CN111057091A - Preparation method and application of bis [ tri (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex - Google Patents
Preparation method and application of bis [ tri (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex Download PDFInfo
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- FBIVKLDWLAMJMB-UHFFFAOYSA-N propyltin Chemical compound CCC[Sn] FBIVKLDWLAMJMB-UHFFFAOYSA-N 0.000 title claims abstract description 54
- KBZFDRWPMZESDI-UHFFFAOYSA-N 5-aminobenzene-1,3-dicarboxylic acid Chemical compound NC1=CC(C(O)=O)=CC(C(O)=O)=C1 KBZFDRWPMZESDI-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 claims description 48
- 239000007983 Tris buffer Substances 0.000 claims description 36
- 239000013078 crystal Substances 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 18
- -1 5-amino isophthalic acid ester Chemical class 0.000 claims description 15
- FIDXVVHZWRFINX-UHFFFAOYSA-N tris(2-methyl-2-phenylpropyl)tin Chemical compound C=1C=CC=CC=1C(C)(C)C[Sn](CC(C)(C)C=1C=CC=CC=1)CC(C)(C)C1=CC=CC=C1 FIDXVVHZWRFINX-UHFFFAOYSA-N 0.000 claims description 14
- 229910001887 tin oxide Inorganic materials 0.000 claims description 13
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 12
- 201000005202 lung cancer Diseases 0.000 claims description 12
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- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 10
- 201000010881 cervical cancer Diseases 0.000 claims description 10
- 206010017758 gastric cancer Diseases 0.000 claims description 10
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- 230000001093 anti-cancer Effects 0.000 claims description 9
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- 238000001816 cooling Methods 0.000 claims description 8
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- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- CKXHZTXMENDKEZ-UHFFFAOYSA-N (2-methyl-2-phenylpropyl)tin Chemical compound [Sn]CC(C)(C)C1=CC=CC=C1 CKXHZTXMENDKEZ-UHFFFAOYSA-N 0.000 claims 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 230000003595 spectral effect Effects 0.000 claims 1
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- 229940041181 antineoplastic drug Drugs 0.000 abstract description 12
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- 229910052718 tin Inorganic materials 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
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- 230000004071 biological effect Effects 0.000 description 5
- 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
- 230000001988 toxicity Effects 0.000 description 4
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- 125000000217 alkyl group Chemical group 0.000 description 2
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 150000003606 tin compounds Chemical class 0.000 description 2
- 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
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 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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- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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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- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- 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
Abstract
The invention discloses bis [ tri (2-methyl-2-phenyl) propyl tin]A preparation method and application of a 5-aminoisophthalate complex which is a complex with the following structural formula (I)
. The invention also discloses bis [ tri (2-methyl-2-phenyl) propyl tin]A preparation method of the 5-amino isophthalate complex and application thereof in preparing antitumor drugs.
Description
Technical Field
The invention relates to a bis [ tri (2-methyl-2-phenyl) propyl tin ] 5-amino isophthalate complex, a preparation method thereof and application of the complex in preparing antitumor drugs.
Background
The organic tin carboxylate has high bioactivity and wide application prospect in the fields of sterilization, insecticide, anti-cancer drug preparation and the like, so that research on synthesis, structure and bioactivity of organic tin carboxylate complexes is widely concerned by scientists. The existing research shows that the alkyl R in the organotin carboxylate is the main factor for determining the anticancer activity of the compound, for example, cyclohexyl, n-butyl and phenyl tin compounds have stronger anticancer activity, and ethyl has almost no anticancer activity, and the known organotin compounds generally have stronger toxicity, so the application is limited. Regulating the balance between toxicity and biological activity is an important direction of research. 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 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 stronger biological activity than bis [ tris (2-methyl-2-phenylpropyl) tin ] oxide.
Chinese patent CN 106279256B discloses the application of bis [ tris (2-methyl-2-phenyl) propyl tin ]2, 2' -biphenyl diformate complex in the preparation of drugs for treating lung cancer, breast cancer and liver cancer.
Chinese patent CN 106279253B discloses the application of bis [ tris (2-methyl-2-phenyl) propyl tin ] 5-nitroisophthalate complex in the preparation of drugs for treating lung cancer, breast cancer and liver cancer.
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 the ligand 5-aminoisophthalic 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 bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate 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-aminoisophthalate complex.
The third purpose of the invention is to provide the application of the bis [ tri (2-methyl-2-phenyl) propyl tin ] 5-aminoisophthalate complex in preparing anti-cancer drugs.
A bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex as the first aspect of the present invention has the following structural formula (I):
(I)。
the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex of the invention is subjected to elemental analysis, infrared spectroscopic analysis, nuclear magnetic resonance spectroscopy and X-ray single crystal structure analysis, and the results are as follows:
elemental analysis (C)68H83NO4Sn2): theoretical value: c, 67.18; h, 6.88; and N, 1.15. Measurement value: c, 67.22; h, 6.85; and 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)。
1H NMR (CDCl3, 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)。
13CNMR(CDCl3, 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。
119Sn NMR (CDCl3, 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 the crystallographic data thereof are as follows: the crystal belongs to a 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) nm3，Dc=1.281 Mg·m-3，μ(MoKa)=0.834mm-1，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26X 0.25X 0.23 mm,R=0.0467，wR=0.1007。
the structure of the bis [ tri (2-methyl-2-phenyl) propyl tin ] 5-amino isophthalic acid ester complex is characterized in that: the central tin in the molecule forms a distorted tetrahedral configuration with the coordinating atoms.
In the second aspect of the present invention, a bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex is prepared by sequentially adding bis [ tris (2-methyl-2-phenyl) propyltin ] oxide, 5-aminoisophthalic acid and a solvent, namely anhydrous methanol, to a microwave reaction tank, and performing microwave reaction at an irradiation power of 800W and a temperature of 100 ℃ for a period of 60 to 120 min in an air atmosphere. After the reaction is finished, naturally cooling, filtering, and naturally volatilizing the solvent at room temperature to crystallize to obtain a light yellow crystal, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex.
In a preferred embodiment of the invention, the mass ratio of the bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide to the 5-aminoisophthalic acid is 1 (1-1.05).
In a preferred embodiment of the present invention, the solvent is anhydrous methanol in an amount of 10 to 15 ml per mmol of bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide.
The application of the bis [ tri (2-methyl-2-phenyl) propyl tin ] 5-amino isophthalate complex as the third aspect of the invention in preparing 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 bis [ tri (2-methyl-2-phenyl) propyl tin ] 5-amino isophthalate 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 medicaments. Compared with the currently commonly used platinum anticancer drugs, the bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate 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 a crystal molecular structural diagram of a bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex.
FIG. 2 is an IR spectrum of a bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex.
FIG. 3 shows bis [ tris (2-methyl-2-phenyl) propyltin]Process for preparing 5-aminoisophthalate complexes1H NMR spectrum.
FIG. 4 shows bis [ tris (2-methyl-2-phenyl) propyltin]Process for preparing 5-aminoisophthalate complexes13C NMR spectrum.
FIG. 5 shows bis [ tris (2-methyl-2-phenyl) propyltin]Process for preparing 5-aminoisophthalate complexes119Sn 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 bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex:
1.0526 g (1mmol) of bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide, 0.1816 g (1mmol) of 5-aminoisophthalic acid and 10 mL of solvent anhydrous methanol are sequentially added into a microwave reaction tank, and microwave reaction is carried out at the radiation power of 800W and the temperature of 100 ℃ for 60 min under the air atmosphere. After the reaction is finished, naturally cooling, filtering, and naturally volatilizing the solvent at room temperature to crystallize to obtain a light yellow crystal, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex. Yield: 71%, melting point: 112 ℃ and 114 ℃.
Elemental analysis (C)68H83NO4Sn2): theoretical value: c, 67.18; h, 6.88; and N, 1.15. Measurement value: c, 67.22; h, 6.85; and 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)。
1H NMR (CDCl3, 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)。
13CNMR(CDCl3, 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。
119Sn NMR (CDCl3, 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 the crystallographic data thereof are as follows: the crystal belongs to a 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) nm3，Dc=1.281 Mg·m-3，μ(MoKa)=0.834mm-1，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26X 0.25X 0.23 mm,R=0.0467，wR=0.1007。
example 2:
preparation of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex:
the method comprises the steps of sequentially adding 1.0530 g (1mmol) of bis [ tri (2-methyl-2-phenylpropyl) ] tin oxide, 0.1906 g (1.05 mmol) of 5-aminoisophthalic acid and 15 mL of solvent anhydrous methanol into a microwave reaction tank, and carrying out microwave reaction at the radiation power of 800W and the temperature of 100 ℃ for 60 min under the air atmosphere. After the reaction is finished, naturally cooling, filtering, and naturally volatilizing the solvent at room temperature to crystallize to obtain a light yellow crystal, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex. Yield: 70%, melting point: 112 ℃ and 114 ℃.
Elemental analysis (C)68H83NO4Sn2): theoretical value: c, 67.18; h, 6.88; and N, 1.15. Measurement value: c, 67.22; h, 6.85; and 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)。
1H NMR (CDCl3, 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)。
13CNMR(CDCl3, 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。
119Sn NMR (CDCl3, 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 the crystallographic data thereof are as follows: the crystal belongs to a 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) nm3，Dc=1.281 Mg·m-3，μ(MoKa)=0.834mm-1，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26X 0.25X 0.23 mm,R=0.0467，wR=0.1007。
example 3:
preparation of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex:
the method comprises the steps of sequentially adding 1.0529g (1mmol) of bis [ tri (2-methyl-2-phenylpropyl) ] tin oxide, 0.1812 g (1mmol) of 5-aminoisophthalic acid and 12 mL of solvent anhydrous methanol into a microwave reaction tank, and carrying out microwave reaction at the radiation power of 800W and the temperature of 100 ℃ for 120 min under the air atmosphere. After the reaction is finished, naturally cooling, filtering, and naturally volatilizing the solvent at room temperature to crystallize to obtain a light yellow crystal, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex. Yield: 73%, melting point: 112 ℃ and 114 ℃.
Elemental analysis (C)68H83NO4Sn2): theoretical value: c, 67.18; h, 6.88; and N, 1.15. Measurement value: c, 67.22; h, 6.85; and 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)。
1H NMR (CDCl3, 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)。
13CNMR(CDCl3, 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。
119Sn NMR (CDCl3, 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 the crystallographic data thereof are as follows: the crystal belongs to a 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) nm3，Dc=1.281 Mg·m-3，μ(MoKa)=0.834mm-1，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26X 0.25X 0.23 mm,R=0.0467，wR=0.1007。
example 4:
preparation of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex:
2.1052 g (2mmol) of bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide, 0.3622 g (2mmol) of 5-aminoisophthalic acid and 25mL of solvent anhydrous methanol are sequentially added into a microwave reaction tank, and microwave reaction is carried out at the radiation power of 800W and the temperature of 100 ℃ for 60 min under the air atmosphere. After the reaction is finished, naturally cooling, filtering, and naturally volatilizing the solvent at room temperature to crystallize to obtain a light yellow crystal, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex. Yield: 72%, melting point: 112 ℃ and 114 ℃.
Elemental analysis (C)68H83NO4Sn2): theoretical value: c, 67.18; h, 6.88; and N, 1.15. Measurement value: c, 67.22; h, 6.85; and 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)。
1H NMR (CDCl3, 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)。
13CNMR(CDCl3, 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。
119Sn NMR (CDCl3, 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 the crystallographic data thereof are as follows: the crystal belongs to a 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) nm3，Dc=1.281 Mg·m-3，μ(MoKa)=0.834mm-1，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26X 0.25X 0.23 mm,R=0.0467，wR=0.1007。
example 5:
preparation of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex:
2.1040g (2mmol) of bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide, 0.3712 g (2.05 mmol) of 5-aminoisophthalic acid and 25mL of solvent anhydrous methanol are sequentially added into a microwave reaction tank, and microwave reaction is carried out at the radiation power of 800W and the temperature of 100 ℃ for 90 min under the air atmosphere. After the reaction is finished, naturally cooling, filtering, and naturally volatilizing the solvent at room temperature to crystallize to obtain a light yellow crystal, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex. Yield: 72%, melting point: 112 ℃ and 114 ℃.
Elemental analysis (C)68H83NO4Sn2): theory of the inventionThe value: c, 67.18; h, 6.88; and N, 1.15. Measurement value: c, 67.22; h, 6.85; and 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)。
1H NMR (CDCl3, 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)。
13CNMR(CDCl3, 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。
119Sn NMR (CDCl3, 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 the crystallographic data thereof are as follows: the crystal belongs to a 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) nm3，Dc=1.281 Mg·m-3，μ(MoKa)=0.834mm-1，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26X 0.25X 0.23 mm,R=0.0467，wR=0.1007。
example 6:
preparation of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex:
3.1577 g (3mmol) of bis [ tri (2-methyl-2-phenylpropyl) ] tin oxide, 0.5438 g (3mmol) of 5-aminoisophthalic acid and 30 mL of solvent anhydrous methanol are sequentially added into a microwave reaction tank, and microwave reaction is carried out at the radiation power of 800W and the temperature of 100 ℃ for 120 min under the air atmosphere. After the reaction is finished, naturally cooling, filtering, and naturally volatilizing the solvent at room temperature to crystallize to obtain a light yellow crystal, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex. Yield: 72%, melting point: 112 ℃ and 114 ℃.
Elemental analysis (C)68H83NO4Sn2): theoretical value: c, 67.18; h, 6.88; and N, 1.15. Measurement value: c, 67.22; h, 6.85; and 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)。
1H NMR (CDCl3, 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)。
13CNMR(CDCl3, 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。
119Sn NMR (CDCl3, 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 the crystallographic data thereof are as follows: the crystal belongs to a 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) nm3，Dc=1.281 Mg·m-3，μ(MoKa)=0.834mm-1，F(000)= 2532，2.22°＜θ< 28.30 °, crystal size: 0.26X 0.25X 0.23 mm,R=0.0467，wR=0.1007。
test example:
the in vitro anticancer activity of the bis [ tri (2-methyl-2-phenyl) propyl tin ] 5-aminoisophthalate complex is determined 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 bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate 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 determined 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 by a nonlinear 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 is clear from the data in the table, bis [ tris (2-methyl-2-phenyl) propyltin ] of the present invention]The 5-amino isophthalate complex is used as an anticancer drug, has high 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 for bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex anticancer drugs.
| Human lung cancer cell | Human cervical cancer cell | Human gastric cancer cell | |
| Cell line | A549 | Hela | HGC-27 |
| IC50μM | 0.4201 | 0.3459 | 0.2787 |
The anti-cancer activity of the bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex prepared in the remaining examples was measured by MTT method against human lung cancer cells (A549), human cervical cancer cells (Hela) and human gastric cancer cells (HGC-27) in the same experimental examples, and the results were substantially the same as those in Table 1.
Claims (8)
1. A bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex which is a complex of the following structural formula (I):
(I)。
2. the compound of claim 1 comprising a bis [ tris (2-methyl-2-phenyl) propyltin]5-amino isophthalate complex having infrared spectral data: FT-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); nuclear magnetic spectrum data thereof:1H NMR (CDCl3, 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);13CNMR(CDCl3, 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;119Sn NMR (CDCl3, 186 MHz)δ(ppm): 91.48。
3. bis [ tris (2-methyl-2-phenyl) propyltin according to claim 1]5-aminoisophthalate complex wherein said bis [ tris (2-methyl-2-phenyl) propyltin]The 5-amino isophthalic acid ester complex has a crystal structure, and the crystallographic data of the complex are as follows: triclinic, 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) nm3(ii) a The central tin in the molecule forms a distorted tetrahedral configuration with the coordinating atoms.
4. The preparation method of bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex as described in claim 1, wherein bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide, 5-aminoisophthalic acid and anhydrous methanol as a solvent are sequentially added into a microwave reaction tank in order, and the microwave reaction is carried out at a radiation power of 800W and a temperature of 100 ℃ for a period of 60-120 min under an air atmosphere; after the reaction is finished, naturally cooling, filtering, and naturally volatilizing the solvent at room temperature to crystallize to obtain a light yellow crystal, namely the bis [ tri (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex.
5. The method according to claim 4, wherein the bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide and 5-aminoisophthalic acid are present in an amount of 1 (1 to 1.05).
6. The method according to claim 4, wherein the solvent is 10 to 15 ml of anhydrous methanol per mmol of bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide.
7. The use of the bis [ tris (2-methyl-2-phenyl) propyltin ] 5-aminoisophthalate complex of claim 1 in the preparation of an anti-cancer medicament.
8. The use of claim 7, wherein the cancer cell is lung cancer, cervical cancer, gastric cancer.
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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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