CN111057093B - Tricyclohexyltin benzothiophene-2-formate complex and preparation method and application thereof - Google Patents
Tricyclohexyltin benzothiophene-2-formate complex and preparation method and application thereof Download PDFInfo
- Publication number
- CN111057093B CN111057093B CN201911368224.7A CN201911368224A CN111057093B CN 111057093 B CN111057093 B CN 111057093B CN 201911368224 A CN201911368224 A CN 201911368224A CN 111057093 B CN111057093 B CN 111057093B
- Authority
- CN
- China
- Prior art keywords
- benzothiophene
- tricyclohexyltin
- complex
- preparation
- formate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- YBNYTXXWBXQNDU-UHFFFAOYSA-M tricyclohexylstannyl 1-benzothiophene-2-carboxylate Chemical compound S1C(=CC2=C1C=CC=C2)C(=O)[O-].C2(CCCCC2)[Sn+](C2CCCCC2)C2CCCCC2 YBNYTXXWBXQNDU-UHFFFAOYSA-M 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000010668 complexation reaction Methods 0.000 title description 2
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 12
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 18
- DYSJMQABFPKAQM-UHFFFAOYSA-N 1-benzothiophene-2-carboxylic acid Chemical compound C1=CC=C2SC(C(=O)O)=CC2=C1 DYSJMQABFPKAQM-UHFFFAOYSA-N 0.000 claims description 11
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 11
- 206010017758 gastric cancer Diseases 0.000 claims description 11
- 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
- 201000005202 lung cancer Diseases 0.000 claims description 10
- 208000020816 lung neoplasm Diseases 0.000 claims description 10
- WCMMILVIRZAPLE-UHFFFAOYSA-M cyhexatin Chemical compound C1CCCCC1[Sn](C1CCCCC1)(O)C1CCCCC1 WCMMILVIRZAPLE-UHFFFAOYSA-M 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 24
- 229910052718 tin Inorganic materials 0.000 description 12
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical group [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- 238000000921 elemental analysis Methods 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 230000001093 anti-cancer Effects 0.000 description 6
- 230000004071 biological effect Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- -1 hydrocarbyl tin Chemical compound 0.000 description 6
- 239000003446 ligand Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 4
- 239000000203 mixture 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
- 238000000134 MTT assay Methods 0.000 description 3
- 231100000002 MTT assay Toxicity 0.000 description 3
- 239000003560 cancer drug Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 239000012531 culture fluid Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
- 240000009038 Viola odorata Species 0.000 description 1
- 235000013487 Viola odorata Nutrition 0.000 description 1
- 235000002254 Viola papilionacea Nutrition 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 238000012790 confirmation Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing 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
- 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
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 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
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000001942 tin-119 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Images
Classifications
-
- 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 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a tricyclohexyl tin benzothiophene-2-formate complex, a preparation method and application thereof, which is a complex with the following structural formula (I)
Description
Technical Field
The invention relates to a tricyclohexyltin benzothiophene-2-formate complex, a preparation method thereof and application of the complex in preparing antitumor drugs.
Background
Since Brown discovered for the first time that organotin carboxylates (CH 3CO2SnPh 3) have inhibitory activity against mouse tumor bioactivity, studies on the synthesis, structure and bioactivity of organotin carboxylate complexes have received extensive attention from scientists. However, the known organotin compounds are generally highly toxic and therefore limited in application. Studies have shown that the structure, reactivity and biological activity of organotin compounds are related to both the hydrocarbon-based structure directly attached to the tin atom and the nature of the ligand. The organic tin complex structure is optimized through molecular design, so that the balance between toxicity and biological activity of the organic tin complex is regulated, and the organic tin complex 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 complex is synthesized, and the structure and the biological activity of the complex are researched, so that the complex has important research significance.
It is well known that azacyclic rings are important and common structural units of medicines, pesticides, functional materials, etc., most of which are closely related to life systems, so that studying the structure of organotin derivatives of such ligands can provide useful information not only for the disclosed anticancer mechanism, but also for the development of novel drugs as possible molecular designs. It is necessary to synthesize a novel nitrogen-containing heterocyclic organotin carboxylate compound and conduct a study on the bioactivity of the compound, the nitrogen-containing heteroatom carboxylic acid being an important carboxylic acid ligand. For example, chinese patent CN101402650B discloses an application of a dibutyl tin and quinolinecarboxylic acid complex in preparing medicines for treating gastric cancer, nasopharyngeal carcinoma, human liver cancer or leukemia.
Based on the fact that the tricyclohexyl tin hydroxide is a substance with good biological activity, and the 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 benzothiophene-2-formic 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 way 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 tricyclohexyltin benzothiophene-2-carboxylate complex.
The second object of the present invention is to provide a process for preparing the above tricyclohexyltin benzothiophene-2-carboxylate complex.
The third object of the invention is to provide the application of the tricyclohexyltin benzothiophene-2-formate complex in preparing anticancer drugs.
As a first aspect of the present invention, a tricyclohexyltin benzothiophene-2-carboxylate complex is a complex of the following structural formula (I):
(I)。
the result of element analysis, infrared spectrum analysis and nuclear magnetic resonance spectrum of the tricyclohexyltin benzothiophene-2-formate complex is as follows:
elemental analysis (C) 28 H 42 O 3 SSn): theoretical value: c,58.24; h,7.33. Measurement value: c,58.22; h,7.35.
IR(KBr, v/cm -1 ):3730.33 (w), 3626.17 (w), 3589.53 (w), 3302.13 (w), 2920.23 (s), 2845.00 (m), 1649.14 (w), 1602.85 (m), 1558.48 (w), 1521.84 (m), 1444.68 (m), 1359.82 (m), 1319.31 (m), 1257.59 (w), 1170.79 (m), 1155.36 (w), 1083.99 (w), 1022.27 (m), 991.41 (m), 939.33 (w), 869.90 (w), 775.38 (m), 680.87 (m), 653.87 (m), 590.22 (w), 472.56 (w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.96 (s, 1H), 7.84(d, J =8Hz, 2H), 7.41-7.35 (m, 2H), 3.48(s, 3H), 2.06-1.98 (m, 9H), 1.79-1.65 (m, 15H), 1.44-1.34 (m, 9H)。
13 C NMR(CDCl 3 , 125 MHz), δ(ppm): 167.04, 142.36, 139.27, 137.05, 129.41, 126.14, 125.17, 124.47, 122.67, 50.82, 34.28, 31.12, 28.93, 26.90。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm):30.21。
The tricyclohexyltin benzothiophene-2-formate complex of the present invention has the structural characteristics that: the central tin in the molecule and the coordination atoms form a twisted triangle bipyramid configuration.
As a preparation method of the tricyclohexyltin benzothiophene-2-formate complex in the second aspect of the invention, the tricyclohexyltin benzothiophene-2-formate complex and solvent toluene are sequentially arranged in a 250 mL round bottom flask, a Dean-Stark water separator is arranged, and heating reflux reaction is carried out for 6-12 hours at 112-120 ℃. After the reaction is finished, filtering while the solution is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using methanol to obtain the tricyclohexyltin benzothiophene-2-formate complex.
In a preferred embodiment of the present invention, the mass ratio of the tricyclohexyltin hydroxide to the benzothiophene-2-carboxylic acid is 1 (1-1.1).
In a preferred embodiment of the invention, the solvent toluene is added in an amount of 25-35 ml per millimole of tricyclohexyl tin hydroxide.
The invention relates to application of tricyclohexyltin benzothiophene-2-formate complex as a third aspect of the invention in preparation of 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 tricyclohexyltin benzothiophene-2-formate complex of 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 raw materials for preparing medicines for resisting lung cancer, cervical cancer and gastric cancer. Compared with the currently commonly used platinum anti-cancer drugs, the tricyclohexyltin benzothiophene-2-formate 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 an IR spectrum of tricyclohexyltin benzothiophene-2-carboxylate complex.
FIG. 2 is a tricyclohexyltin benzothiophene-2-carboxylate complex 1 H NMR spectrum.
FIG. 3 is a tricyclohexyltin benzothiophene-2-carboxylate complex 13 C NMR spectrum.
FIG. 4 is a tricyclohexyltin benzothiophene-2-carboxylate 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 tricyclohexyltin benzothiophene-2-carboxylate complex:
into a 250 mL round bottom flask, 0.385 g (1 mmol) of tricyclohexyltin hydroxide, 0.1785 g (1 mmol) of benzothiophene-2-carboxylic acid, 25 mL (solvent toluene) were added sequentially, and a Dean-Stark trap was installed, and the mixture was heated to reflux at 112-120℃for reaction 6 h. After the reaction is finished, filtering while the solution is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using methanol to obtain the tricyclohexyltin benzothiophene-2-formate complex. Yield: 81%, melting point: 56-57 ℃.
Elemental analysis (C) 28 H 42 O 3 SSn): theoretical value: c,58.24; h,7.33. Measurement value: c,58.22; h,7.35.
IR(KBr, v/cm -1 ):3730.33 (w), 3626.17 (w), 3589.53 (w), 3302.13 (w), 2920.23 (s), 2845.00 (m), 1649.14 (w), 1602.85 (m), 1558.48 (w), 1521.84 (m), 1444.68 (m), 1359.82 (m), 1319.31 (m), 1257.59 (w), 1170.79 (m), 1155.36 (w), 1083.99 (w), 1022.27 (m), 991.41 (m), 939.33 (w), 869.90 (w), 775.38 (m), 680.87 (m), 653.87 (m), 590.22 (w), 472.56 (w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.96 (s, 1H), 7.84(d, J =8Hz, 2H), 7.41-7.35 (m, 2H), 3.48(s, 3H), 2.06-1.98 (m, 9H), 1.79-1.65 (m, 15H), 1.44-1.34 (m, 9H)。
13 C NMR(CDCl 3 , 125 MHz), δ(ppm): 167.04, 142.36, 139.27, 137.05, 129.41, 126.14, 125.17, 124.47, 122.67, 50.82, 34.28, 31.12, 28.93, 26.90。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm):30.21
Example 2:
preparation of tricyclohexyltin benzothiophene-2-carboxylate complex:
to a 250 mL round bottom flask was added, in order, tin 0.3852 g (1.0 mmol) tricyclohexyl hydroxide, benzothiophene-2-carboxylic acid 0.1962 g (1.1 mmol), toluene 25 mL as solvent, and the mixture was fitted with a Dean-Stark trap and heated to reflux at 112-120℃for reaction 8 h. After the reaction is finished, filtering while the solution is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain yellow solid, and recrystallizing the yellow solid by using methanol to obtain the tricyclohexyltin benzothiophene-2-formate complex. Yield: 82%, melting point: 56-57 ℃.
Elemental analysis (C) 28 H 42 O 3 SSn): theoretical value: c,58.24; h,7.33. Measurement value: c,58.22; h,7.35.
IR(KBr, v/cm -1 ):3730.33 (w), 3626.17 (w), 3589.53 (w), 3302.13 (w), 2920.23 (s), 2845.00 (m), 1649.14 (w), 1602.85 (m), 1558.48 (w), 1521.84 (m), 1444.68 (m), 1359.82 (m), 1319.31 (m), 1257.59 (w), 1170.79 (m), 1155.36 (w), 1083.99 (w), 1022.27 (m), 991.41 (m), 939.33 (w), 869.90 (w), 775.38 (m), 680.87 (m), 653.87 (m), 590.22 (w), 472.56 (w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.96 (s, 1H), 7.84(d, J =8Hz, 2H), 7.41-7.35 (m, 2H), 3.48(s, 3H), 2.06-1.98 (m, 9H), 1.79-1.65 (m, 15H), 1.44-1.34 (m, 9H)。
13 C NMR(CDCl 3 , 125 MHz), δ(ppm): 167.04, 142.36, 139.27, 137.05, 129.41, 126.14, 125.17, 124.47, 122.67, 50.82, 34.28, 31.12, 28.93, 26.90。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm):30.21。
Example 3:
preparation of tricyclohexyltin benzothiophene-2-carboxylate complex:
to a 250 mL round bottom flask was added, in order, tricyclohexyltin hydroxide 0.3850 g (1.0 mmol), benzothiophene-2-carboxylic acid 0.1958 g (1.1 mmol), solvent toluene 35 mL, and equipped with a Dean-Stark trap, and heated to reflux at 112-120℃for reaction 8 h. After the reaction is finished, filtering while the solution is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using methanol to obtain the tricyclohexyltin benzothiophene-2-formate complex. Yield: 83%, melting point: 56-57 ℃.
Elemental analysis (C) 28 H 42 O 3 SSn): theoretical value: c,58.24; h,7.33. Measurement value: c,58.22; h,7.35.
IR(KBr, v/cm -1 ):3730.33 (w), 3626.17 (w), 3589.53 (w), 3302.13 (w), 2920.23 (s), 2845.00 (m), 1649.14 (w), 1602.85 (m), 1558.48 (w), 1521.84 (m), 1444.68 (m), 1359.82 (m), 1319.31 (m), 1257.59 (w), 1170.79 (m), 1155.36 (w), 1083.99 (w), 1022.27 (m), 991.41 (m), 939.33 (w), 869.90 (w), 775.38 (m), 680.87 (m), 653.87 (m), 590.22 (w), 472.56 (w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.96 (s, 1H), 7.84(d, J =8Hz, 2H), 7.41-7.35 (m, 2H), 3.48(s, 3H), 2.06-1.98 (m, 9H), 1.79-1.65 (m, 15H), 1.44-1.34 (m, 9H)。
13 C NMR(CDCl 3 , 125 MHz), δ(ppm): 167.04, 142.36, 139.27, 137.05, 129.41, 126.14, 125.17, 124.47, 122.67, 50.82, 34.28, 31.12, 28.93, 26.90。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm):30.21。
Example 4:
preparation of tricyclohexyltin benzothiophene-2-carboxylate complex:
to a 250 mL round bottom flask was added, in order, tin 0.7705 g (2.0 mmol) tricyclohexyl hydroxide, benzothiophene-2-carboxylic acid 0.3735 g (2.1 mmol), toluene 50 mL as solvent, and the mixture was fitted with a Dean-Stark trap and heated to reflux at 112-120℃for reaction 8 h. After the reaction is finished, filtering while the solution is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using methanol to obtain the tricyclohexyltin benzothiophene-2-formate complex. Yield: 81%, melting point: 56-57 ℃.
Elemental analysis (C) 28 H 42 O 3 SSn): theoretical value: c,58.24; h,7.33. Measurement value: c,58.22; h,7.35.
IR(KBr, v/cm -1 ):3730.33 (w), 3626.17 (w), 3589.53 (w), 3302.13 (w), 2920.23 (s), 2845.00 (m), 1649.14 (w), 1602.85 (m), 1558.48 (w), 1521.84 (m), 1444.68 (m), 1359.82 (m), 1319.31 (m), 1257.59 (w), 1170.79 (m), 1155.36 (w), 1083.99 (w), 1022.27 (m), 991.41 (m), 939.33 (w), 869.90 (w), 775.38 (m), 680.87 (m), 653.87 (m), 590.22 (w), 472.56 (w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.96 (s, 1H), 7.84(d, J =8Hz, 2H), 7.41-7.35 (m, 2H), 3.48(s, 3H), 2.06-1.98 (m, 9H), 1.79-1.65 (m, 15H), 1.44-1.34 (m, 9H)。
13 C NMR(CDCl 3 , 125 MHz), δ(ppm): 167.04, 142.36, 139.27, 137.05, 129.41, 126.14, 125.17, 124.47, 122.67, 50.82, 34.28, 31.12, 28.93, 26.90。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm):30.21。
Example 5:
tricyclohexyltin benzothiophene-2-carboxylate complex:
in a 250 mL round bottom flask, tin 0.7701 g (2.0 mmol), benzothiophene-2-carboxylic acid 0.3564 g (2.0 mmol), toluene 60 mL as solvent, and a Dean-Stark trap were added in this order, and the reaction was performed under reflux at 112-120deg.C with heating 12 h. After the reaction is finished, filtering while the solution is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using methanol to obtain the tricyclohexyltin benzothiophene-2-formate complex. Yield: 80%, melting point: 56-57 ℃.
Elemental analysis (C) 28 H 42 O 3 SSn): theoretical value: c,58.24; h,7.33. Measurement value: c,58.22; h,7.35.
IR(KBr, v/cm -1 ):3730.33 (w), 3626.17 (w), 3589.53 (w), 3302.13 (w), 2920.23 (s), 2845.00 (m), 1649.14 (w), 1602.85 (m), 1558.48 (w), 1521.84 (m), 1444.68 (m), 1359.82 (m), 1319.31 (m), 1257.59 (w), 1170.79 (m), 1155.36 (w), 1083.99 (w), 1022.27 (m), 991.41 (m), 939.33 (w), 869.90 (w), 775.38 (m), 680.87 (m), 653.87 (m), 590.22 (w), 472.56 (w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.96 (s, 1H), 7.84(d, J =8Hz, 2H), 7.41-7.35 (m, 2H), 3.48(s, 3H), 2.06-1.98 (m, 9H), 1.79-1.65 (m, 15H), 1.44-1.34 (m, 9H)。
13 C NMR(CDCl 3 , 125 MHz), δ(ppm): 167.04, 142.36, 139.27, 137.05, 129.41, 126.14, 125.17, 124.47, 122.67, 50.82, 34.28, 31.12, 28.93, 26.90。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm):30.21。
Example 6:
preparation of tricyclohexyltin benzothiophene-2-carboxylate complex:
to a 250 mL round bottom flask was added, in order, tin 1.1553 g (3.0 mmol) tricyclohexyl hydroxide, benzothiophene-2-carboxylic acid 0.5348 g (3.0 mmol), solvent toluene 75 mL, and equipped with a Dean-Stark trap, and heated to reflux at 112-120℃for reaction 12 h. After the reaction is finished, filtering while the solution is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using methanol to obtain the tricyclohexyltin benzothiophene-2-formate complex. Yield: 85%, melting point: 56-57 ℃.
Elemental analysis (C) 28 H 42 O 3 SSn): theoretical value: c,58.24; h,7.33. Measurement value: c,58.22; h,7.35.
IR(KBr, v/cm -1 ):3730.33 (w), 3626.17 (w), 3589.53 (w), 3302.13 (w), 2920.23 (s), 2845.00 (m), 1649.14 (w), 1602.85 (m), 1558.48 (w), 1521.84 (m), 1444.68 (m), 1359.82 (m), 1319.31 (m), 1257.59 (w), 1170.79 (m), 1155.36 (w), 1083.99 (w), 1022.27 (m), 991.41 (m), 939.33 (w), 869.90 (w), 775.38 (m), 680.87 (m), 653.87 (m), 590.22 (w), 472.56 (w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.96 (s, 1H), 7.84(d, J =8Hz, 2H), 7.41-7.35 (m, 2H), 3.48(s, 3H), 2.06-1.98 (m, 9H), 1.79-1.65 (m, 15H), 1.44-1.34 (m, 9H)。
13 C NMR(CDCl 3 , 125 MHz), δ(ppm): 167.04, 142.36, 139.27, 137.05, 129.41, 126.14, 125.17, 124.47, 122.67, 50.82, 34.28, 31.12, 28.93, 26.90。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm):30.21。
Example 7:
preparation of tricyclohexyltin benzothiophene-2-carboxylate complex:
to a 250 mL round bottom flask was added, in order, tin 1.1556 g (3.0 mmol) tricyclohexyl hydroxide, benzothiophene-2-carboxylic acid 0.5873 g (3.3 mmol), toluene 90 mL as solvent, and equipped with a Dean-Stark trap, and heated to reflux at 112-120℃for reaction 6 h. After the reaction is finished, filtering while the solution is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using methanol to obtain the tricyclohexyltin benzothiophene-2-formate complex. Yield: 82%, melting point: 56-57 ℃.
Elemental analysis (C) 28 H 42 O 3 SSn): theoretical value: c,58.24; h,7.33. Measurement value: c,58.22; h,7.35.
IR(KBr, v/cm -1 ):3730.33 (w), 3626.17 (w), 3589.53 (w), 3302.13 (w), 2920.23 (s), 2845.00 (m), 1649.14 (w), 1602.85 (m), 1558.48 (w), 1521.84 (m), 1444.68 (m), 1359.82 (m), 1319.31 (m), 1257.59 (w), 1170.79 (m), 1155.36 (w), 1083.99 (w), 1022.27 (m), 991.41 (m), 939.33 (w), 869.90 (w), 775.38 (m), 680.87 (m), 653.87 (m), 590.22 (w), 472.56 (w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.96 (s, 1H), 7.84(d, J =8Hz, 2H), 7.41-7.35 (m, 2H), 3.48(s, 3H), 2.06-1.98 (m, 9H), 1.79-1.65 (m, 15H), 1.44-1.34 (m, 9H)。
13 C NMR(CDCl 3 , 125 MHz), δ(ppm): 167.04, 142.36, 139.27, 137.05, 129.41, 126.14, 125.17, 124.47, 122.67, 50.82, 34.28, 31.12, 28.93, 26.90。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm):30.21。
Test example:
the tricyclohexyltin benzothiophene-2-formate complex of the present invention has in vitro anticancer activity determination realized by MTT experimental method.
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 inhibitory activity of the tricyclohexyltin benzothiophene-2-formate 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 shown in the table, the tricyclohexyltin benzothiophene-2-formate complex of the present invention 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 data for in vitro activity test of tricyclohexyltin benzothiophene-2-carboxylate complex anticancer drugs.
| Human lung cancer cell | Human cervical cancer cell | Human gastric cancer cell | |
| Cell strain | A549 | Hela | HGC-27 |
| IC 50 μM | 0.1354 | 0.2201 | 0.1732 |
The test methods of the anti-cancer activity of the tricyclohexyltin benzothiophene-2-formate complex prepared in the other examples on human lung cancer cells (A549), human cervical cancer cells (Hela) and human gastric cancer cells (HGC-27) by using the MTT method are the same as those of the test examples, and the test results are basically the same as those of Table 1.
Claims (4)
1. A tricyclohexyltin benzothiophene-2-carboxylate complex, which is a complex of the following structural formula (I):
2. the preparation method of the tricyclohexyltin benzothiophene-2-formate complex according to claim 1, which is characterized in that tricyclohexyltin hydroxide, benzothiophene-2-formic acid and solvent toluene are sequentially added into a 250 mL round bottom flask, a Dean-Stark water separator is arranged, and heating reflux reaction is carried out for 6-12 hours at 112-120 ℃; after the reaction is finished, filtering while the solution is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using methanol to obtain the tricyclohexyltin benzothiophene-2-formate complex; the mass ratio of the tricyclohexyl tin hydroxide to the benzothiophene-2-formic acid is 1 (1-1.1).
3. The preparation method according to claim 2, wherein the toluene solvent is added in an amount of 25-35 ml per millimole of tricyclohexyl tin hydroxide.
4. The use of the tricyclohexyltin benzothiophene-2-formate complex according to claim 1 for preparing anticancer drugs, wherein the cancer cells aimed at are lung cancer, cervical cancer and gastric cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911368224.7A CN111057093B (en) | 2019-12-26 | 2019-12-26 | Tricyclohexyltin benzothiophene-2-formate complex and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911368224.7A CN111057093B (en) | 2019-12-26 | 2019-12-26 | Tricyclohexyltin benzothiophene-2-formate complex and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111057093A CN111057093A (en) | 2020-04-24 |
| CN111057093B true CN111057093B (en) | 2023-06-23 |
Family
ID=70302854
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911368224.7A Active CN111057093B (en) | 2019-12-26 | 2019-12-26 | Tricyclohexyltin benzothiophene-2-formate complex and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111057093B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101353357A (en) * | 2008-09-11 | 2009-01-28 | 聊城大学 | Organo-tin compound, preparation and use thereof |
-
2019
- 2019-12-26 CN CN201911368224.7A patent/CN111057093B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101353357A (en) * | 2008-09-11 | 2009-01-28 | 聊城大学 | Organo-tin compound, preparation and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis, Characterization, and In Vitro Cytotoxicity of Triorganotin 3,5-Di-tert-butyl-4-hydroxybenzoates;Wenchao Ding等，;《Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry》;20120131;参见83页SCH.1、摘要 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111057093A (en) | 2020-04-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111057092B (en) | Tris (2-methyl-2-phenylpropyl) tin 3-aminopyrazinate complex and preparation method and application thereof | |
| CN111138480B (en) | Preparation method and application of tricyclohexyltin quinoline-4-formate complex | |
| CN111057093B (en) | Tricyclohexyltin benzothiophene-2-formate complex and preparation method and application thereof | |
| CN111138478B (en) | Tricyclohexyltin quinoxaline-2-formate complex, and preparation method and application thereof | |
| CN111138479B (en) | Tricyclohexyltin 3-methylbenzofuran-2-formate complex and preparation method and application thereof | |
| CN111138483B (en) | Tricyclohexyltin 2-chlorothiophene-5-formate complex and preparation method and application thereof | |
| CN111057094B (en) | Tris (2-methyl-2-phenylpropyl) tin benzothiophene-2-formate complex and preparation method and application thereof | |
| CN111138482B (en) | Tris (2-methyl-2-phenylpropyl) tin 5-bromo-2-furoate complex and preparation method and application thereof | |
| CN111138476B (en) | Tris (2-methyl-2-phenylpropyl) tin 2-chlorothiophene-5-formate complex and preparation method and application thereof | |
| CN111116638A (en) | Tricyclohexyltin 3-methylthiophene-2-formate complex, and preparation method and application thereof | |
| CN111057095B (en) | Tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex and preparation method and application thereof | |
| CN111138473B (en) | Tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate and preparation method and application thereof | |
| CN111116637B (en) | Tris (2-methyl-2-phenylpropyl) stannquinoxaline-2-formate complex and preparation method and application thereof | |
| CN111269260B (en) | Tris (2-methyl-2-phenylpropyl) tin 3-bromothiophene-2-formate complex and preparation method and application thereof | |
| CN111138474B (en) | Tricyclohexyltin 2-bromothiophene-5-formate complex and preparation method and application thereof | |
| CN111138475B (en) | Tris (2-methyl-2-phenylpropyl) tin 3-methylbenzofuran formate complex and preparation method and application thereof | |
| CN111116641B (en) | Bis [ tri (2-methyl-2-phenyl) propyltin ] furan-2-formate complex and preparation method and application thereof | |
| CN111116636B (en) | Preparation method and application of tricyclohexyltin indole-6-formate complex | |
| CN111138477B (en) | Preparation method and application of tricyclohexyltin quinoline-6-formate complex | |
| CN111217851B (en) | Preparation method and application of tricyclohexyltin indole-4-formate complex | |
| CN111138481B (en) | Preparation method and application of tricyclohexyltin indole-3-formate complex | |
| CN111138485B (en) | Preparation method and application of tricyclohexyl tin cinnamate complex | |
| CN111153929A (en) | Preparation method and application of tricyclohexyltin 4-chlorobenzoate complex | |
| CN111138487B (en) | Preparation method and application of tricyclohexyltin 1-naphthoate complex | |
| CN111704631B (en) | Preparation method and application of bis [ tri (2-methyl-2-phenyl) propyltin ] pamoate complex |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20200424 Assignee: Shanghai Yuanzuo Pharmaceutical Technology Co.,Ltd. Assignor: Hengyang Normal University Contract record no.: X2023980047748 Denomination of invention: A tricyclohexyltin benzothiophene-2-carboxylate complex and its preparation method and application Granted publication date: 20230623 License type: Common License Record date: 20231122 |
|
| EE01 | Entry into force of recordation of patent licensing contract |