CN103288868B - A kind of dibutyl tin 4-p t butylbenzoic acid ester of tin oxa-ring structure and preparation method and application - Google Patents
A kind of dibutyl tin 4-p t butylbenzoic acid ester of tin oxa-ring structure and preparation method and application Download PDFInfo
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- CN103288868B CN103288868B CN201310239174.9A CN201310239174A CN103288868B CN 103288868 B CN103288868 B CN 103288868B CN 201310239174 A CN201310239174 A CN 201310239174A CN 103288868 B CN103288868 B CN 103288868B
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- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 title claims abstract description 46
- AYOHIQLKSOJJQH-UHFFFAOYSA-N dibutyltin Chemical compound CCCC[Sn]CCCC AYOHIQLKSOJJQH-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 201000007270 liver cancer Diseases 0.000 claims abstract description 10
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 10
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 8
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims abstract description 7
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims abstract description 7
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims abstract description 7
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 5
- 201000005202 lung cancer Diseases 0.000 claims abstract description 5
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- 229910052718 tin Inorganic materials 0.000 claims description 37
- RJGHQTVXGKYATR-UHFFFAOYSA-L dibutyl(dichloro)stannane Chemical compound CCCC[Sn](Cl)(Cl)CCCC RJGHQTVXGKYATR-UHFFFAOYSA-L 0.000 claims description 13
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 claims description 13
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 10
- 239000012046 mixed solvent Substances 0.000 claims description 10
- 239000013078 crystal Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 229910020923 Sn-O Inorganic materials 0.000 claims description 6
- 229910009053 Sn—O—Sn Inorganic materials 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 125000006850 spacer group Chemical group 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- SMNNDVUKAKPGDD-UHFFFAOYSA-N 2-butylbenzoic acid Chemical class CCCCC1=CC=CC=C1C(O)=O SMNNDVUKAKPGDD-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- ZHUXMBYIONRQQX-UHFFFAOYSA-N hydroxidodioxidocarbon(.) Chemical group [O]C(O)=O ZHUXMBYIONRQQX-UHFFFAOYSA-N 0.000 claims description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 2
- QHGNHLZPVBIIPX-UHFFFAOYSA-N tin(ii) oxide Chemical compound [Sn]=O QHGNHLZPVBIIPX-UHFFFAOYSA-N 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 claims 1
- 201000010989 colorectal carcinoma Diseases 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 11
- 230000000259 anti-tumor effect Effects 0.000 abstract description 10
- 238000011275 oncology therapy Methods 0.000 abstract description 7
- 208000029742 colonic neoplasm Diseases 0.000 abstract description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052697 platinum Inorganic materials 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 229910020813 Sn-C Inorganic materials 0.000 description 4
- 229910018732 Sn—C Inorganic materials 0.000 description 4
- 238000002447 crystallographic data Methods 0.000 description 4
- -1 phenyltin compound Chemical class 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 3
- 201000005296 lung carcinoma Diseases 0.000 description 3
- 238000000034 method Methods 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
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 201000000498 stomach carcinoma Diseases 0.000 description 2
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 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
- 238000013016 damping Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The dibutyl tin 4-p t butylbenzoic acid ester of a kind of tin oxa-ring structure disclosed by the invention, it is the compound of following structural formula (1), wherein: R represents normal-butyl.The invention also discloses the preparation method of the dibutyl tin 4-p t butylbenzoic acid ester of this tin oxa-ring structure.The dibutyl tin 4-p t butylbenzoic acid ester of a kind of tin oxa-ring structure of the present invention has good antitumour activity, it can prepare anti-liver cancer, anti-nasopharyngeal carcinoma, anti-breast cancer, anti-lung cancer, drugs against colon cancer for raw material.Compared with the platinum-containing anticancer drug generally used at present, the dibutyl tin 4-p t butylbenzoic acid ester of a kind of tin oxa-ring structure of the present invention has the features such as antitumour activity is high, cost is low, preparation method is simple, for exploitation cancer therapy drug provides new way.
Description
Technical field
The present invention relates to dibutyl tin 4-p t butylbenzoic acid ester technical field, dibutyl tin 4-p t butylbenzoic acid ester being specifically related to a kind of tin oxa-ring structure and preparation method thereof, and prepare the application in antitumor drug.
Background technology
Organotin is the compound that a class has compared with high biological activity, has wide practical use in sterilization, cancer therapy drug preparation.There are some researches show, the radicals R of organotin and playing an important role with the antitumour activity of ligand structure to compound of tin atom coordination, e.g., the antitumour activity of cyclohexyl, normal-butyl and phenyltin compound is comparatively strong, and ethyl takes second place, and methyl is non-activity almost.Chinese patent CN101402650B discloses a kind of dibutyl tin and quinolinecarboxylic acid title complex preparing to treat in cancer of the stomach, nasopharyngeal carcinoma, people's liver cancer or leukemic medicine and applies; Chinese patent CN101434616B discloses a kind of dibutyl tin Schiff base complex and applies in preparation treatment cancer of the stomach, nasopharyngeal carcinoma, people's liver cancer or leukemic medicine.The ester compound formed based on aromatic carboxylic acid and dibutyl tin the experiment proved that the material with antitumour activity, the present invention selects the organotin of dibutyl tin dichloride or Dibutyltin oxide, 4-p t butylbenzoic acid is part, react under certain condition, synthesis obtains the compound stronger to the inhibit activities of human liver cancer cell (HEPG2), KB cell (KB), human breast cancer cell (MCF-7), human lung carcinoma cell (A549), human colon cancer cell (HT-29), for exploitation cancer therapy drug provides new way.
Summary of the invention
One of to the object of the invention is to the dibutyl tin 4-p t butylbenzoic acid ester being to provide a kind of tin oxa-ring structure.
Two of object of the present invention is the preparation method of the dibutyl tin 4-p t butylbenzoic acid ester providing above-mentioned tin oxa-ring structure.
Three of object of the present invention is the application of dibutyl tin 4-p t butylbenzoic acid ester in medicine providing above-mentioned tin oxa-ring structure.
In order to realize foregoing invention object, the technical solution adopted in the present invention is as follows:
A dibutyl tin 4-p t butylbenzoic acid ester for tin oxa-ring structure, it is the compound of following structural formula (1):
Wherein: R represents normal-butyl.
In a preferred embodiment of the invention, the dibutyl tin 4-p t butylbenzoic acid ester of described tin oxa-ring structure is crystalline structure, and its crystal is oblique system, spacer P2
1/ n, crystallographic parameter: 1.63835 (6) nm, b=1.16361 (4) nm, c=2.19897 (7) nm, α=γ=90 °, β=94.611 (2) °, Z=2, V=4.1785 (2) nm
3, D
c=1.329Mgm
-3; The Sn formed with tin and Sauerstoffatom is there is in molecule
2o
2planar four-element ring, three tetra-atomic rings utilize Sn-O key atom to condense formation four core tin oxygen bunch ladder structure for bridgehead atom, middle Ring current distribution is the symmetry centre of molecule, has three tin atoms of two Sauerstoffatoms difference bridging ladders in ladder, separately has two methoxyl group Sauerstoffatoms bridging ladder tin atoms respectively.Other two the 4-p t butylbenzoic acids of ladder utilize its carboxyl oxygen atom to become key to form the hexa-atomic tin oxa-ring structure of chain common with it with the tin atom of Sn-O-Sn chain respectively.
The preparation method of the dibutyl tin 4-p t butylbenzoic acid ester of tin oxa-ring structure: add 4-p t butylbenzoic acid, Dibutyltin oxide or dibutyl tin dichloride and a solvent anhydrous methanol in order successively in reaction vessel, reacts 8 ~ 12h under stirring and refluxing; Cooling, filters; At pressure 0.005 ~ 0.01MPa, temperature is under 30 ~ 35 DEG C of conditions, with Rotary Evaporators evaporate to dryness filtrate, obtains white solid, with methylene chloride-methanol mixed solvent recrystallization, obtains clear crystal, is the dibutyl tin 4-p t butylbenzoic acid ester of tin oxa-ring structure; Wherein 4-p t butylbenzoic acid, dibutyl tin dichloride or Dibutyltin oxide are reactant, anhydrous methanol is reaction solvent, methylene chloride-methanol mixed solvent is crystallization solvent, reactant 4-p t butylbenzoic acid is 1:1 ~ 1:1.08 with the amount of substance ratio of Dibutyltin oxide or dibutyl tin dichloride, the consumption of solvent anhydrous methanol is that every mmole Dibutyltin oxide or dibutyl tin dichloride add 20 ~ 25 ml methanol, and in methylene chloride-methanol mixed solvent, the volume ratio of methylene dichloride and methyl alcohol is 1:10 ~ 1:20.
In a preferred embodiment of the invention, in reaction vessel, add 4-p t butylbenzoic acid, Dibutyltin oxide or dibutyl tin dichloride, sodium formiate and solvent anhydrous methanol in order successively, wherein catalyst sodium methoxide and the amount of substance of reactant 4-p t butylbenzoic acid are than being 0.1:1 ~ 2.12:1.
The dibutyl tin 4-p t butylbenzoic acid ester of applicant to above-mentioned tin oxa-ring structure has carried out anti tumor activity in vitro and has confirmed research, confirm that the dibutyl tin 4-p t butylbenzoic acid ester of this tin oxa-ring structure has anti-tumor biological, that is the purposes of the dibutyl tin 4-p t butylbenzoic acid ester of above-mentioned a kind of tin oxa-ring structure is preparing the application in antitumor drug, is exactly specifically the application in the anti-liver cancer of preparation or anti-nasopharyngeal carcinoma or anti-breast cancer or anti-lung cancer or drugs against colon cancer.
The dibutyl tin 4-p t butylbenzoic acid ester of a kind of tin oxa-ring structure of the present invention has good antitumour activity, it can prepare anti-liver cancer, anti-nasopharyngeal carcinoma, anti-breast cancer, anti-lung cancer, drugs against colon cancer for raw material.Compared with the platinum-containing anticancer drug generally used at present, the dibutyl tin 4-p t butylbenzoic acid ester of a kind of tin oxa-ring structure of the present invention has the features such as antitumour activity is high, cost is low, preparation method is simple, for exploitation cancer therapy drug provides new way.
Accompanying drawing explanation
Fig. 1 is a kind of dibutyl tin 4-p t butylbenzoic acid crystalline esters structure iron of tin oxa-ring structure.
Embodiment
Further describe the present invention by following examples, but scope of the present invention should be noted not by any restriction of these embodiments.
Embodiment 1:
Prepare a kind of dibutyl tin 4-p t butylbenzoic acid ester of tin oxa-ring structure: in round-bottomed flask, add 4-p t butylbenzoic acid 0.089g (0.5mmol), dibutyl tin dichloride 0.164g (0.54mmol), sodium methylate 0.057g (1.06mmol) and 12mL anhydrous methanol, stir lower reflux 8h; Cooling, filters; At pressure 0.005MPa, temperature is under 30 DEG C of conditions, with Rotary Evaporators evaporate to dryness filtrate, obtain white solid, with methylene chloride-methanol mixed solvent recrystallization, obtain clear crystal, be the dibutyl tin 4-p t butylbenzoic acid ester of tin oxa-ring structure, productive rate: 52.4%, fusing point: 192 ~ 193 DEG C.
Ultimate analysis (C
76h
124o
10sn
4): theoretical value: C, 54.57; H, 7.47.Measured value: C, 54.41; H, 7.48.
IR(KBr,cm
-1):2958,2926,2870ν(C-H),1624,1539ν
as(COO
-),1404,1340ν
s(COO
-),636ν(Sn-O-Sn),545ν(Sn-C),419ν(Sn-O)。
1H NMR(CDCl
3)δ(ppm):0.86(t,24H,J=6.8,-CH
3,n-butyl)；1.36-1.73(m,84H,SnCH
2CH
2CH
2,-C(CH
3)
3,n-butyl and t-butyl)；7.49(s,8H,Ar-H,)；7.93-8.17(m,8H,Ar-H,)。
13C NMR(CDCl
3)δ(ppm):13.67-29.73(n-Bu-C)；31.29,35.09(t-bu-C)；125.15,129.84,130.72,155.53(Ar-C)；172.80(-COO)。
Crystallographic data: oblique system, spacer P2
1/ n, crystallographic parameter: a=1.63835 (6) nm, b=1.16361 (4) nm, c=2.19897 (7) nm, α=γ=90 °, β=94.611 (2) °, Z=2, V=4.1785 (2) nm
3, D
c=1.329Mgm
-3, μ (MoK
α)=1.231mm
-1, F (000)=1720,1.73 ° of < θ < 25.00 °, crystalline size: 0.29 × 0.22 × 0.17mm, R=0.0438, wR=0.1256.
Embodiment 2:
Prepare a kind of dibutyl tin 4-p t butylbenzoic acid ester of tin oxa-ring structure: in round-bottomed flask, add 4-p t butylbenzoic acid 0.089g (0.50mmol), Dibutyltin oxide 0.142g (0.50mmol), sodium methylate 0.003g (0.05mmol) and 10mL anhydrous methanol, stir lower reflux 12h; Cooling, filters; At pressure 0.01MPa, temperature is under 35 DEG C of conditions, with Rotary Evaporators evaporate to dryness filtrate, obtain white solid, with methylene chloride-methanol mixed solvent recrystallization, obtain clear crystal, be the dibutyl tin 4-p t butylbenzoic acid ester of tin oxa-ring structure, productive rate: 54%, fusing point: 192 ~ 193 DEG C.
Ultimate analysis (C
76h
124o
10sn
4): theoretical value: C, 54.57; H, 7.47.Measured value: C, 54.41; H, 7.48.
IR(KBr,cm
-1):2958,2926,2870ν(C-H),1624,1539ν
as(COO
-),1404,1340ν
s(COO
-),636ν(Sn-O-Sn),545ν(Sn-C),419ν(Sn-O)。
1H NMR(CDCl
3)δ(ppm):0.86(t,24H,J=6.8,-CH
3,n-butyl)；1.36-1.73(m,84H,SnCH
2CH
2CH
2,-C(CH
3)
3,n-butyl and t-butyl)；7.49(s,8H,Ar-H,)；7.93-8.17(m,8H,Ar-H,)。
13C NMR(CDCl
3)δ(ppm):13.67-29.73(n-Bu-C)；31.29,35.09(t-bu-C)；125.15,129.84,130.72,155.53(Ar-C)；172.80(-COO)。
Crystallographic data: oblique system, spacer P2
1/ n, crystallographic parameter: a=1.63835 (6) nm, b=1.16361 (4) nm, c=2.19897 (7) nm, α=γ=90 °, β=94.611 (2) °, Z=2, V=4.1785 (2) nm
3, D
c=1.329Mgm
-3, μ (MoK
α)=1.231mm
-1, F (000)=1720,1.98 ° of < θ < 25.00 °, crystalline size: 0.29 × 0.22 × 0.17mm, R=0.0438, wR=0.1256.
Embodiment 3:
Prepare a kind of dibutyl tin 4-p t butylbenzoic acid ester of tin oxa-ring structure: in round-bottomed flask, add 4-p t butylbenzoic acid 0.177g (1.0mmol), dibutyl tin dichloride 0.319g (1.0mmol), sodium methylate 0.112g (2.07mmol) and 25mL anhydrous methanol, stir lower reflux 10h; Cooling, filters; At pressure 0.007MPa, temperature is under 32 DEG C of conditions, with Rotary Evaporators evaporate to dryness filtrate, obtain white solid, with methylene chloride-methanol mixed solvent recrystallization, obtain clear crystal, be the dibutyl tin 4-p t butylbenzoic acid ester of tin oxa-ring structure, productive rate: 50%, fusing point: 192 ~ 193 DEG C.
Ultimate analysis (C
76h
124o
10sn
4): theoretical value: C, 54.57; H, 7.47.Measured value: C, 54.41; H, 7.48.
IR(KBr,cm
-1):2958,2926,2870ν(C-H),1624,1539ν
as(COO
-),1404,1340ν
s(COO
-),636ν(Sn-O-Sn),545ν(Sn-C),419ν(Sn-O)。
1H NMR(CDCl
3)δ(ppm):0.86(t,24H,J=6.8,-CH
3,n-butyl)；1.36-1.73(m,84H,SnCH
2CH
2CH
2,-C(CH
3)
3,n-butyl and t-butyl)；7.49(s,8H,Ar-H,)；7.93-8.17(m,8H,Ar-H,)。
13C NMR(CDCl
3)δ(ppm):13.67-29.73(n-Bu-C)；31.29,35.09(t-bu-C)；125.15,129.84,130.72,155.53(Ar-C)；172.80(-COO)。
Crystallographic data: oblique system, spacer P2
1/ n, crystallographic parameter: a=1.63835 (6) nm, b=1.16361 (4) nm, c=2.19897 (7) nm, α=γ=90 °, β=94.611 (2) °, Z=2, V=4.1785 (2) nm
3, D
c=1.329Mgm
-3, μ (MoK
α)=1.231mm
-1, F (000)=1720,1.98 ° of < θ < 25.00 °, crystalline size: 0.29 × 0.22 × 0.17mm, R=0.0438, wR=0.1256.
Embodiment 4:
Prepare a kind of dibutyl tin 4-p t butylbenzoic acid ester of tin oxa-ring structure: in round-bottomed flask, add 4-p t butylbenzoic acid 0.214g (1.20mmol), Dibutyltin oxide 0.314g (1.26mmol), sodium methylate 0.006g (0.12mmol) and 31mL anhydrous methanol, stir lower reflux 9h; Cooling, filters; At pressure 0.009MPa, temperature is under 32 DEG C of conditions, with Rotary Evaporators evaporate to dryness filtrate, obtain white solid, with methylene chloride-methanol mixed solvent recrystallization, obtain clear crystal, be the dibutyl tin 4-p t butylbenzoic acid ester of tin oxa-ring structure, productive rate: 55%, fusing point: 192 ~ 193 DEG C.
Ultimate analysis (C
76h
124o
10sn
4): theoretical value: C, 54.57; H, 7.47.Measured value: C, 54.41; H, 7.48.
IR(KBr,cm
-1):2958,2926,2870ν(C-H),1624,1539ν
as(COO
-),1404,1340ν
s(COO
-),636ν(Sn-O-Sn),545ν(Sn-C),419ν(Sn-O)。
1H NMR(CDCl
3)δ(ppm):0.86(t,24H,J=6.8,-CH
3,n-butyl)；1.36-1.73(m,84H,SnCH
2CH
2CH
2,-C(CH
3)
3,n-butyl and t-butyl)；7.49(s,8H,Ar-H,)；7.93-8.17(m,8H,Ar-H,)。
13C NMR(CDCl
3)δ(ppm):13.67-29.73(n-Bu-C)；31.29,35.09(t-bu-C)；125.15,129.84,130.72,155.53(Ar-C);172.80(-COO)。
Crystallographic data: oblique system, spacer P2
1/ n, crystallographic parameter: a=1.63835 (6) nm, b=1.16361 (4) nm, c=2.19897 (7) nm, α=γ=90 °, β=94.611 (2) °, Z=2, V=4.1785 (2) nm
3, D
c=1.329Mgm
-3, μ (MoK
α)=1.231mm
-1, F (000)=1720,1.98 ° of < θ < 25.00 °, crystalline size: 0.29 × 0.22 × 0.17mm, R=0.0438, wR=0.1256.
Test example:
The dibutyl tin 4-p t butylbenzoic acid ester of a kind of tin oxa-ring structure of the present invention, its Anticancer Activity in vitro is measured and is realized by MTT experiment method.
MTT analytical method:
Based on metabolism reduction 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide.Succinodehydrogenase in viable cell plastosome can make exogenous MTT be reduced to water-insoluble bluish voilet crystallization first a ceremonial jade-ladle, used in libation (Formazan) and be deposited in cell, and dead cell is without this function.First a ceremonial jade-ladle, used in libation in dimethyl sulfoxide (DMSO) (DMSO) energy dissolved cell, measures the optical density(OD) of characteristic wavelength, can indirectly reflect viable cell quantity by microplate reader.
Mtt assay is adopted to measure the inhibit activities of dibutyl tin 4-p t butylbenzoic acid ester to human liver cancer cell (HEPG2), KB cell (KB), human breast cancer cell (MCF-7), human lung carcinoma cell (A549), human colon cancer cell (HT-29).
Cell strain and culture system: HT-29, HEPG2, MCF-7, KB and A549 cell strain takes from American. tissue incubator (ATCC).With RPMI1640 (GIBICO company) substratum containing 10% foetal calf serum, at 5% (volume fraction) CO
2, carry out vitro culture in 37 DEG C of saturated humidity incubators.
Test process: join in each hole respectively by testing the concentration gradient of liquid (0.1nM-10uM) according to concentration, each concentration establishes 6 parallel holes.Experiment is divided into drug test group (adding the test medicine of different concns respectively), control group (only add nutrient solution and cell, do not add test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).Orifice plate after dosing is placed in 37 DEG C, 5%CO
272h is cultivated in incubator.The activity of control drug measures according to the method for test sample.In orifice plate after having cultivated 72h, every hole adds MTT40uL (being made into 4mg/mL with D-Hanks damping fluid).After placing 4h at 37 DEG C, remove supernatant liquor.Every hole adds 150uLDMSO, and vibration 5min, makes Formazan dissolving crystallized.Finally, automatic microplate reader is utilized to detect the optical density(OD) in each hole at 570nm wavelength place.
Data processing: data processing uses Graph Pad Prism version5.0 program, Compound I C
50carry out matching by the nonlinear regression model (NLRM) in program with S shape dose response to obtain.
With MTT analytical method, human liver cancer cell (HEPG2) cell strain, KB cell (KB) cell strain, human breast cancer cell (MCF-7) cell strain, human lung carcinoma cell (A549) cell strain, human colon cancer cell (HT-29) cell strain are analyzed, measure its IC
50value, result is as shown in table 1, and conclusion is: from data in table, be used as cancer therapy drug with dibutyl tin 4-p t butylbenzoic acid ester of the present invention, higher to people's liver cancer, human nasopharyngeal carcinoma, human breast carcinoma, people's lung cancer, human colon carcinoma antitumour activity, can be used as the candidate compound of cancer therapy drug.
The dibutyl tin 4-p t butylbenzoic acid ester cancer therapy drug external activity test data of table 1 tin oxa-ring structure
Claims (5)
1. a dibutyl tin 4-p t butylbenzoic acid ester for tin oxa-ring structure, is characterized in that, the compound for following structural formula (1):
Wherein: R represents normal-butyl;
The dibutyl tin 4-p t butylbenzoic acid ester of described tin oxa-ring structure is crystalline structure, and its crystal is oblique system, spacer P2
1/ n, crystallographic parameter: 1.63835 (6) nm, b=1.16361 (4) nm, c=2.19897 (7) nm, α=γ=90 °, β=94.611 (2) °, Z=2, V=4.1785 (2) nm
3, D
c=1.329Mgm
-3; The Sn formed with tin and Sauerstoffatom is there is in molecule
2o
2planar four-element ring, three tetra-atomic rings utilize Sn-O key atom to condense formation four core tin oxygen bunch ladder structure for bridgehead atom, middle Ring current distribution is the symmetry centre of molecule, has three tin atoms of two Sauerstoffatoms difference bridging ladders in ladder, separately has two Sauerstoffatoms bridging ladder tin atoms respectively; Other two the 4-p t butylbenzoic acids of ladder utilize its carboxyl oxygen atom to become key to form the hexa-atomic tin oxa-ring structure of chain common with it with the tin atom of Sn-O-Sn chain respectively.
2. the preparation method of the dibutyl tin 4-p t butylbenzoic acid ester of a claim 1 tin oxa-ring structure, it is characterized in that, in reaction vessel, add 4-p t butylbenzoic acid, Dibutyltin oxide or dibutyl tin dichloride and solvent anhydrous methanol in order successively, under stirring and refluxing, react 8 ~ 12h; Cooling, filters; At pressure 0.005 ~ 0.01MPa, temperature is under 30 ~ 35 DEG C of conditions, with Rotary Evaporators evaporate to dryness filtrate, obtains white solid, with methylene chloride-methanol mixed solvent recrystallization, obtains clear crystal, is the dibutyl tin 4-p t butylbenzoic acid ester of tin oxa-ring structure; Wherein 4-p t butylbenzoic acid, dibutyl tin dichloride or Dibutyltin oxide are reactant, anhydrous methanol is reaction solvent, methylene chloride-methanol mixed solvent is crystallization solvent, reactant 4-p t butylbenzoic acid is 1:1 ~ 1:1.08 with the amount of substance ratio of Dibutyltin oxide or dibutyl tin dichloride, the consumption of solvent anhydrous methanol is that every mmole Dibutyltin oxide or dibutyl tin dichloride add 20 ~ 25 ml methanol, and in methylene chloride-methanol mixed solvent, the volume ratio of methylene dichloride and methyl alcohol is 1:10 ~ 1:20.
3. preparation method as claimed in claim 2, it is characterized in that, in reaction vessel, add 4-p t butylbenzoic acid, Dibutyltin oxide or dibutyl tin dichloride, sodium formiate and solvent anhydrous methanol in order successively, wherein catalyst sodium methoxide and the amount of substance of reactant 4-p t butylbenzoic acid are than being 0.1:1 ~ 2.12:1.
4. the dibutyl tin 4-p t butylbenzoic acid ester of a kind of tin oxa-ring structure according to claim 1 is preparing the application in antitumor drug.
5. application according to claim 4, is characterized in that, described tumour behaviour liver cancer, nasopharyngeal carcinoma, mammary cancer, lung cancer or colorectal carcinoma.
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| DD275690A1 (en) * | 1988-09-19 | 1990-01-31 | Greiz Doelau Chemie | PROCESS FOR THE PRODUCTION OF ORGANOZIN NITROGENS |
| CN103087115A (en) * | 2013-02-04 | 2013-05-08 | 衡阳师范学院 | Ferrocenyl-containing tributyltin benzoate coordination polymer, and preparation method and application thereof |
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| DD275690A1 (en) * | 1988-09-19 | 1990-01-31 | Greiz Doelau Chemie | PROCESS FOR THE PRODUCTION OF ORGANOZIN NITROGENS |
| CN103087115A (en) * | 2013-02-04 | 2013-05-08 | 衡阳师范学院 | Ferrocenyl-containing tributyltin benzoate coordination polymer, and preparation method and application thereof |
| CN103113420A (en) * | 2013-02-04 | 2013-05-22 | 衡阳师范学院 | Ferrocenyl containing dibutyl tin-oxo cluster as well as preparation method and application thereof |
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