)C=1C=CC=CC=1)(CC(C)(C)C=1C=CC=CC=1)CC(C)(C)C1=CC=CC=C1 HOXINJBQVZWYGZ-UHFFFAOYSA-N 0.000 description 1
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- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- ODOPKAJVFRHHGM-UHFFFAOYSA-N phenyltin Chemical class [Sn]C1=CC=CC=C1 ODOPKAJVFRHHGM-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
-
- 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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- General Chemical & Material Sciences (AREA)
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Abstract
The invention discloses a bis [ tri (2-methyl-2-phenyl) propyl tin]Preparation method and application of 5-amino isophthalic acid ester complex, which is a complex with the following structural formula (I)
. The invention also discloses bis [ tri (2-methyl-2-phenyl) propyltin]A preparation method of 5-amino isophthalic acid ester complex and application thereof in preparing antitumor drugs.
Description
Technical Field
The invention relates to a bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex, a preparation method thereof and application of the complex in preparing antitumor drugs.
Background
The organotin carboxylate has higher bioactivity and wide application prospect in the fields of sterilization, disinsection, anticancer drug preparation and the like, so that the synthesis, structure and bioactivity research of the organotin carboxylate complex is widely focused by scientists. The existing researches show that the alkyl R in the organotin carboxylate is a main factor for determining the anticancer activity of the compound, for example, the cyclohexyl, n-butyl and phenyltin compounds have strong anticancer activity, the ethyl is almost free of anticancer activity, and the known organotin compounds have strong toxicity generally, so that the application is limited. Regulating the balance between toxicity and biological activity is an important direction of current research. The coordination mode of tin atoms can be greatly changed by functionalizing hydrocarbon groups or ligands, so that the biological activity of the organotin complex is affected. Studies have shown that the toxicity of organotin compounds is related to their relative molecular masses, with smaller relative molecular masses being more toxic and larger relative molecular masses being more bulky hydrocarbyl tin. Therefore, the novel large-steric-hindrance alkyl tin carboxylate complex is synthesized, and the structure and the biological activity of the complex are researched, so that the complex has important research significance.
The bis [ tris (2-methyl-2-phenylpropyl) tin ] carboxylate disclosed in European patent EP0177785B1 has a greater biological activity than the bis [ tris (2-methyl-2-phenylpropyl) tin ] oxide.
Chinese patent CN 106279256B discloses the use of bis [ tris (2-methyl-2-phenyl) propyltin ]2, 2' -biphthalate complex in the preparation of a medicament for the treatment of lung cancer, breast cancer and liver cancer.
Chinese patent CN 106279253B discloses the use of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-nitroisophthalate complex in the preparation of a medicament for the treatment of lung cancer, breast cancer and liver cancer.
Based on the fact that bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide is a substance with good biological activity, and the 2-methyl-2-phenylpropyl has the characteristics of large steric hindrance, large molecular weight and the like, bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide is selected to react with ligand 5-amino isophthalic acid under certain conditions, and a complex with strong inhibition activity on A549 (human lung cancer cells), hela (human cervical cancer cells) and HGC-27 (human gastric cancer cells) is synthesized, so that a new approach is provided for developing anticancer drugs.
Disclosure of Invention
In view of the above problems of the prior art, a first object of the present invention is to provide a bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex.
The second object of the present invention is to provide a process for producing the above bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex.
The third object of the invention is to provide an application of the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex in preparing anticancer drugs.
A bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex as the first aspect of the present invention has the following structural formula (I):
(I)。
the bis [ tris (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex of the invention is subjected to elemental analysis, infrared spectrum analysis, nuclear magnetic resonance spectrum and X-ray single crystal structure analysis, and the results are as follows:
elemental analysis (C) 68 H 83 NO 4 Sn 2 ): theoretical value: c,67.18; h,6.88; n,1.15. Measurement value: c,67.22; h,6.85; n,1.12.
IR(KBr, v/cm -1 ): 3454.51(w), 3356.14(w), 3053.32(w), 2960.73(s), 2920.23(m), 1649.14(s), 1637.56(s), 1598.99(s), 1494.83(m), 1440.83(m), 1365.60(s), 1298.09(s), 1267.23(m), 1188.15(w), 1128.36 (w), 1076.28(m), 1029.99(w), 999.13(w), 974.05(w), 927.76(w), 906.54(w), 887.26(w), 844.82(w), 796.60(w), 767.67(s), 732.95(m), 698.23(s), 615.29(w), 555.50(w), 491.85(w), 445.56(w), 424.34(w)。
1 H NMR (CDCl 3 , 500 MHz) δ(ppm): 8.10 (s, 1H),7.48 (s, 2H), 7.33-7.28 (m, 12H), 7.25-7.22 (m, 6H), 7.15-7.14 (m,12H), 3.83 (s, 2H), 1.35-1.18 (m, 48H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 170.48, 150.98, 146.00, 134.21, 128.36, 125.82, 125.34, 121.98, 119.70, 37.78, 37.50, 32.87。
119 Sn NMR (CDCl 3 , 186 MHz)δ(ppm): 91.48。
Bis [ tris (2-methyl-2-phenyl) propyltin ] of the present invention]5-Aminoisophthalic acid ester complexThe object is a crystal structure, and the crystallographic data thereof are as follows: the crystal belongs to a triclinic system, the space group P-1,a=0.99506(6) nm，b=1.81244(11) nm，c=3.5632(2) nm，α=89°，β=83°，γ=82°，Z=4，V=6.3333(7) nm 3 ，Dc=1.281 Mg·m -3 ，μ(MoKa)= 0.834mm -1 ，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26 x 0.25 x 0.23 mm,R=0.0467，wR=0.1007。
the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex of the invention is structurally characterized in that: the central tin in the molecule forms a distorted tetrahedral configuration with the coordinating atoms.
As a preparation method of the bis [ tris (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex in the second aspect of the invention, bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide, 5-amino isophthalic acid and solvent anhydrous methanol are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 60-120 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain light yellow crystals, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex.
In a preferred embodiment of the present invention, the ratio of the amounts of the substances of the bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide and the 5-aminoisophthalic acid is 1 (1 to 1.05).
In a preferred embodiment of the invention, the solvent anhydrous methanol is used in an amount of 10-15 ml per millimole of tin bis [ tris (2-methyl-2-phenylpropyl) ] oxide.
The invention relates to an application of a bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex in preparing anticancer drugs.
The applicant carries out in vitro anti-tumor activity confirmation research on the complex, and confirms that the complex has certain anti-tumor biological activity, namely the application of the complex in preparing anti-tumor drugs, in particular the application in preparing anti-human lung cancer drugs, human cervical cancer drugs and human gastric cancer drugs.
The bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex disclosed by the invention has 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 anti-cancer drugs, the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex has the characteristics of high anti-cancer activity, low cost, simple preparation method and the like, and provides a new way for developing anti-cancer drugs.
Drawings
FIG. 1 is a diagram showing the structure of the crystal molecular structure of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex.
FIG. 2 is an IR spectrum of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex.
FIG. 3 is bis [ tris (2-methyl-2-phenyl) propyltin]5-Aminoisophthalic acid ester complex 1 H NMR spectrum.
FIG. 4 is bis [ tris (2-methyl-2-phenyl) propyltin]5-Aminoisophthalic acid ester complex 13 C NMR spectrum.
FIG. 5 is bis [ tris (2-methyl-2-phenyl) propyltin]5-Aminoisophthalic acid ester complex 119 Sn 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 any of these examples.
Example 1:
preparation of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex:
bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide 1.0526 g (1 mmol), 5-amino isophthalic acid 0.1816 g (1 mmol) and anhydrous methanol 10 mL as solvents are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 60 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain light yellow crystals, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex. Yield: 71%, melting point: 112-114 ℃.
Elemental analysis (C) 68 H 83 NO 4 Sn 2 ): theoretical value: c,67.18; h,6.88; n,1.15. Measurement value: c,67.22; h,6.85; n,1.12.
IR(KBr, v/cm -1 ): 3454.51(w), 3356.14(w), 3053.32(w), 2960.73(s), 2920.23(m), 1649.14(s), 1637.56(s), 1598.99(s), 1494.83(m), 1440.83(m), 1365.60(s), 1298.09(s), 1267.23(m), 1188.15(w), 1128.36 (w), 1076.28(m), 1029.99(w), 999.13(w), 974.05(w), 927.76(w), 906.54(w), 887.26(w), 844.82(w), 796.60(w), 767.67(s), 732.95(m), 698.23(s), 615.29(w), 555.50(w), 491.85(w), 445.56(w), 424.34(w)。
1 H NMR (CDCl 3 , 500 MHz) δ(ppm): 8.10 (s, 1H),7.48 (s, 2H), 7.33-7.28 (m, 12H), 7.25-7.22 (m, 6H), 7.15-7.14 (m,12H), 3.83 (s, 2H), 1.35-1.18 (m, 48H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 170.48, 150.98, 146.00, 134.21, 128.36, 125.82, 125.34, 121.98, 119.70, 37.78, 37.50, 32.87。
119 Sn NMR (CDCl 3 , 186 MHz)δ(ppm): 91.48。
Bis [ tris (2-methyl-2-phenyl) propyltin ] of the present invention]The 5-amino isophthalic acid ester complex has a crystal structure and has crystallographic data: the crystal belongs to a triclinic system, the space group P-1,a=0.99506(6) nm，b=1.81244(11) nm，c=3.5632(2) nm，α=89°，β=83°，γ=82°，Z=4，V=6.3333(7) nm 3 ，Dc=1.281 Mg·m -3 ，μ(MoKa)= 0.834mm -1 ，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26 x 0.25 x 0.23 mm,R=0.0467，wR=0.1007。
example 2:
preparation of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex:
bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide 1.0530 g (1 mmol), 5-amino isophthalic acid 0.1906 g (1.05 mmol) and solvent anhydrous methanol 15 mL are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 60 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain light yellow crystals, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex. Yield: 70%, melting point: 112-114 ℃.
Elemental analysis (C) 68 H 83 NO 4 Sn 2 ): theoretical value: c,67.18; h,6.88; n,1.15. Measurement value: c,67.22; h,6.85; n,1.12.
IR(KBr, v/cm -1 ): 3454.51(w), 3356.14(w), 3053.32(w), 2960.73(s), 2920.23(m), 1649.14(s), 1637.56(s), 1598.99(s), 1494.83(m), 1440.83(m), 1365.60(s), 1298.09(s), 1267.23(m), 1188.15(w), 1128.36 (w), 1076.28(m), 1029.99(w), 999.13(w), 974.05(w), 927.76(w), 906.54(w), 887.26(w), 844.82(w), 796.60(w), 767.67(s), 732.95(m), 698.23(s), 615.29(w), 555.50(w), 491.85(w), 445.56(w), 424.34(w)。
1 H NMR (CDCl 3 , 500 MHz) δ(ppm): 8.10 (s, 1H),7.48 (s, 2H), 7.33-7.28 (m, 12H), 7.25-7.22 (m, 6H), 7.15-7.14 (m,12H), 3.83 (s, 2H), 1.35-1.18 (m, 48H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 170.48, 150.98, 146.00, 134.21, 128.36, 125.82, 125.34, 121.98, 119.70, 37.78, 37.50, 32.87。
119 Sn NMR (CDCl 3 , 186 MHz)δ(ppm): 91.48。
Bis [ tris (2-methyl-2-phenyl) propyltin ] of the present invention]The 5-amino isophthalic acid ester complex has a crystal structure and has crystallographic data: the crystal belongs to a triclinic system, the space group P-1,a=0.99506(6) nm，b=1.81244(11) nm，c=3.5632(2) nm，α=89°，β=83°，γ=82°，Z=4，V=6.3333(7) nm 3 ，Dc=1.281 Mg·m -3 ，μ(MoKa)= 0.834mm -1 ，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26 x 0.25 x 0.23 mm,R=0.0467，wR=0.1007。
example 3:
preparation of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex:
1.0529g (1 mmol) of bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide, 0.1812 g (1 mmol) of 5-amino isophthalic acid and 12 mL of absolute methanol solvent are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 120 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain light yellow crystals, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex. Yield: 73%, melting point: 112-114 ℃.
Elemental analysis (C) 68 H 83 NO 4 Sn 2 ): theoretical value: c,67.18; h,6.88; n,1.15. Measurement value: c,67.22; h,6.85; n,1.12.
IR(KBr, v/cm -1 ): 3454.51(w), 3356.14(w), 3053.32(w), 2960.73(s), 2920.23(m), 1649.14(s), 1637.56(s), 1598.99(s), 1494.83(m), 1440.83(m), 1365.60(s), 1298.09(s), 1267.23(m), 1188.15(w), 1128.36 (w), 1076.28(m), 1029.99(w), 999.13(w), 974.05(w), 927.76(w), 906.54(w), 887.26(w), 844.82(w), 796.60(w), 767.67(s), 732.95(m), 698.23(s), 615.29(w), 555.50(w), 491.85(w), 445.56(w), 424.34(w)。
1 H NMR (CDCl 3 , 500 MHz) δ(ppm): 8.10 (s, 1H),7.48 (s, 2H), 7.33-7.28 (m, 12H), 7.25-7.22 (m, 6H), 7.15-7.14 (m,12H), 3.83 (s, 2H), 1.35-1.18 (m, 48H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 170.48, 150.98, 146.00, 134.21, 128.36, 125.82, 125.34, 121.98, 119.70, 37.78, 37.50, 32.87。
119 Sn NMR (CDCl 3 , 186 MHz)δ(ppm): 91.48。
Bis [ tris (2-methyl-2-phenyl) propyltin ] of the present invention]The 5-amino isophthalic acid ester complex has a crystal structure and has crystallographic data: the crystal belongs to a triclinic system, the space group P-1,a=0.99506(6) nm，b=1.81244(11) nm，c=3.5632(2) nm，α=89°，β=83°，γ=82°，Z=4，V=6.3333(7) nm 3 ，Dc=1.281 Mg·m -3 ，μ(MoKa)= 0.834mm -1 ，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26 x 0.25 x 0.23 mm,R=0.0467，wR=0.1007。
example 4:
preparation of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex:
bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide 2.1052 g (2 mmol), 5-amino isophthalic acid 0.3622 g (2 mmol) and solvent anhydrous methanol 25mL are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 60 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain light yellow crystals, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex. Yield: 72%, melting point: 112-114 ℃.
Elemental analysis (C) 68 H 83 NO 4 Sn 2 ): theoretical value: c,67.18; h,6.88; n,1.15. Measurement value: c,67.22; h,6.85; n,1.12.
IR(KBr, v/cm -1 ): 3454.51(w), 3356.14(w), 3053.32(w), 2960.73(s), 2920.23(m), 1649.14(s), 1637.56(s), 1598.99(s), 1494.83(m), 1440.83(m), 1365.60(s), 1298.09(s), 1267.23(m), 1188.15(w), 1128.36 (w), 1076.28(m), 1029.99(w), 999.13(w), 974.05(w), 927.76(w), 906.54(w), 887.26(w), 844.82(w), 796.60(w), 767.67(s), 732.95(m), 698.23(s), 615.29(w), 555.50(w), 491.85(w), 445.56(w), 424.34(w)。
1 H NMR (CDCl 3 , 500 MHz) δ(ppm): 8.10 (s, 1H),7.48 (s, 2H), 7.33-7.28 (m, 12H), 7.25-7.22 (m, 6H), 7.15-7.14 (m,12H), 3.83 (s, 2H), 1.35-1.18 (m, 48H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 170.48, 150.98, 146.00, 134.21, 128.36, 125.82, 125.34, 121.98, 119.70, 37.78, 37.50, 32.87。
119 Sn NMR (CDCl 3 , 186 MHz)δ(ppm): 91.48。
Bis [ tris (2-methyl-2-phenyl) propyltin ] of the present invention]The 5-amino isophthalic acid ester complex has a crystal structure and has crystallographic data: the crystal belongs to a triclinic system, the space group P-1,a=0.99506(6) nm，b=1.81244(11) nm，c=3.5632(2) nm，α=89°，β=83°，γ=82°，Z=4，V=6.3333(7) nm 3 ，Dc=1.281 Mg·m -3 ，μ(MoKa)= 0.834mm -1 ，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26 x 0.25 x 0.23 mm,R=0.0467，wR=0.1007。
example 5:
preparation of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex:
2.1040g (2 mmol) of bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide, 0.3712 g (2.05 mmol) of 5-amino isophthalic acid and 25mL of solvent anhydrous methanol are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 90 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain light yellow crystals, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex. Yield: 72%, melting point: 112-114 ℃.
Elemental analysis (C) 68 H 83 NO 4 Sn 2 ): theoretical value: c,67.18; h,6.88; n,1.15. Measurement value: c,67.22; h,6.85; n,1.12.
IR(KBr, v/cm -1 ): 3454.51(w), 3356.14(w), 3053.32(w), 2960.73(s), 2920.23(m), 1649.14(s), 1637.56(s), 1598.99(s), 1494.83(m), 1440.83(m), 1365.60(s), 1298.09(s), 1267.23(m), 1188.15(w), 1128.36 (w), 1076.28(m), 1029.99(w), 999.13(w), 974.05(w), 927.76(w), 906.54(w), 887.26(w), 844.82(w), 796.60(w), 767.67(s), 732.95(m), 698.23(s), 615.29(w), 555.50(w), 491.85(w), 445.56(w), 424.34(w)。
1 H NMR (CDCl 3 , 500 MHz) δ(ppm): 8.10 (s, 1H),7.48 (s, 2H), 7.33-7.28 (m, 12H), 7.25-7.22 (m, 6H), 7.15-7.14 (m,12H), 3.83 (s, 2H), 1.35-1.18 (m, 48H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 170.48, 150.98, 146.00, 134.21, 128.36, 125.82, 125.34, 121.98, 119.70, 37.78, 37.50, 32.87。
119 Sn NMR (CDCl 3 , 186 MHz)δ(ppm): 91.48。
Bis [ tris (2-methyl-2-phenyl) propyltin ] of the present invention]The 5-amino isophthalic acid ester complex has a crystal structure and has crystallographic data: the crystal belongs to a triclinic system, the space group P-1,a=0.99506(6) nm，b=1.81244(11) nm，c=3.5632(2) nm，α=89°，β=83°，γ=82°，Z=4，V=6.3333(7) nm 3 ，Dc=1.281 Mg·m -3 ，μ(MoKa)= 0.834mm -1 ，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26 x 0.25 x 0.23 mm,R=0.0467，wR=0.1007。
example 6:
preparation of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex:
bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide 3.1577 g (3 mmol), 5-amino isophthalic acid 0.5438 g (3 mmol) and solvent anhydrous methanol 30 mL are sequentially added into a microwave reaction tank, and microwave reaction is carried out under the air atmosphere at the radiation power of 800W and the temperature of 100 ℃ for 120 min. After the reaction is finished, naturally cooling, filtering, naturally volatilizing and crystallizing the solvent at room temperature to obtain light yellow crystals, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex. Yield: 72%, melting point: 112-114 ℃.
Elemental analysis (C) 68 H 83 NO 4 Sn 2 ): theoretical value: c,67.18; h,6.88; n,1.15. Measurement value: c,67.22; h,6.85; n,1.12.
IR(KBr, v/cm -1 ): 3454.51(w), 3356.14(w), 3053.32(w), 2960.73(s), 2920.23(m), 1649.14(s), 1637.56(s), 1598.99(s), 1494.83(m), 1440.83(m), 1365.60(s), 1298.09(s), 1267.23(m), 1188.15(w), 1128.36 (w), 1076.28(m), 1029.99(w), 999.13(w), 974.05(w), 927.76(w), 906.54(w), 887.26(w), 844.82(w), 796.60(w), 767.67(s), 732.95(m), 698.23(s), 615.29(w), 555.50(w), 491.85(w), 445.56(w), 424.34(w)。
1 H NMR (CDCl 3 , 500 MHz) δ(ppm): 8.10 (s, 1H),7.48 (s, 2H), 7.33-7.28 (m, 12H), 7.25-7.22 (m, 6H), 7.15-7.14 (m,12H), 3.83 (s, 2H), 1.35-1.18 (m, 48H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 170.48, 150.98, 146.00, 134.21, 128.36, 125.82, 125.34, 121.98, 119.70, 37.78, 37.50, 32.87。
119 Sn NMR (CDCl 3 , 186 MHz)δ(ppm): 91.48。
Bis [ tris (2-methyl-2-phenyl) propyltin ] of the present invention]The 5-amino isophthalic acid ester complex has a crystal structure and has crystallographic data: the crystal belongs to a triclinic system, the space group P-1,a=0.99506(6) nm，b=1.81244(11) nm，c=3.5632(2) nm，α=89°，β=83°，γ=82°，Z=4，V=6.3333(7) nm 3 ，Dc=1.281 Mg·m -3 ，μ(MoKa)= 0.834mm -1 ，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26 x 0.25 x 0.23 mm,R=0.0467，wR=0.1007。
test example:
the bis [ tris (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex is realized by an MTT experimental method in vitro anticancer activity determination.
MTT assay:
based on the metabolic reduction of 3- (4, 5-dimethylazol-2-yl) -2,5-diArenyltetrazolium bromide. Succinate dehydrogenase in the mitochondria of living cells reduces exogenous MTT to water insoluble blue-violet crystalline Formazan (Formazan) and deposits in cells, whereas dead cells do not. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and the optical density of characteristic wavelength can be measured by an enzyme-labeled instrument, so that the number of living cells can be indirectly reflected.
The inhibition activity of the bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex prepared in example 1 on human lung cancer cells (A549), human cervical cancer cells (Hela), and human gastric cancer cells (HGC-27) was determined by MTT assay.
Cell lines and culture system: a549, hela, and HGC-27 cell lines were obtained from American Tissue Culture Collection (ATCC). With 10% fetal bovine serum in RPMI1640 (GIBICO) medium at 5% (volume fraction) CO 2 In vitro culture was performed in a saturated humidity incubator at 37 ℃.
The testing process comprises the following steps: the test liquid medicine (0.0625 mu mol/L-0.5 mu mol/L) is added into each hole according to concentration gradient, and 3 parallel holes are arranged for each concentration. The experiments were divided into drug test groups (with different concentrations of test agent added), control groups (with only culture fluid and cells without test agent) and blank groups (with only culture fluid and no cells and test agent). The orifice plate after the drug addition is placed at 37 ℃ and 5 percent CO 2 Culturing in an incubator for 24 hours. The activity of the control drug was determined by the method of the test sample. In the well plate after 48 hours of incubation, MTT 20uL (5 g/L in PBS) was added to each well. After 4h at 37℃the supernatant was removed. 150uL DMSO was added to each well and the mixture was shaken for 10min to dissolve Formazan crystals. Finally, absorbance values of each well were measured at 570nm using a BioTek multifunctional microplate reader.
And (3) data processing: data processing using the GraAr Pad Prism version5.0 program, complex IC 50 Fitting is performed through a nonlinear regression model with S-shaped dose response in the program.
The IC of the human lung cancer cell (A549) cell strain, the human cervical cancer cell (Hela) cell strain and the human gastric cancer cell (HGC-27) cell strain are determined by an MTT assay 50 Values, results are shown in table 1, conclusions are: as can be seen from the data in the table, the inventionMing bis [ tris (2-methyl-2-phenyl) propyltin]The 5-amino isophthalic acid ester complex is used as an anticancer drug, has higher anticancer activity on human lung cancer, human cervical cancer and human gastric cancer, and can be used as a candidate complex of the anticancer drug.
Table 1 in vitro activity test data of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex anticancer drugs.
| Human lung cancer cell | Human cervical cancer cell | Human gastric cancer cell | |
| Cell strain | A549 | Hela | HGC-27 |
| IC 50 μM | 0.4201 | 0.3459 | 0.2787 |
The anti-cancer activity test method of the bis [ tris (2-methyl-2-phenyl) propyltin ] 5-amino isophthalic acid ester complex prepared in the rest examples on human lung cancer cells (A549), human cervical cancer cells (Hela) and human gastric cancer cells (HGC-27) by using an MTT method is the same as that of the test examples, and the test results are basically the same as that of Table 1.
Claims (1)
1. Use of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalic acid ester complex of formula (I) in the preparation of anticancer drugs:
said bis [ tris (2-methyl-2-phenyl) propyltin]The 5-amino isophthalic acid ester complex has a crystal structure, and the crystallography data are as follows: triclinic system, space group P-1, a= 0.99506 (6) nm, b= 1.81244 (11) nm, c= 3.5632 (2) nm, α=89 °, β=83 °, γ=82 °, z=4, v= 6.3333 (7) nm 3 The method comprises the steps of carrying out a first treatment on the surface of the The central tin in the molecule and the coordination atoms form a distorted tetrahedral configuration;
the cancer cells aimed by the anticancer drug are human cervical cancer cells Hela and human gastric cancer cells HGC-27.
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| Organotin(IV) complexes with 5-aminoisophthalic acid: Synthesis, characterization, theoretical study, and biological activities;S. Hussain;《Russian Journal of General Chemistry》;20151115;2386-2394 * |
| Synthesis, characterization, and cytotoxic activity of tricyclohexyltin(IV) carboxylates derived from cyclic dicarboxylic anhydrides;20130228;《Journal of Coordination Chemistry》;20130228;624-637 * |
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Application publication date: 20200424 Assignee: Shanghai Yuanzuo Pharmaceutical Technology Co.,Ltd. Assignor: Hengyang Normal University Contract record no.: X2023980047748 Denomination of invention: Preparation method and application of a complex of bis [tri (2-methyl-2-phenyl) propyltin] 5-aminoisophthalate Granted publication date: 20230505 License type: Common License Record date: 20231122 |
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