CN111057095B - Tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex and preparation method and application thereof - Google Patents
Tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex and preparation method and application thereof Download PDFInfo
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- LIEBYXBJTRFHAJ-UHFFFAOYSA-M tricyclohexylstannyl 5-chloro-2-oxo-1H-pyridine-3-carboxylate Chemical compound C1CCC(CC1)[Sn](C2CCCCC2)(C3CCCCC3)OC(=O)C4=CC(=CNC4=O)Cl LIEBYXBJTRFHAJ-UHFFFAOYSA-M 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 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
- 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
- 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
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000013078 crystal Substances 0.000 description 20
- 239000002904 solvent Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 14
- 229910052718 tin Inorganic materials 0.000 description 14
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical group [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- XBHXNMLFJZTSAS-UHFFFAOYSA-N 5-chloro-2-oxo-1h-pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC(Cl)=CNC1=O XBHXNMLFJZTSAS-UHFFFAOYSA-N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 206010008342 Cervix carcinoma Diseases 0.000 description 9
- 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
- 201000005202 lung cancer Diseases 0.000 description 9
- 208000020816 lung neoplasm Diseases 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 230000004071 biological effect Effects 0.000 description 8
- 238000002447 crystallographic data Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000001914 filtration 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
- 238000010992 reflux Methods 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
- 229940079593 drug Drugs 0.000 description 6
- -1 hydrocarbyl tin Chemical compound 0.000 description 6
- WCMMILVIRZAPLE-UHFFFAOYSA-M cyhexatin Chemical compound C1CCCCC1[Sn](C1CCCCC1)(O)C1CCCCC1 WCMMILVIRZAPLE-UHFFFAOYSA-M 0.000 description 5
- 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
- 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
- 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
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
- 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 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 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
- 238000010438 heat treatment 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- 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
- 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
- 238000013459 approach Methods 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
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000012790 confirmation Methods 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
- 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
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000007789 gas 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
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- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
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- 239000008204 material by function Substances 0.000 description 1
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- 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
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (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)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex, a preparation method and application thereof, which are complexes of the following structural formula (I):. The invention also discloses a preparation method of the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex and application thereof in preparing antitumor drugs.
Description
Technical Field
The invention relates to a tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex, a preparation method thereof and application of the complex in preparing 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. Studies have shown that the toxicity of organotin compounds is related to their relative molecular masses, with smaller relative molecular masses, greater toxicity, and greater steric hindrance of the hydrocarbyl tin relative molecular massesLarger. 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 5-chloro-2-hydroxypyridine-3-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 approach is provided for developing anticancer drugs.
Disclosure of Invention
In view of the above problems of the prior art, a first object of the present invention is to provide a tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex.
The second object of the present invention is to provide a process for preparing the above tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex.
The third object of the invention is to provide the application of the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex in preparing anticancer drugs.
As a first aspect of the present invention, a tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex is a complex of the following structural formula (I):
(I)。
the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex of the invention is subjected to elemental analysis, infrared spectrum analysis, nuclear magnetic resonance spectrum and X-ray single crystal structure analysis, and the results are as follows:
elemental analysis (C) 25 H 40 ClNO 4 Sn): theoretical value: c,52.43; h,7.04; n,2.45. Measurement value: c,52.49; h,7.08; n,2.41.
IR(KBr, v/cm -1 ): 3242.34(w), 2920.23(s), 2846.93(s), 1627.92(s), 1570.06(s), 1444.68(s), 1419.61(s), 1386.82(s), 1334.74(w), 1301.95(w), 1236.37(m),1209.37(m), 1170.79 (w), 1124.50(w), 1089.78(w), 1039.63(w), 1014.56(m), 991.41(m), 914.26(w), 877.61(w), 819.75(m), 725.23(s), 659.66(w), 594.08(w), 536.21(w), 487.99(w), 464.84(w), 422.41(m)。
1 HNMR (CDCl 3 , 500 MHz) δ(ppm): 12.24 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 3.48 (s, 3H), 2.06-1.94 (m, 9H), 1.74-1.68 (m, 15H), 1.35-1.33 (m, 9H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 171.87, 164.25, 151.73, 139.82, 122.60, 110.82, 50.80, 34.90, 31.04, 28.86, 26.77。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 50.10。
The tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex of the invention has a crystal structure, and the crystallographic data thereof are as follows: the crystals belong to monoclinic system and space groupP 2 1 /c，a=0.98532(7) nm，b=2.04085(15) nm，c=1.39537(11) nm，α=90°，β=101°，γ=90°，Z=4，V=2.7522(8) nm 3 ，Dc=1.382 Mg·m -3 ，μ(MoKa)=1.054mm -1 ，F(000)= 1184，1.79°＜θCrystal size < 25.01 °:0.24 x 0.22 x 0.20 x mm,R=0.0370，wR=0.0954。
the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex of the invention is structurally characterized in that: the central tin in the molecule and the coordination atoms form a triangle bipyramid configuration.
As a preparation method of the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex, which is the second aspect of the invention, in a 250 mL round-bottomed flask, tricyclohexyltin hydroxide, 5-chloro-2-hydroxypyridine-3-carboxylic acid and solvent toluene are sequentially arranged, a Dean-Stark water separator is arranged, and heating reflux reaction is carried out for 6-12 hours at the temperature of 112-120 ℃. 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 reddish brown solid, and recrystallizing the reddish brown solid by using methanol to obtain the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex.
In a preferred embodiment of the present invention, the mass ratio of the tricyclohexyl tin hydroxide to the 5-chloro-2-hydroxypyridine-3-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 an application of tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex as a third aspect of the invention in preparing anticancer drugs.
The applicant carries out in vitro anti-tumor activity confirmation research on the complex, and confirms that the complex has certain anti-tumor biological activity, namely the application of the complex in preparing anti-tumor drugs, in particular the application in preparing anti-human lung cancer drugs, human cervical cancer drugs and human gastric cancer drugs.
The tricyclohexyltin 5-chloro-2-hydroxypyridine-3-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 a raw material for preparing medicines for resisting lung cancer, cervical cancer and gastric cancer. Compared with the currently commonly used platinum anti-cancer drugs, the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-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 a diagram showing the structure of the crystal molecular structure of tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex.
FIG. 2 is an IR spectrum of tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex.
FIG. 3 is a tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex 1 H NMR spectrum.
FIG. 4 is a tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex 13 C NMR spectrum.
FIG. 5 is a tricyclohexyltin 5-chloro-2-hydroxypyridine-3-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 5-chloro-2-hydroxypyridine-3-carboxylate complex:
into a 250 mL round bottom flask, tin 0.3854 g (1 mmol), 5-chloro-2-hydroxypyridine-3-carboxylic acid 0.1741 g (1 mmol), toluene 25 mL as solvent, and a Dean-Stark trap were added in this order, and the mixture was heated to reflux at 112-120℃for reaction 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 reddish brown solid, and recrystallizing the reddish brown solid by using methanol to obtain the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex. Yield: 71%, melting point: 119-122 ℃.
Elemental analysis (C) 25 H 40 ClNO 4 Sn): theoretical value: c,52.43; h,7.04; n,2.45. Measurement value: c,52.49; h,7.08; n,2.41.
IR(KBr, v/cm -1 ): 3242.34(w), 2920.23(s), 2846.93(s), 1627.92(s), 1570.06(s), 1444.68(s), 1419.61(s), 1386.82(s), 1334.74(w), 1301.95(w), 1236.37(m),1209.37(m), 1170.79 (w), 1124.50(w), 1089.78(w), 1039.63(w), 1014.56(m), 991.41(m), 914.26(w), 877.61(w), 819.75(m), 725.23(s), 659.66(w), 594.08(w), 536.21(w), 487.99(w), 464.84(w), 422.41(m)。
1 HNMR (CDCl 3 , 500 MHz) δ(ppm): 12.24 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 3.48 (s, 3H), 2.06-1.94 (m, 9H), 1.74-1.68 (m, 15H), 1.35-1.33 (m, 9H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 171.87, 164.25, 151.73, 139.82, 122.60, 110.82, 50.80, 34.90, 31.04, 28.86, 26.77。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 50.10。
The crystallographic data thereof: the crystals belong to monoclinic system and space groupP 2 1 /c，a=0.98532(7) nm，b=2.04085(15) nm，c=1.39537(11) nm，α=90°，β=101°，γ=90°，Z=4，V=2.7522(8) nm 3 ，Dc=1.382 Mg·m -3 ，μ(MoKa)=1.054mm -1 ，F(000)= 1184，1.79°＜θCrystal size < 25.01 °:0.24 x 0.22 x 0.20 x mm,R=0.0370，wR=0.0954。
example 2:
preparation of tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex:
to a 250 mL round bottom flask was added, in order, tin tricyclohexyl hydroxide 0.3852 g (1.0 mmol), 5-chloro-2-hydroxypyridine-3-carboxylic acid 0.1915 g (1.1 mmol), solvent toluene 25 mL, and equipped with a Dean-Stark trap, heated to 112-120℃and refluxed 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 reddish brown solid, and recrystallizing the reddish brown solid by using methanol to obtain the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex. Yield: 72%, melting point: 119-122 ℃.
Elemental analysis (C) 25 H 40 ClNO 4 Sn): theoretical value: c,52.43; h,7.04; n,2.45. Measurement value: c,52.49; h,7.08; n,2.41.
IR(KBr, v/cm -1 ): 3242.34(w), 2920.23(s), 2846.93(s), 1627.92(s), 1570.06(s), 1444.68(s), 1419.61(s), 1386.82(s), 1334.74(w), 1301.95(w), 1236.37(m),1209.37(m), 1170.79 (w), 1124.50(w), 1089.78(w), 1039.63(w), 1014.56(m), 991.41(m), 914.26(w), 877.61(w), 819.75(m), 725.23(s), 659.66(w), 594.08(w), 536.21(w), 487.99(w), 464.84(w), 422.41(m)。
1 HNMR (CDCl 3 , 500 MHz) δ(ppm): 12.24 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 3.48 (s, 3H), 2.06-1.94 (m, 9H), 1.74-1.68 (m, 15H), 1.35-1.33 (m, 9H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 171.87, 164.25, 151.73, 139.82, 122.60, 110.82, 50.80, 34.90, 31.04, 28.86, 26.77。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 50.10。
The crystallographic data thereof: the crystals belong to monoclinic system and space groupP 2 1 /c，a=0.98532(7) nm，b=2.04085(15) nm，c=1.39537(11) nm，α=90°，β=101°，γ=90°，Z=4，V=2.7522(8) nm 3 ，Dc=1.382 Mg·m -3 ，μ(MoKa)=1.054mm -1 ，F(000)= 1184，1.79°＜θCrystal size < 25.01 °:0.24 x 0.22 x 0.20 x mm,R=0.0370，wR=0.0954。
example 3:
preparation of tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex:
to a 250 mL round bottom flask was added, in order, tin 0.3857 g (1.0 mmol), 5-chloro-2-hydroxypyridine-3-carboxylic acid 0.1916 g (1.1 mmol), solvent toluene 35 mL, and a Dean-Stark trap was fitted, and the reaction was performed under reflux at 112-120℃with heating 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 reddish brown solid, and recrystallizing the reddish brown solid by using methanol to obtain the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex. Yield: 70%, melting point: 119-122 ℃.
Elemental analysis (C) 25 H 40 ClNO 4 Sn): theoretical value: c,52.43; the gas phase is taken as H,7.04; n,2.45. Measurement value: c,52.49; h,7.08; n,2.41.
IR(KBr, v/cm -1 ): 3242.34(w), 2920.23(s), 2846.93(s), 1627.92(s), 1570.06(s), 1444.68(s), 1419.61(s), 1386.82(s), 1334.74(w), 1301.95(w), 1236.37(m),1209.37(m), 1170.79 (w), 1124.50(w), 1089.78(w), 1039.63(w), 1014.56(m), 991.41(m), 914.26(w), 877.61(w), 819.75(m), 725.23(s), 659.66(w), 594.08(w), 536.21(w), 487.99(w), 464.84(w), 422.41(m)。
1 HNMR (CDCl 3 , 500 MHz) δ(ppm): 12.24 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 3.48 (s, 3H), 2.06-1.94 (m, 9H), 1.74-1.68 (m, 15H), 1.35-1.33 (m, 9H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 171.87, 164.25, 151.73, 139.82, 122.60, 110.82, 50.80, 34.90, 31.04, 28.86, 26.77。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 50.10。
The crystallographic data thereof: the crystals belong to monoclinic system and space groupP 2 1 /c，a=0.98532(7) nm，b=2.04085(15) nm，c=1.39537(11) nm，α=90°，β=101°，γ=90°，Z=4，V=2.7522(8) nm 3 ，Dc=1.382 Mg·m -3 ，μ(MoKa)=1.054mm -1 ，F(000)= 1184，1.79°＜θCrystal size < 25.01 °:0.24 x 0.22 x 0.20 x mm,R=0.0370，wR=0.0954。
example 4:
preparation of tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex:
to a 250 mL round bottom flask was added tin 0.7705 g tricyclohexyl hydroxide (2.0 mmol), 5-chloro-2-hydroxypyridine-3-carboxylic acid 0.3652 g (2.1 mmol), solvent toluene 50 mL, and the mixture was charged with a Dean-Stark trap and heated to reflux at 112-120℃for 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 reddish brown solid, and recrystallizing the reddish brown solid by using methanol to obtain the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex. Yield: 73%, melting point: 119-122 ℃.
Elemental analysis (C) 25 H 40 ClNO 4 Sn): theoretical value: c,52.43; h,7.04; n,2.45. Measurement value: c,52.49; h,7.08; n,2.41.
IR(KBr, v/cm -1 ): 3242.34(w), 2920.23(s), 2846.93(s), 1627.92(s), 1570.06(s), 1444.68(s), 1419.61(s), 1386.82(s), 1334.74(w), 1301.95(w), 1236.37(m),1209.37(m), 1170.79 (w), 1124.50(w), 1089.78(w), 1039.63(w), 1014.56(m), 991.41(m), 914.26(w), 877.61(w), 819.75(m), 725.23(s), 659.66(w), 594.08(w), 536.21(w), 487.99(w), 464.84(w), 422.41(m)。
1 HNMR (CDCl 3 , 500 MHz) δ(ppm): 12.24 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 3.48 (s, 3H), 2.06-1.94 (m, 9H), 1.74-1.68 (m, 15H), 1.35-1.33 (m, 9H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 171.87, 164.25, 151.73, 139.82, 122.60, 110.82, 50.80, 34.90, 31.04, 28.86, 26.77。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 50.10。
The crystallographic data thereof: the crystals belong to monoclinic system and space groupP 2 1 /c，a=0.98532(7) nm，b=2.04085(15) nm，c=1.39537(11) nm，α=90°，β=101°，γ=90°，Z=4，V=2.7522(8) nm 3 ，Dc=1.382 Mg·m -3 ，μ(MoKa)=1.054mm -1 ，F(000)= 1184，1.79°＜θCrystal size < 25.01 °:0.24 x 0.22 x 0.20 x mm,R=0.0370，wR=0.0954。
example 5:
preparation of tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex:
to a 250 mL round bottom flask was added tin 0.7703 g tricyclohexyl hydroxide (2.0 mmol), 5-chloro-2-hydroxypyridine-3-carboxylic acid 0.3489 g (2.0 mmol), solvent toluene 60 mL, and the mixture was charged with a Dean-Stark trap and heated to reflux at 112-120℃to give 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 reddish brown solid, and recrystallizing the reddish brown solid by using methanol to obtain the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex. Yield: 72%, melting point: 119-122 ℃.
Elemental analysis (C) 25 H 40 ClNO 4 Sn): theoretical value: c,52.43; h,7.04; n,2.45. Measurement value: c,52.49; h,7.08; n,2.41.
IR(KBr, v/cm -1 ): 3242.34(w), 2920.23(s), 2846.93(s), 1627.92(s), 1570.06(s), 1444.68(s), 1419.61(s), 1386.82(s), 1334.74(w), 1301.95(w), 1236.37(m),1209.37(m), 1170.79 (w), 1124.50(w), 1089.78(w), 1039.63(w), 1014.56(m), 991.41(m), 914.26(w), 877.61(w), 819.75(m), 725.23(s), 659.66(w), 594.08(w), 536.21(w), 487.99(w), 464.84(w), 422.41(m)。
1 HNMR (CDCl 3 , 500 MHz) δ(ppm): 12.24 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 3.48 (s, 3H), 2.06-1.94 (m, 9H), 1.74-1.68 (m, 15H), 1.35-1.33 (m, 9H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 171.87, 164.25, 151.73, 139.82, 122.60, 110.82, 50.80, 34.90, 31.04, 28.86, 26.77。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 50.10。
The crystallographic data thereof: the crystals belong to monoclinic system and space groupP 2 1 /c，a=0.98532(7) nm，b=2.04085(15) nm，c=1.39537(11) nm，α=90°，β=101°，γ=90°，Z=4，V=2.7522(8) nm 3 ，Dc=1.382 Mg·m -3 ，μ(MoKa)=1.054mm -1 ，F(000)= 1184，1.79°＜θCrystal size < 25.01 °:0.24 x 0.22 x 0.20 x mm,R=0.0370，wR=0.0954。
example 6:
preparation of tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex:
to a 250 mL round bottom flask was added tin 1.1556 g tricyclohexyl hydroxide (3.0 mmol), 5-chloro-2-hydroxypyridine-3-carboxylic acid 0.5229 g (3.0 mmol), solvent toluene 75 mL, and the mixture was charged with a Dean-Stark trap and heated to reflux at 112-120℃for reaction 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 reddish brown solid, and recrystallizing the reddish brown solid by using methanol to obtain the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex. Yield: 74%, melting point: 119-122 ℃.
Elemental analysis (C) 25 H 40 ClNO 4 Sn): theoretical value: c,52.43; h,7.04; n,2.45. Measurement value: c,52.49; h,7.08; n,2.41.
IR(KBr, v/cm -1 ): 3242.34(w), 2920.23(s), 2846.93(s), 1627.92(s), 1570.06(s), 1444.68(s), 1419.61(s), 1386.82(s), 1334.74(w), 1301.95(w), 1236.37(m),1209.37(m), 1170.79 (w), 1124.50(w), 1089.78(w), 1039.63(w), 1014.56(m), 991.41(m), 914.26(w), 877.61(w), 819.75(m), 725.23(s), 659.66(w), 594.08(w), 536.21(w), 487.99(w), 464.84(w), 422.41(m)。
1 HNMR (CDCl 3 , 500 MHz) δ(ppm): 12.24 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 3.48 (s, 3H), 2.06-1.94 (m, 9H), 1.74-1.68 (m, 15H), 1.35-1.33 (m, 9H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 171.87, 164.25, 151.73, 139.82, 122.60, 110.82, 50.80, 34.90, 31.04, 28.86, 26.77。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 50.10。
The crystallographic data thereof: the crystals belong to monoclinic system and space groupP 2 1 /c，a=0.98532(7) nm，b=2.04085(15) nm，c=1.39537(11) nm，α=90°，β=101°，γ=90°，Z=4，V=2.7522(8) nm 3 ，Dc=1.382 Mg·m -3 ，μ(MoKa)=1.054mm -1 ，F(000)= 1184，1.79°＜θCrystal size < 25.01 °:0.24 x 0.22 x 0.20 x mm,R=0.0370，wR=0.0954。
example 7:
preparation of tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate complex:
to a 250 mL round bottom flask was added, in order, tin 1.1557 g (3.0 mmol), 5-chloro-2-hydroxypyridine-3-carboxylic acid 0.5743 g (3.3 mmol), solvent toluene 90 mL, and a Dean-Stark trap was fitted, and the reaction was heated to reflux 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 reddish brown solid, and recrystallizing the reddish brown solid by using methanol to obtain the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex. Yield: 72%, melting point: 119-122 ℃.
Elemental analysis (C) 25 H 40 ClNO 4 Sn): theoretical value: c,52.43; h,7.04; n,2.45. Measurement value: c,52.49; h,7.08; n,2.41.
IR(KBr, v/cm -1 ): 3242.34(w), 2920.23(s), 2846.93(s), 1627.92(s), 1570.06(s), 1444.68(s), 1419.61(s), 1386.82(s), 1334.74(w), 1301.95(w), 1236.37(m),1209.37(m), 1170.79 (w), 1124.50(w), 1089.78(w), 1039.63(w), 1014.56(m), 991.41(m), 914.26(w), 877.61(w), 819.75(m), 725.23(s), 659.66(w), 594.08(w), 536.21(w), 487.99(w), 464.84(w), 422.41(m)。
1 HNMR (CDCl 3 , 500 MHz) δ(ppm): 12.24 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 3.48 (s, 3H), 2.06-1.94 (m, 9H), 1.74-1.68 (m, 15H), 1.35-1.33 (m, 9H)。
13 CNMR(CDCl 3 , 125MHz) δ(ppm): 171.87, 164.25, 151.73, 139.82, 122.60, 110.82, 50.80, 34.90, 31.04, 28.86, 26.77。
119 Sn NMR(CDCl 3 , 186 MHz), δ(ppm): 50.10。
The crystallographic data thereof: the crystals belong to monoclinic system and space groupP 2 1 /c，a=0.98532(7) nm，b=2.04085(15) nm，c=1.39537(11) nm，α=90°，β=101°，γ=90°，Z=4，V=2.7522(8) nm 3 ，Dc=1.382 Mg·m -3 ，μ(MoKa)=1.054mm -1 ，F(000)= 1184，1.79°＜θCrystal size < 25.01 °:0.24 x 0.22 x 0.20 x mm,R=0.0370，wR=0.0954。
test example:
the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex of the invention has in vitro anticancer activity determination realized by an 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 5-chloro-2-hydroxypyridine-3-carboxylate complex prepared in example 1 on human lung cancer cells (A549), human cervical cancer cells (Hela), and human gastric cancer cells (HGC-27) was measured 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 is added into each hole, and the mixture is oscillated for 10min to form a formalzan junctionAnd dissolving the crystal. 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 tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex of 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 tricyclohexyltin 5-chloro-2-hydroxypyridine-3-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 | 0.4332 | 0.703 | 0.1249 |
The test methods of the anti-cancer activity of the tricyclohexyltin 5-chloro-2-hydroxypyridine-3-carboxylate 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 an 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 tricyclohexyltin 5-chloro-2-hydroxypyridine-3-formate complex in preparing anticancer drugs is characterized in that the complex has the following structural formula (I):
(I)；
the cancer cell is gastric cancer HGC-27.
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