CN111217851A - Preparation method and application of tricyclohexyltin indole-4-formate complex - Google Patents
Preparation method and application of tricyclohexyltin indole-4-formate complex Download PDFInfo
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- RPHINJQGZUOAIT-UHFFFAOYSA-M tricyclohexylstannyl 1H-indole-4-carboxylate Chemical compound N1C=CC=2C(=CC=CC12)C(=O)[O-].C1(CCCCC1)[Sn+](C1CCCCC1)C1CCCCC1 RPHINJQGZUOAIT-UHFFFAOYSA-M 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000013078 crystal Substances 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 18
- WCMMILVIRZAPLE-UHFFFAOYSA-M cyhexatin Chemical compound C1CCCCC1[Sn](C1CCCCC1)(O)C1CCCCC1 WCMMILVIRZAPLE-UHFFFAOYSA-M 0.000 claims description 14
- ROGHUJUFCRFUSO-UHFFFAOYSA-N 1h-indole-4-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1C=CN2 ROGHUJUFCRFUSO-UHFFFAOYSA-N 0.000 claims description 11
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 11
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- 201000011549 stomach cancer Diseases 0.000 claims description 11
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 10
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 10
- 201000010881 cervical cancer Diseases 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 201000005202 lung cancer Diseases 0.000 claims description 10
- 208000020816 lung neoplasm Diseases 0.000 claims description 10
- 238000000902 119Sn nuclear magnetic resonance spectroscopy Methods 0.000 claims description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 claims description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 claims description 8
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- 238000001914 filtration Methods 0.000 claims description 8
- 230000005855 radiation Effects 0.000 claims description 8
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 7
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- 238000000034 method Methods 0.000 claims description 7
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- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
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- 239000002246 antineoplastic agent Substances 0.000 abstract description 10
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 10
- 210000004027 cell Anatomy 0.000 description 30
- 229910052718 tin Inorganic materials 0.000 description 10
- 238000012360 testing method Methods 0.000 description 9
- 238000011160 research Methods 0.000 description 8
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- 229940079593 drug Drugs 0.000 description 7
- 238000000921 elemental analysis Methods 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
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- 230000004071 biological effect Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000003446 ligand Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 4
- 239000003560 cancer drug Substances 0.000 description 4
- 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
- 150000007942 carboxylates Chemical class 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
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- 238000000134 MTT assay Methods 0.000 description 1
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- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
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- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 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
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- AYOHIQLKSOJJQH-UHFFFAOYSA-N dibutyltin Chemical compound CCCC[Sn]CCCC AYOHIQLKSOJJQH-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
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- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
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- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 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
- 230000008569 process Effects 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
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001942 tin-119 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- RNVJQUPAEIQUTC-UHFFFAOYSA-N tricyclohexyltin Chemical compound C1CCCCC1[Sn](C1CCCCC1)C1CCCCC1 RNVJQUPAEIQUTC-UHFFFAOYSA-N 0.000 description 1
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- 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 preparation method and application of a tricyclohexyltin indole-4-formate complex, which is a complex with the following structural formula (I)
. The invention also discloses a preparation method of the tricyclohexyltin indole-4-formate complex and application of the tricyclohexyltin indole-4-formate complex in preparation of antitumor drugs.
Description
Technical Field
The invention relates to a tricyclohexyl tin indole-4-formate complex, a preparation method thereof and application of the complex in preparing an anti-tumor medicament.
Background
Since Brown's first discovery of organotin Carboxylates (CH)3CO2SnPh3) Since the composition has the bioactivity of inhibiting mouse tumors, scientists have paid extensive attention to the synthesis, structure and bioactivity research of organotin carboxylate complexes. However, the known organotin compounds are generally strongly toxic and thus are subject to certain applicationsAnd (4) limiting. 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 tricyclohexyl tin hydroxide is a substance which is proved to have good biological activity by experiments, and cyclohexyl has the characteristics of large steric hindrance, large molecular weight and the like, the tricyclohexyl tin hydroxide is selected to react with heterocyclic carboxylic acid ligand indole-4-formic acid under certain conditions to synthesize the complex with strong inhibitory activity to A549 (human lung cancer cells), Hela (human cervical cancer cells) and HGC-27 (human gastric cancer cells), and a new way is provided for developing anti-cancer drugs.
Disclosure of Invention
In view of the problems of the prior art, the first object of the present invention is to provide a tricyclohexyltin indole-4-carboxylate complex.
The second object of the present invention is to provide a process for preparing the above tricyclohexyltin indole-4-carboxylate complex.
The third purpose of the invention is to provide the application of the tricyclohexyl tin indole-4-formate complex in preparing anti-cancer drugs.
A tricyclohexyltin indole-4-carboxylate complex as a first aspect of the present invention has the following structural formula (I):
(I)。
the tricyclohexyl tin indole-4-formate complex has the following results after element analysis, infrared spectrum analysis, nuclear magnetic resonance spectrum and X-ray single crystal structure analysis:
elemental analysis (C)27H39NO2Sn): theoretical value: c, 61.38; h, 7.44; and N, 2.65. Measurement value: c, 61.32; h, 7.45; and N, 2.61.
IR(KBr, v/cm-1): 3271.27 (s), 2918.30 (s), 2843.07 (s), 1593.20 (s),1500.62 (m), 1442.75 (s), 1365.60 (s), 1332.81 (s), 1267.23 (w), 1190.08 (s),1170.79 (m), 1114.86 (w), 989.48 (m), 898.83 (m), 875.68 (w), 844.82 (w),785.03 (w), 758.02 (s), 729.09 (m), 636.51 (m), 578.64 (w), 480.28 (m),414.70 (w)。
1H NMR (CDCl3, 500 MHz)δ(ppm): 8.43 (s, 1H), 7.94 (d,J= 7.5 Hz,1H), 7.54 (d,J= 8 Hz, 1H), 7.31 (t,J= 3 Hz, 1H), 7.24 - 7.21 (m, 2H),2.08 - 1.38 (m, 33H)。
13C NMR(CDCl3, 125 MHz), δ(ppm): 172.67, 136.64, 127.84, 125.53,124.07, 123.91, 121.19, 114.91, 104.48, 33.84, 31.24 (t,J= 7.3 Hz), 29.01(t,J= 32.3 Hz), 27.00。
119Sn NMR (CDCl3, 186 MHz)δ(ppm): 11.65。
The tricyclohexyl tin indole-4-formate complex has a crystal structure, and the crystallographic data of the complex are as follows: the crystals belong to the orthorhombic system, space groupP212121，a=0.92771(8) nm，b=2.2943(2) nm，c=2.4973(2) nm，α=90°，β=90°，γ=90°，Z=8，V=5.3155(8) nm3，Dc=1.320 Mg·m-3，μ(MoKa)=0.983 mm-1，F(000)=2192，1.63°＜θ< 27.59 °, crystal size: 0.25X 0.20X 0.21 mm,R=0.1068，wR=0.3005。
the tricyclohexyl tin indole-4-formic ether complex has the structural characteristics that: the central tin in the molecule forms a distorted tetrahedral configuration with the coordinating atoms.
In the second aspect of the invention, the preparation method of the tricyclohexyl tin indole-4-formate complex comprises the steps of sequentially adding tricyclohexyl tin hydroxide, indole-4-formic acid and 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 60-120 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 yellow crystal, namely the tricyclohexyltin indole-4-formate complex.
In a preferred embodiment of the invention, the mass ratio of the tricyclohexyltin hydroxide to the indole-4-carboxylic acid is 1 (1-1.05).
In a preferred embodiment of the present invention, the solvent anhydrous methanol is used in an amount of 10 to 15 ml per mmol of tricyclohexyltin hydroxide.
The third aspect of the invention relates to the application of tricyclohexyltin indole-4-formate complex in preparing anticancer 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 tricyclohexylstannane indole-4-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 platinum anticancer drugs commonly used at present, the tricyclohexyltin indole-4-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 a crystal molecular structure diagram of tricyclohexyltin indole-4-carboxylate complex.
FIG. 2 is an IR spectrum of tricyclohexyltin indole-4-carboxylate complex.
FIG. 3 is a scheme of tricyclohexyltin indole-4-carboxylate complex1H NMR spectrum.
FIG. 4 is a schematic representation of tricyclohexyltin indole-4-carboxylate complex13C NMR spectrum.
FIG. 5 is a schematic representation of tricyclohexyltin indole-4-carboxylate complex119Sn NMR spectrum.
FIG. 6 is a TG-DTG curve of tricyclohexyltin indole-4-carboxylate complex.
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 tricyclohexyltin indole-4-carboxylate complex:
0.3857 g (1 mmol) of tricyclohexyl tin hydroxide, 0.1617 g (1 mmol) of indole-4-formic 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 yellow crystal, namely the tricyclohexyltin indole-4-formate complex. Yield: 69%, melting point: 168 ℃ and 171 ℃.
Elemental analysis (C)27H39NO2Sn): theoretical value: c, 61.38; h, 7.44; and N, 2.65. Measurement value: c, 61.32; h, 7.45; and N, 2.61.
IR(KBr, v/cm-1): 3271.27 (s), 2918.30 (s), 2843.07 (s), 1593.20 (s),1500.62 (m), 1442.75 (s), 1365.60 (s), 1332.81 (s), 1267.23 (w), 1190.08 (s),1170.79 (m), 1114.86 (w), 989.48 (m), 898.83 (m), 875.68 (w), 844.82 (w),785.03 (w), 758.02 (s), 729.09 (m), 636.51 (m), 578.64 (w), 480.28 (m),414.70 (w)。
1H NMR (CDCl3, 500 MHz)δ(ppm): 8.43 (s, 1H), 7.94 (d,J= 7.5 Hz,1H), 7.54 (d,J= 8 Hz, 1H), 7.31 (t,J= 3 Hz, 1H), 7.24 - 7.21 (m, 2H),2.08 - 1.38 (m, 33H)。
13C NMR(CDCl3, 125 MHz), δ(ppm): 172.67, 136.64, 127.84, 125.53,124.07, 123.91, 121.19, 114.91, 104.48, 33.84, 31.24 (t,J= 7.3 Hz), 29.01(t,J= 32.3 Hz), 27.00。
119Sn NMR (CDCl3, 186 MHz)δ(ppm): 11.65。
The crystallographic data are as follows: the crystals belong to the orthorhombic system, space groupP212121，a=0.92771(8) nm，b=2.2943(2)nm，c=2.4973(2) nm，α=90°，β=90°，γ=90°，Z=8，V=5.3155(8) nm3，Dc=1.320 Mg·m-3，μ(MoKa)=0.983 mm-1，F(000)=2192，1.63°＜θ< 27.59 °, crystal size: 0.25X 0.20X 0.21 mm,R=0.1068，wR=0.3005。
example 2:
preparation of tricyclohexyltin indole-4-carboxylate complex:
0.3846 g (1 mmol) of tricyclohexyl tin hydroxide, 0.1693 g (1.05 mmol) of indole-4-formic acid and 15 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 yellow crystal, namely the tricyclohexyltin indole-4-formate complex. Yield: 70%, melting point: 168 ℃ and 171 ℃.
Elemental analysis (C)27H39NO2Sn): theoretical value: c, 61.38; h, 7.44; and N, 2.65. Measurement value: c, 61.32; h, 7.45; and N, 2.61.
IR(KBr, v/cm-1): 3271.27 (s), 2918.30 (s), 2843.07 (s), 1593.20 (s),1500.62 (m), 1442.75 (s), 1365.60 (s), 1332.81 (s), 1267.23 (w), 1190.08 (s),1170.79 (m), 1114.86 (w), 989.48 (m), 898.83 (m), 875.68 (w), 844.82 (w),785.03 (w), 758.02 (s), 729.09 (m), 636.51 (m), 578.64 (w), 480.28 (m),414.70 (w)。
1H NMR (CDCl3, 500 MHz)δ(ppm): 8.43 (s, 1H), 7.94 (d,J= 7.5 Hz,1H), 7.54 (d,J= 8 Hz, 1H), 7.31 (t,J= 3 Hz, 1H), 7.24 - 7.21 (m, 2H),2.08 - 1.38 (m, 33H)。
13C NMR(CDCl3, 125 MHz), δ(ppm): 172.67, 136.64, 127.84, 125.53,124.07, 123.91, 121.19, 114.91, 104.48, 33.84, 31.24 (t,J= 7.3 Hz), 29.01(t,J= 32.3 Hz), 27.00。
119Sn NMR (CDCl3, 186 MHz)δ(ppm): 11.65。
The crystallographic data are as follows: the crystals belong to the orthorhombic system, space groupP212121，a=0.92771(8) nm，b=2.2943(2)nm，c=2.4973(2) nm，α=90°，β=90°，γ=90°，Z=8，V=5.3155(8) nm3，Dc=1.320 Mg·m-3，μ(MoKa)=0.983 mm-1，F(000)=2192，1.63°＜θ< 27.59 °, crystal size: 0.25X 0.20X 0.21 mm,R=0.1068，wR=0.3005。
example 3:
preparation of tricyclohexyltin indole-4-carboxylate complex:
0.3848 g (1 mmol) of tricyclohexyl tin hydroxide, 0.1620 g (1 mmol) of indole-4-formic acid and 12 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 yellow crystal, namely the tricyclohexyltin indole-4-formate complex. Yield: 71%, melting point: 168 ℃ and 171 ℃.
Elemental analysis (C)27H39NO2Sn): theoretical value: c, 61.38; h, 7.44; and N, 2.65. Measurement value: c, 61.32; h, 7.45; and N, 2.61.
IR(KBr, v/cm-1): 3271.27 (s), 2918.30 (s), 2843.07 (s), 1593.20 (s),1500.62 (m), 1442.75 (s), 1365.60 (s), 1332.81 (s), 1267.23 (w), 1190.08 (s),1170.79 (m), 1114.86 (w), 989.48 (m), 898.83 (m), 875.68 (w), 844.82 (w),785.03 (w), 758.02 (s), 729.09 (m), 636.51 (m), 578.64 (w), 480.28 (m),414.70 (w)。
1H NMR (CDCl3, 500 MHz)δ(ppm): 8.43 (s, 1H), 7.94 (d,J= 7.5 Hz,1H), 7.54 (d,J= 8 Hz, 1H), 7.31 (t,J= 3 Hz, 1H), 7.24 - 7.21 (m, 2H),2.08 - 1.38 (m, 33H)。
13C NMR(CDCl3, 125 MHz), δ(ppm): 172.67, 136.64, 127.84, 125.53,124.07, 123.91, 121.19, 114.91, 104.48, 33.84, 31.24 (t,J= 7.3 Hz), 29.01(t,J= 32.3 Hz), 27.00。
119Sn NMR (CDCl3, 186 MHz)δ(ppm): 11.65。
The crystallographic data are as follows: the crystals belong to the orthorhombic system, space groupP212121，a=0.92771(8) nm，b=2.2943(2)nm，c=2.4973(2) nm，α=90°，β=90°，γ=90°，Z=8，V=5.3155(8) nm3，Dc=1.320 Mg·m-3，μ(MoKa)=0.983 mm-1，F(000)=2192，1.63°＜θ< 27.59 °, crystal size: 0.25X 0.20X 0.21 mm,R=0.1068，wR=0.3005。
example 4:
preparation of tricyclohexyltin indole-4-carboxylate complex:
0.7707 g (2.0 mmol) of tricyclohexyl tin hydroxide, 0.3224 g (2 mmol) of indole-4-formic acid and 25mL of solvent absolute 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 yellow crystal, namely the tricyclohexyltin indole-4-formate complex. Yield: 70%, melting point: 168 ℃ and 171 ℃.
Elemental analysis (C)27H39NO2Sn): theoretical value: c, 61.38; h, 7.44; and N, 2.65. Measurement value: c, 61.32; h, 7.45; and N, 2.61.
IR(KBr, v/cm-1): 3271.27 (s), 2918.30 (s), 2843.07 (s), 1593.20 (s),1500.62 (m), 1442.75 (s), 1365.60 (s), 1332.81 (s), 1267.23 (w), 1190.08 (s),1170.79 (m), 1114.86 (w), 989.48 (m), 898.83 (m), 875.68 (w), 844.82 (w),785.03 (w), 758.02 (s), 729.09 (m), 636.51 (m), 578.64 (w), 480.28 (m),414.70 (w)。
1H NMR (CDCl3, 500 MHz)δ(ppm): 8.43 (s, 1H), 7.94 (d,J= 7.5 Hz,1H), 7.54 (d,J= 8 Hz, 1H), 7.31 (t,J= 3 Hz, 1H), 7.24 - 7.21 (m, 2H),2.08 - 1.38 (m, 33H)。
13C NMR(CDCl3, 125 MHz), δ(ppm): 172.67, 136.64, 127.84, 125.53,124.07, 123.91, 121.19, 114.91, 104.48, 33.84, 31.24 (t,J= 7.3 Hz), 29.01(t,J= 32.3 Hz), 27.00。
119Sn NMR (CDCl3, 186 MHz)δ(ppm): 11.65。
The crystallographic data are as follows: the crystals belong to the orthorhombic system, space groupP212121，a=0.92771(8) nm，b=2.2943(2)nm，c=2.4973(2) nm，α=90°，β=90°，γ=90°，Z=8，V=5.3155(8) nm3，Dc=1.320 Mg·m-3，μ(MoKa)=0.983 mm-1，F(000)=2192，1.63°＜θ< 27.59 °, crystal size: 0.25X 0.20X 0.21 mm,R=0.1068，wR=0.3005。
example 5:
preparation of tricyclohexyltin indole-4-carboxylate complex:
0.7709 g (2.0 mmol) of tricyclohexyl tin hydroxide, 0.3305 g (2.05 mmol) of indole-4-formic 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 yellow crystal, namely the tricyclohexyltin indole-4-formate complex. Yield: 71%, melting point: 168 ℃ and 171 ℃.
Elemental analysis (C)27H39NO2Sn): theoretical value: c, 61.38; h, 7.44; and N, 2.65. Measurement value: c, 61.32; h, 7.45; and N, 2.61.
IR(KBr, v/cm-1): 3271.27 (s), 2918.30 (s), 2843.07 (s), 1593.20 (s),1500.62 (m), 1442.75 (s), 1365.60 (s), 1332.81 (s), 1267.23 (w), 1190.08 (s),1170.79 (m), 1114.86 (w), 989.48 (m), 898.83 (m), 875.68 (w), 844.82 (w),785.03 (w), 758.02 (s), 729.09 (m), 636.51 (m), 578.64 (w), 480.28 (m),414.70 (w)。
1H NMR (CDCl3, 500 MHz)δ(ppm): 8.43 (s, 1H), 7.94 (d,J= 7.5 Hz,1H), 7.54 (d,J= 8 Hz, 1H), 7.31 (t,J= 3 Hz, 1H), 7.24 - 7.21 (m, 2H),2.08 - 1.38 (m, 33H)。
13C NMR(CDCl3, 125 MHz), δ(ppm): 172.67, 136.64, 127.84, 125.53,124.07, 123.91, 121.19, 114.91, 104.48, 33.84, 31.24 (t,J= 7.3 Hz), 29.01(t,J= 32.3 Hz), 27.00。
119Sn NMR (CDCl3, 186 MHz)δ(ppm): 11.65。
The crystallographic data are as follows: the crystals belong to the orthorhombic system, space groupP212121，a=0.92771(8) nm，b=2.2943(2)nm，c=2.4973(2) nm，α=90°，β=90°，γ=90°，Z=8，V=5.3155(8) nm3，Dc=1.320 Mg·m-3，μ(MoKa)=0.983 mm-1，F(000)=2192，1.63°＜θ< 27.59 °, crystal size: 0.25X 0.20X 0.21 mm,R=0.1068，wR=0.3005。
example 6:
preparation of tricyclohexyltin indole-4-carboxylate complex:
1.1557 g (3.0 mmol) of tricyclohexyl tin hydroxide, 0.4835 g (3 mmol) of indole-4-formic 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 yellow crystal, namely the tricyclohexyltin indole-4-formate complex. Yield: 72%, melting point: 168 ℃ and 171 ℃.
Elemental analysis (C)27H39NO2Sn): theoretical value: c, 61.38; h, 7.44; and N, 2.65. Measurement value: c, 61.32; h, 7.45; and N, 2.61.
IR(KBr, v/cm-1): 3271.27 (s), 2918.30 (s), 2843.07 (s), 1593.20 (s),1500.62 (m), 1442.75 (s), 1365.60 (s), 1332.81 (s), 1267.23 (w), 1190.08 (s),1170.79 (m), 1114.86 (w), 989.48 (m), 898.83 (m), 875.68 (w), 844.82 (w),785.03 (w), 758.02 (s), 729.09 (m), 636.51 (m), 578.64 (w), 480.28 (m),414.70 (w)。
1H NMR (CDCl3, 500 MHz)δ(ppm): 8.43 (s, 1H), 7.94 (d,J= 7.5 Hz,1H), 7.54 (d,J= 8 Hz, 1H), 7.31 (t,J= 3 Hz, 1H), 7.24 - 7.21 (m, 2H),2.08 - 1.38 (m, 33H)。
13C NMR(CDCl3, 125 MHz), δ(ppm): 172.67, 136.64, 127.84, 125.53,124.07, 123.91, 121.19, 114.91, 104.48, 33.84, 31.24 (t,J= 7.3 Hz), 29.01(t,J= 32.3 Hz), 27.00。
119Sn NMR (CDCl3, 186 MHz)δ(ppm): 11.65。
The crystallographic data are as follows: the crystals belong to the orthorhombic system, space groupP212121，a=0.92771(8) nm，b=2.2943(2)nm，c=2.4973(2) nm，α=90°，β=90°，γ=90°，Z=8，V=5.3155(8) nm3，Dc=1.320 Mg·m-3，μ(MoKa)=0.983 mm-1，F(000)=2192，1.63°＜θ< 27.59 °, crystal size: 0.25X 0.20X 0.21 mm,R=0.1068，wR=0.3005。
test example:
the determination of the in vitro anticancer activity of the tricyclohexyl tin indole-4-formate complex is realized 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.
MTT method was used to measure the inhibitory activity of the tricyclohexyltin indole-4-carboxylate complex prepared in example 1 on human lung cancer cells (A549), human cervical cancer cells (Hela), and human gastric cancer cells (HGC-27).
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 tricyclohexyltin indole-4-formate complex has high 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 tricyclohexyltin indole-4-carboxylate complex anticancer drug in vitro activity test data.
| Human lung cancer cell | Human cervical cancer cell | Human gastric cancer cell | |
| Cell line | A549 | Hela | HGC-27 |
| IC50 μM | 0.2462 | 0.1865 | 0.1372 |
The tricyclohexyltin indole-4-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 example, and the test results were substantially the same as in table 1.
Claims (9)
1. A tricyclohexyltin indole-4-carboxylate complex is a complex of the following structural formula (I):
(I)。
2. the tricyclohexyltin indole-4-carboxylate complex of claim 1 having an infrared spectrum of: FT-IR (KBr, v/cm)-1) 3271.27(s), 2918.30(s), 2843.07(s), 1593.20(s), 1500.62 (m), 1442.75(s), 1365.60(s), 1332.81(s), 1267.23 (w), 1190.08(s), 1170.79 (m), 1114.86 (w), 989.48 (m), 898.83 (m), 875.68 (w), 844.82 (w),785.03 (w), 758.02(s), 729.09 (m), 636.51 (m), 578.64 (w), 480.28 (m),414.70 (w); nuclear magnetic spectrum data thereof:1H NMR (CDCl3, 500 MHz)δ(ppm): 8.43 (s, 1H), 7.94(d,J= 7.5 Hz, 1H), 7.54 (d,J= 8 Hz, 1H), 7.31 (t,J= 3 Hz, 1H), 7.24 -7.21 (m, 2H), 2.08 - 1.38 (m, 33H);13C NMR (CDCl3, 125 MHz)δ(ppm): 172.67,136.64, 127.84, 125.53, 124.07, 123.91, 121.19, 114.91, 104.48, 33.84, 31.24(t,J= 7.3 Hz), 29.01 (t,J= 32.3 Hz), 27.00;119Sn NMR (CDCl3, 186MHz)δ(ppm): 11.65。
3. the tricyclohexyltin indole-4-carboxylate complex of claim 1, wherein the tricyclohexyltin indole-4-carboxylate complex has a crystal structure with crystallographic data as follows: orthorhombic, space groupP212121，a=0.92771(8) nm，b=2.2943(2) nm，c=2.4973(2) nm，α=90°，β=90°，γ=90°，Z=8，V=5.3155(8) nm3(ii) a The central tin in the molecule forms a distorted tetrahedral configuration with the coordinating atoms.
4. The preparation method of tricyclohexyltin indole-4-formate complex as claimed in claim 1, characterized in that tricyclohexyltin hydroxide, indole-4-carboxylic acid and solvent anhydrous methanol are sequentially added into a microwave reaction tank, and microwave reaction is carried out at a radiation power of 800W and a temperature of 100 ℃ for 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 yellow crystal, namely the tricyclohexyltin indole-4-formate complex.
5. The method according to claim 4, wherein the ratio of the amounts of tricyclohexyltin hydroxide and indole-4-carboxylic acid is 1 (1-1.05).
6. The method according to claim 4, wherein the solvent is 10 to 15 ml of anhydrous methanol per mmol of tricyclohexyltin hydroxide.
7. The tricyclohexyltin indole-4-carboxylate complex of claim 1 having a range of thermal stability that is stable below 235 ℃.
8. Use of the tricyclohexyltin indole-4-carboxylate complex of claim 1 in the preparation of an anti-cancer medicament.
9. The use of claim 8, wherein the cancer cell is lung cancer, cervical cancer, gastric cancer.
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