CN111138473B - Tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate and preparation method and application thereof - Google Patents
Tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate and preparation method and application thereof Download PDFInfo
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- XWFBWJQUXQBGNO-UHFFFAOYSA-M tris(2-methyl-2-phenylpropyl)stannyl 3-methylthiophene-2-carboxylate Chemical compound CC1=C(SC=C1)C(=O)O[Sn](CC(C)(C)C2=CC=CC=C2)(CC(C)(C)C3=CC=CC=C3)CC(C)(C)C4=CC=CC=C4 XWFBWJQUXQBGNO-UHFFFAOYSA-M 0.000 title claims abstract description 49
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- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims 1
- 210000004027 cell Anatomy 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- IFLKEBSJTZGCJG-UHFFFAOYSA-N 3-methylthiophene-2-carboxylic acid Chemical compound CC=1C=CSC=1C(O)=O IFLKEBSJTZGCJG-UHFFFAOYSA-N 0.000 description 19
- 239000013078 crystal Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 17
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- 238000005481 NMR spectroscopy Methods 0.000 description 16
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- 206010058467 Lung neoplasm malignant Diseases 0.000 description 9
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 9
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- 238000000921 elemental analysis Methods 0.000 description 9
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- 239000000203 mixture Substances 0.000 description 9
- 229910001887 tin oxide Inorganic materials 0.000 description 9
- 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 description 9
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- 229910052718 tin Inorganic materials 0.000 description 8
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical group [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 7
- 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
- 238000010438 heat treatment Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 238000010586 diagram Methods 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
- 238000011160 research Methods 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
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XOLBLPGZBRYERU-UHFFFAOYSA-N tin dioxide Chemical compound O=[Sn]=O XOLBLPGZBRYERU-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OAVCWZUKQIEFGG-UHFFFAOYSA-O 2-(5-methyl-2H-tetrazol-1-ium-1-yl)-1,3-thiazole Chemical compound CC1=NN=N[NH+]1C1=NC=CS1 OAVCWZUKQIEFGG-UHFFFAOYSA-O 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
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000699670 Mus sp. Species 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
- 101150041109 Snph gene Proteins 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 235000005811 Viola adunca Nutrition 0.000 description 1
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- 238000012258 culturing Methods 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
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- 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
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Classifications
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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 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
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Abstract
The invention discloses tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate and a preparation method and application thereof, and the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate is a complex with the following structural formula (I):. The invention also discloses a preparation method of the tri (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate and application thereof in preparing antitumor drugs.
Description
Technical Field
The invention relates to tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate, a preparation method thereof and application of the complex in preparation of antitumor drugs.
Background
Since Brown first discovered organotin carboxylates (CH 3 CO 2 SnPh 3 ) The synthesis, structure and biological activity research of the organotin carboxylate complex are widely focused by scientists since the biological activity of inhibiting the tumor of mice is inhibited. 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. Study formThe toxicity of the organotin compounds is related to their relative molecular masses, the smaller the relative molecular mass, the greater the toxicity, and the greater the relative molecular mass of the more sterically hindered 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 characteristics that the bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide is a substance with better biological activity, and the 2-methyl-2-phenylpropyl has larger steric hindrance, larger molecular weight and the like, the bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide is selected to react with the heterocyclic carboxylic acid ligand 3-methyl-thiophene-2-formic acid under certain conditions, and the complex with stronger inhibition activity on A549 (human lung cancer cells), hela (human cervical cancer cells) and HGC-27 (human stomach cancer cells) is synthesized, so that a new approach is provided for developing anticancer drugs.
Disclosure of Invention
A first object of the present invention, which addresses the problems of the prior art described above, is to provide tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate.
A second object of the present invention is to provide a process for preparing the above tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate.
The third object of the invention is to provide the application of the tri (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate in preparing anticancer drugs.
As a first aspect of the present invention, a tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate is a complex of the following structural formula (I):
(I)。
the three (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate of the present invention is subjected to elemental analysis, infrared spectrum analysis, nuclear magnetic resonance spectrum and X-ray single crystal structure analysis, and the results are as follows:
elemental analysis (C) 36 H 44 O 2 SSn): theoretical value: c,65.56; h,6.72. Measurement value: c,65.62; h,6.75.
IR(KBr, v/cm -1 ): 3086.11(w), 3051.39(m), 2964.59(s), 2922.16(s), 2862.36(m), 1637.56(s), 1598.99(w), 1541.12(w), 1494.83m), 1458.18(w), 1440.83(m), 1413.82(m), 1382.96(w), 1363.67(w), 1300.02(s), 1205.51(w), 1188.15(w),1111.00(m), 1074.35(m), 1029.99(w), 945.12(w), 906.54(w), 842.89(w), 802.39(m), 767.67(s), 744.52(w), 719.45(m), 698.23(s), 617.22(w), 599.86(m), 553.57(m), 505.35(w), 457.13(w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.29-7.24(m, 7H),7.21-7.18 (m, 3H), 7.12-7.10(m, 6H), 6.88(d,J = 5 Hz, 1H), 2.53 (s, 3H), 1.30-1.14(m, 24H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 166.62, 150.96, 143.61, 132.67, 131.49, 11.08, 128.35, 125.80, 125.30, 37.74, 37.68, 32.77, 15.81。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 93.62。
The tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate of the present invention is a crystalline structure, and the crystallographic data thereof are as follows: the crystals belong to triclinic system and space groupP-1，a=0.94737(12) nm，b=1.15682(15) nm，c=1.6297(2) nm，α=100°，β=99°，γ=102°，Z=2，V=1.6839(8) nm 3 ，Dc=1.301 Mg·m -3 ，μ(MoKa)= 0.849mm -1 ，F(000)= 684，2.47°＜θ< 25.10 °, crystal size: 0.22 x 0.24 x 0.26 x mm,R=0.0259，wR=0.0684。
the structural feature of the tri (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate of the present invention is: the central tin in the molecule forms a distorted tetrahedral configuration with the coordinating atoms.
As a preparation method of the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate, which is a second aspect of the invention, bis [ tris (2-methyl-2-phenylpropyl) ] tin, 3-methyl-thiophene-2-carboxylic acid and solvent toluene are sequentially oxidized in a 250 mL round bottom flask, a Dean-Stark water separator is arranged, and a heating reflux reaction is carried out at 112-120 ℃ for 6-12 hours. After the reaction is finished, filtering while the mixture is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate.
In a preferred embodiment of the present invention, the mass ratio of the two substances of bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide and 3-methyl-thiophene-2-carboxylic acid is 1 (2-2.2).
In a preferred embodiment of the invention, the solvent toluene is added in an amount of 25 to 35 ml per millimole of tin bis [ tris (2-methyl-2-phenylpropyl) ] oxide.
The use of tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate as a third aspect of the present invention in the manufacture of an anticancer drug.
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 tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate of the invention 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 medicaments for resisting lung cancer, cervical cancer and gastric cancer. Compared with the currently commonly used platinum anti-cancer drugs, the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate has the characteristics of high anti-cancer activity, low cost, simple preparation method and the like, and provides a new way for developing anti-cancer drugs.
Drawings
FIG. 1 is a diagram showing the structure of the crystal molecular structure of tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate.
FIG. 2 is an IR spectrum of tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate.
FIG. 3 is a diagram of tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate 1 H NMR spectrum.
FIG. 4 is a diagram of tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate 13 C NMR spectrum.
FIG. 5 is a diagram of tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate 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 tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate:
to a 250 mL round bottom flask was added successively tin oxide 1.0534 g (1 mmol), 3-methyl-thiophene-2-carboxylic acid 0.2845 g (2 mmol), solvent toluene 25 mL, and a Dean-Stark trap, followed by heating reflux reaction at 112-120℃for 6 h. After the reaction is finished, filtering while the mixture is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate. Yield: 71%, melting point: 67-69 ℃.
Elemental analysis (C) 36 H 44 O 2 SSn): theoretical value: c,65.56; h,6.72. Measurement value: c,65.62; h,6.75.
IR(KBr, v/cm -1 ): 3086.11(w), 3051.39(m), 2964.59(s), 2922.16(s), 2862.36(m), 1637.56(s), 1598.99(w), 1541.12(w), 1494.83m), 1458.18(w), 1440.83(m), 1413.82(m), 1382.96(w), 1363.67(w), 1300.02(s), 1205.51(w), 1188.15(w),1111.00(m), 1074.35(m), 1029.99(w), 945.12(w), 906.54(w), 842.89(w), 802.39(m), 767.67(s), 744.52(w), 719.45(m), 698.23(s), 617.22(w), 599.86(m), 553.57(m), 505.35(w), 457.13(w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.29-7.24(m, 7H),7.21-7.18 (m, 3H), 7.12-7.10(m, 6H), 6.88(d,J = 5 Hz, 1H), 2.53 (s, 3H), 1.30-1.14(m, 24H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 166.62, 150.96, 143.61, 132.67, 131.49, 11.08, 128.35, 125.80, 125.30, 37.74, 37.68, 32.77, 15.81。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 93.62。
The tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate of the present invention is a crystalline structure, and the crystallographic data thereof are as follows: the crystals belong to triclinic system and space groupP-1，a=0.94737(12) nm，b=1.15682(15) nm，c=1.6297(2) nm，α=100°，β=99°，γ=102°，Z=2，V=1.6839(8) nm 3 ，Dc=1.301 Mg·m -3 ，μ(MoKa)= 0.849mm -1 ，F(000)= 684，2.47°＜θ< 25.10 °, crystal size: 0.22 x 0.24 x 0.26 x mm,R=0.0259，wR=0.0684。
example 2:
preparation of tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate:
in a 250 mL round bottom flask, bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide 1.0536 g (1.0 mmol), 3-methyl-thiophene-2-carboxylic acid 0.3130 g (2.2 mmol), solvent toluene 25 mL, and a Dean-Stark trap were added sequentially, and the reaction was performed under reflux at 112-120℃with heating of 8 h. After the reaction is finished, filtering while the mixture is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate. Yield: 72%, melting point: 67-69 ℃.
Elemental analysis (C) 36 H 44 O 2 SSn): theoretical value: c,65.56; h,6.72. Measurement value: c,65.62; h,6.75.
IR(KBr, v/cm -1 ): 3086.11(w), 3051.39(m), 2964.59(s), 2922.16(s), 2862.36(m), 1637.56(s), 1598.99(w), 1541.12(w), 1494.83m), 1458.18(w), 1440.83(m), 1413.82(m), 1382.96(w), 1363.67(w), 1300.02(s), 1205.51(w), 1188.15(w),1111.00(m), 1074.35(m), 1029.99(w), 945.12(w), 906.54(w), 842.89(w), 802.39(m), 767.67(s), 744.52(w), 719.45(m), 698.23(s), 617.22(w), 599.86(m), 553.57(m), 505.35(w), 457.13(w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.29-7.24(m, 7H),7.21-7.18 (m, 3H), 7.12-7.10(m, 6H), 6.88(d,J = 5 Hz, 1H), 2.53 (s, 3H), 1.30-1.14(m, 24H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 166.62, 150.96, 143.61, 132.67, 131.49, 11.08, 128.35, 125.80, 125.30, 37.74, 37.68, 32.77, 15.81。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 93.62。
The tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate of the present invention is a crystalline structure, and the crystallographic data thereof are as follows: the crystals belong to triclinic system and space groupP -1，a=0.94737(12) nm，b=1.15682(15) nm，c=1.6297(2) nm，α=100°，β=99°，γ=102°，Z=2，V=1.6839(8) nm 3 ，Dc=1.301 Mg·m -3 ，μ(MoKa)= 0.849mm -1 ，F(000)= 684，2.47°＜θ< 25.10 °, crystal size: 0.22 x 0.24 x 0.26 x mm,R=0.0259，wR=0.0684。
example 3:
preparation of tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate:
to a 250 mL round bottom flask was added successively tin oxide 1.0537 g (1.0 mmol), 3-methyl-thiophene-2-carboxylic acid 0.3125 g (2.2 mmol), solvent toluene 35 mL, equipped with a Dean-Stark trap, and heated at 112-120℃to reflux reaction 8 h. After the reaction is finished, filtering while the mixture is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate. Yield: 73%, melting point: 67-69 ℃.
Elemental analysis (C) 36 H 44 O 2 SSn): theoretical value: c,65.56; h,6.72. Measurement value: c,65.62; h,6.75.
IR(KBr, v/cm -1 ): 3086.11(w), 3051.39(m), 2964.59(s), 2922.16(s), 2862.36(m), 1637.56(s), 1598.99(w), 1541.12(w), 1494.83m), 1458.18(w), 1440.83(m), 1413.82(m), 1382.96(w), 1363.67(w), 1300.02(s), 1205.51(w), 1188.15(w),1111.00(m), 1074.35(m), 1029.99(w), 945.12(w), 906.54(w), 842.89(w), 802.39(m), 767.67(s), 744.52(w), 719.45(m), 698.23(s), 617.22(w), 599.86(m), 553.57(m), 505.35(w), 457.13(w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.29-7.24(m, 7H),7.21-7.18 (m, 3H), 7.12-7.10(m, 6H), 6.88(d,J = 5 Hz, 1H), 2.53 (s, 3H), 1.30-1.14(m, 24H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 166.62, 150.96, 143.61, 132.67, 131.49, 11.08, 128.35, 125.80, 125.30, 37.74, 37.68, 32.77, 15.81。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 93.62。
The tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate of the present invention is a crystalline structure, and the crystallographic data thereof are as follows: the crystals belong to triclinic system and space groupP -1，a=0.94737(12) nm，b=1.15682(15) nm，c=1.6297(2) nm，α=100°，β=99°，γ=102°，Z=2，V=1.6839(8) nm 3 ，Dc=1.301 Mg·m -3 ，μ(MoKa)= 0.849mm -1 ，F(000)= 684，2.47°＜θ＜25.10°，Crystal size: 0.22 x 0.24 x 0.26 x mm,R=0.0259，wR=0.0684。
example 4:
preparation of tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate:
in a 250 mL round bottom flask, bis [ tris (2-methyl-2-phenylpropyl) ] tin 2.1063 g (2.0 mmol), 3-methyl-thiophene-2-carboxylic acid 0.5976 g (4.2 mmol), solvent toluene 50 mL, and a Dean-Stark trap were added in order, and the reaction was heated at 112-120℃under reflux for 8 h. After the reaction is finished, filtering while the mixture is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate. Yield: 70%, melting point: 67-69 ℃.
Elemental analysis (C) 36 H 44 O 2 SSn): theoretical value: c,65.56; h,6.72. Measurement value: c,65.62; h,6.75.
IR(KBr, v/cm -1 ): 3086.11(w), 3051.39(m), 2964.59(s), 2922.16(s), 2862.36(m), 1637.56(s), 1598.99(w), 1541.12(w), 1494.83m), 1458.18(w), 1440.83(m), 1413.82(m), 1382.96(w), 1363.67(w), 1300.02(s), 1205.51(w), 1188.15(w),1111.00(m), 1074.35(m), 1029.99(w), 945.12(w), 906.54(w), 842.89(w), 802.39(m), 767.67(s), 744.52(w), 719.45(m), 698.23(s), 617.22(w), 599.86(m), 553.57(m), 505.35(w), 457.13(w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.29-7.24(m, 7H),7.21-7.18 (m, 3H), 7.12-7.10(m, 6H), 6.88(d,J = 5 Hz, 1H), 2.53 (s, 3H), 1.30-1.14(m, 24H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 166.62, 150.96, 143.61, 132.67, 131.49, 11.08, 128.35, 125.80, 125.30, 37.74, 37.68, 32.77, 15.81。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 93.62。
The tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate of the present invention is a crystalline structure, and the crystallographic data thereof are as follows: the crystals belong to triclinic system and space groupP -1，a=0.94737(12) nm，b=1.15682(15) nm，c=1.6297(2) nm，α=100°，β=99°，γ=102°，Z=2，V=1.6839(8) nm 3 ，Dc=1.301 Mg·m -3 ，μ(MoKa)= 0.849mm -1 ，F(000)= 684，2.47°＜θ< 25.10 °, crystal size: 0.22 x 0.24 x 0.26 x mm,R=0.0259，wR=0.0684。
example 5:
preparation of tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate:
in a 250 mL round bottom flask, bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide 2.1068 g (2.0 mmol), 3-methyl-thiophene-2-carboxylic acid 0.5691 g (4.0 mmol), solvent toluene 60 mL, and a Dean-Stark trap were added sequentially, and the reaction was performed under reflux at 112-120℃with heating 12 h. After the reaction is finished, filtering while the mixture is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate. Yield: 72%, melting point: 67-69 ℃.
Elemental analysis (C) 36 H 44 O 2 SSn): theoretical value: c,65.56; h,6.72. Measurement value: c,65.62; h,6.75.
IR(KBr, v/cm -1 ): 3086.11(w), 3051.39(m), 2964.59(s), 2922.16(s), 2862.36(m), 1637.56(s), 1598.99(w), 1541.12(w), 1494.83m), 1458.18(w), 1440.83(m), 1413.82(m), 1382.96(w), 1363.67(w), 1300.02(s), 1205.51(w), 1188.15(w),1111.00(m), 1074.35(m), 1029.99(w), 945.12(w), 906.54(w), 842.89(w), 802.39(m), 767.67(s), 744.52(w), 719.45(m), 698.23(s), 617.22(w), 599.86(m), 553.57(m), 505.35(w), 457.13(w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.29-7.24(m, 7H),7.21-7.18 (m, 3H), 7.12-7.10(m, 6H), 6.88(d,J = 5 Hz, 1H), 2.53 (s, 3H), 1.30-1.14(m, 24H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 166.62, 150.96, 143.61, 132.67, 131.49, 11.08, 128.35, 125.80, 125.30, 37.74, 37.68, 32.77, 15.81。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 93.62。
The tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate of the present invention is a crystalline structure, and the crystallographic data thereof are as follows: the crystals belong to triclinic system and space groupP -1，a=0.94737(12) nm，b=1.15682(15) nm，c=1.6297(2) nm，α=100°，β=99°，γ=102°，Z=2，V=1.6839(8) nm 3 ，Dc=1.301 Mg·m -3 ，μ(MoKa)= 0.849mm -1 ，F(000)= 684，2.47°＜θ< 25.10 °, crystal size: 0.22 x 0.24 x 0.26 x mm,R=0.0259，wR=0.0684。
example 6:
preparation of tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate:
in a 250 mL round bottom flask, bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide 3.1594 g (3.0 mmol), 3-methyl-thiophene-2-carboxylic acid 0.8535 g (6.0 mmol), solvent toluene 75 mL, and a Dean-Stark trap were added in order, and the reaction was performed under reflux at 112-120℃with heating 12 h. After the reaction is finished, filtering while the mixture is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate. Yield: 74%, melting point: 67-69 ℃.
Elemental analysis (C) 36 H 44 O 2 SSn): theoretical value: c,65.56; h,6.72. Measurement value: c,65.62; h,6.75.
IR(KBr, v/cm -1 ): 3086.11(w), 3051.39(m), 2964.59(s), 2922.16(s), 2862.36(m), 1637.56(s), 1598.99(w), 1541.12(w), 1494.83m), 1458.18(w), 1440.83(m), 1413.82(m), 1382.96(w), 1363.67(w), 1300.02(s), 1205.51(w), 1188.15(w),1111.00(m), 1074.35(m), 1029.99(w), 945.12(w), 906.54(w), 842.89(w), 802.39(m), 767.67(s), 744.52(w), 719.45(m), 698.23(s), 617.22(w), 599.86(m), 553.57(m), 505.35(w), 457.13(w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.29-7.24(m, 7H),7.21-7.18 (m, 3H), 7.12-7.10(m, 6H), 6.88(d,J = 5 Hz, 1H), 2.53 (s, 3H), 1.30-1.14(m, 24H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 166.62, 150.96, 143.61, 132.67, 131.49, 11.08, 128.35, 125.80, 125.30, 37.74, 37.68, 32.77, 15.81。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 93.62。
The tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate of the present invention is a crystalline structure, and the crystallographic data thereof are as follows: the crystals belong to triclinic system and space groupP -1，a=0.94737(12) nm，b=1.15682(15) nm，c=1.6297(2) nm，α=100°，β=99°，γ=102°，Z=2，V=1.6839(8) nm 3 ，Dc=1.301 Mg·m -3 ，μ(MoKa)= 0.849mm -1 ，F(000)= 684，2.47°＜θ< 25.10 °, crystal size: 0.22 x 0.24 x 0.26 x mm,R=0.0259，wR=0.0684。
example 7:
preparation of tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate:
in a 250 mL round bottom flask, bis [ tris (2-methyl-2-phenylpropyl) ] tin oxide 3.1591 g (3.0 mmol), 3-methyl-thiophene-2-carboxylic acid 0.9388 g (6.6 mmol), solvent toluene 90 mL, and a Dean-Stark trap were added in order, and the reaction was performed under reflux at 112-120℃with heating of 6 h. After the reaction is finished, filtering while the mixture is hot, removing the solvent from the filtrate by using a rotary evaporator to obtain a white solid, and recrystallizing the white solid by using ethanol to obtain the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate. Yield: 74%, melting point: 67-69 ℃.
Elemental analysis (C) 36 H 44 O 2 SSn): theoretical value: c,65.56; h,6.72. Measurement value: c,65.62; h,6.75.
IR(KBr, v/cm -1 ): 3086.11(w), 3051.39(m), 2964.59(s), 2922.16(s), 2862.36(m), 1637.56(s), 1598.99(w), 1541.12(w), 1494.83m), 1458.18(w), 1440.83(m), 1413.82(m), 1382.96(w), 1363.67(w), 1300.02(s), 1205.51(w), 1188.15(w),1111.00(m), 1074.35(m), 1029.99(w), 945.12(w), 906.54(w), 842.89(w), 802.39(m), 767.67(s), 744.52(w), 719.45(m), 698.23(s), 617.22(w), 599.86(m), 553.57(m), 505.35(w), 457.13(w)。
1 H NMR(CDCl 3 , 500 MHz), δ(ppm):7.29-7.24(m, 7H),7.21-7.18 (m, 3H), 7.12-7.10(m, 6H), 6.88(d,J = 5 Hz, 1H), 2.53 (s, 3H), 1.30-1.14(m, 24H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 166.62, 150.96, 143.61, 132.67, 131.49, 11.08, 128.35, 125.80, 125.30, 37.74, 37.68, 32.77, 15.81。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 93.62。
The tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate of the present invention is a crystalline structure, and the crystallographic data thereof are as follows: the crystals belong to triclinic system and space groupP -1，a=0.94737(12) nm，b=1.15682(15) nm，c=1.6297(2) nm，α=100°，β=99°，γ=102°，Z=2，V=1.6839(8) nm 3 ，Dc=1.301 Mg·m -3 ，μ(MoKa)= 0.849mm -1 ，F(000)= 684，2.47°＜θ< 25.10 °, crystal size: 0.22 x 0.24 x 0.26 x mm,R=0.0259，wR=0.0684。
test example:
the in vitro anticancer activity determination of the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate is realized by an MTT (methyl thiazolyl tetrazolium) 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 tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate prepared in example 1 on human lung cancer cells (A549), human cervical cancer cells (Hela), and human gastric cancer cells (HGC-27) was determined by MTT assay.
Cell lines and culture system: a549, hela, and HGC-27 cell lines were obtained from American Tissue Culture Collection (ATCC). With 10% fetal bovine serum in RPMI1640 (GIBICO) medium at 5% (volume fraction) CO 2 In vitro culture was performed in a saturated humidity incubator at 37 ℃.
The testing process comprises the following steps: the test liquid medicine (0.0625 mu mol/L-0.5 mu mol/L) is added into each hole according to concentration gradient, and 3 parallel holes are arranged for each concentration. The experiments were divided into drug test groups (with different concentrations of test agent added), control groups (with only culture fluid and cells without test agent) and blank groups (with only culture fluid and no cells and test agent). The orifice plate after the drug addition is placed at 37 ℃ and 5 percent CO 2 Culturing in an incubator for 24 hours. The activity of the control drug was determined by the method of the test sample. In the well plate after 48 hours of incubation, MTT 20uL (5 g/L in PBS) was added to each well. After 4h at 37℃the supernatant was removed. 150uL DMSO was added to each well and the mixture was shaken for 10min to dissolve Formazan crystals. Finally, absorbance values of each well were measured at 570nm using a BioTek multifunctional microplate reader.
And (3) data processing: data processing using the GraAr Pad Prism version5.0 program, complex IC 50 Fitting is performed through a nonlinear regression model with S-shaped dose response in the program.
The IC of the human lung cancer cell (A549) cell strain, the human cervical cancer cell (Hela) cell strain and the human gastric cancer cell (HGC-27) cell strain are determined by an MTT assay 50 Values, results are shown in table 1, conclusions are: as can be seen from the data in the table, the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-formate provided by the 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 tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate anticancer drugs.
| Human lung cancer cell | Human cervical cancer cell | Human gastric cancer cell | |
| Cell strain | A549 | Hela | HGC-27 |
| IC 50 μM | 0.6348 | 0.5368 | 0.3124 |
The test methods of the anti-cancer activity of the tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate prepared in the other examples on human lung cancer cells (A549), human cervical cancer cells (Hela) and human gastric cancer cells (HGC-27) by 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 (1)
1. The application of tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate in preparing anticancer drugs is characterized by being a complex with the following structural formula (I):
(I)；
the cancer is gastric cancer HGC-27.
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Application publication date: 20200512 Assignee: Hunan Hengfei Biopharmaceutical Co.,Ltd. Assignor: Hengyang Normal University Contract record no.: X2024980012455 Denomination of invention: A tris (2-methyl-2-phenylpropyl) tin 3-methyl-thiophene-2-carboxylate and its preparation method and application Granted publication date: 20231103 License type: Common License Record date: 20240821 |