CN103467511B - A kind of tributyl tin 9-anthroic acid ester of macrocyclic structure and preparation method and application - Google Patents
A kind of tributyl tin 9-anthroic acid ester of macrocyclic structure and preparation method and application Download PDFInfo
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- CN103467511B CN103467511B CN201310406293.9A CN201310406293A CN103467511B CN 103467511 B CN103467511 B CN 103467511B CN 201310406293 A CN201310406293 A CN 201310406293A CN 103467511 B CN103467511 B CN 103467511B
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- acid ester
- tributyl tin
- anthroic acid
- macrocyclic structure
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- -1 tributyl tin 9-anthroic acid ester Chemical class 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 5
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- XGWFJBFNAQHLEF-UHFFFAOYSA-N 9-anthroic acid Chemical compound C1=CC=C2C(C(=O)O)=C(C=CC=C3)C3=CC2=C1 XGWFJBFNAQHLEF-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
- 239000002904 solvent Substances 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 11
- 230000008025 crystallization Effects 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 10
- 239000013078 crystal Substances 0.000 claims description 10
- 238000002447 crystallographic data Methods 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- 125000006850 spacer group Chemical group 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 claims description 9
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- GCTFWCDSFPMHHS-UHFFFAOYSA-M Tributyltin chloride Chemical compound CCCC[Sn](Cl)(CCCC)CCCC GCTFWCDSFPMHHS-UHFFFAOYSA-M 0.000 claims description 7
- 201000007270 liver cancer Diseases 0.000 claims description 7
- 208000014018 liver neoplasm Diseases 0.000 claims description 7
- 208000019065 cervical carcinoma Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 208000020816 lung neoplasm Diseases 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 2
- ZHUXMBYIONRQQX-UHFFFAOYSA-N hydroxidodioxidocarbon(.) Chemical group [O]C(O)=O ZHUXMBYIONRQQX-UHFFFAOYSA-N 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 201000010989 colorectal carcinoma Diseases 0.000 claims 1
- 239000003814 drug Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 10
- 229910020813 Sn-C Inorganic materials 0.000 description 9
- 229910018732 Sn—C Inorganic materials 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 229910020923 Sn-O Inorganic materials 0.000 description 8
- 230000000259 anti-tumor effect Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000011275 oncology therapy Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- 201000005296 lung carcinoma Diseases 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
- CKXHZTXMENDKEZ-UHFFFAOYSA-N (2-methyl-2-phenylpropyl)tin Chemical compound [Sn]CC(C)(C)C1=CC=CC=C1 CKXHZTXMENDKEZ-UHFFFAOYSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000003112 inhibitor Substances 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
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000011160 research Methods 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
- 241000894006 Bacteria Species 0.000 description 1
- GMXJKJQTGAUTMB-UHFFFAOYSA-N C1=CC=CC2=CC3=CC=CC=C3C(=C12)C(=O)O.C(CCC)[Sn](CCCC)CCCC Chemical compound C1=CC=CC2=CC3=CC=CC=C3C(=C12)C(=O)O.C(CCC)[Sn](CCCC)CCCC GMXJKJQTGAUTMB-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000007942 carboxylates Chemical class 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 class 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
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 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
- 150000007524 organic acids Chemical group 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 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
- 150000003606 tin compounds Chemical class 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The tributyl tin 9-anthroic acid ester of a kind of macrocyclic structure disclosed by the invention, be the compound of following structural formula (1), wherein Bu is normal-butyl, and R is-C
14h
9(9-anthryl).The invention also discloses the tributyl tin 9-anthroic acid ester preparation method of this macrocyclic structure and preparing the application in antitumor drug.
Description
Technical field
Tributyl tin 9-anthroic acid ester that the present invention relates to a kind of macrocyclic structure and preparation method thereof, and the tributyl tin 9-anthroic acid ester of this macrocyclic structure is preparing the application in antitumor drug.
Background technology
Organotin is the organometallics that a class contains Sn-C key, has higher biological activity, the field such as to prepare have a wide range of applications at sterilization, desinsection, cancer therapy drug.Existing research shows, the alkyl R in organotin is the principal element determining compound anti-cancering activity height, and e.g., the antitumour activity of cyclohexyl, normal-butyl and phenyltin compound is comparatively strong, and ethyl takes second place, and methyl is then almost without antitumour activity.The structure of part also plays an important role to the antitumour activity of compound and the broad spectrum of killing cancer cells, and experiment proves, the biological activity of organotin carboxylate is often high than corresponding organo-tin compound, as:
Disclosed two [three (2-methyl-2-phenyl propyl) tin] monocarboxylate of European patent EP 0177785B1 has stronger biological activity than two [three (2-methyl-2-phenyl propyl) tin] oxide compound; Document (SCI; 2008; 29 (9): 1781-1785.) report; the inhibit activities of dibutyl tin carboxylicesters to Gram-negative and positive bacteria is obviously better than Dibutyltin oxide, and under low concentration, have the function of tumor inhibition stronger than Dibutyltin oxide.
The experiment proved that the material with antitumour activity based on organic tin compound, the present invention selects 9-anthroic acid to be organic acid part, react with bis oxide (tributyl tin), tributyltin chloride respectively under certain condition, synthesis obtains has compound compared with strong inhibitory activity, for exploitation cancer therapy drug provides new way to human cervical carcinoma cell (Hela), human breast cancer cell (MCF7), human liver cancer cell (HepG2), human colon cancer cell (Colo205), human lung carcinoma cell (NCI-H460).
Summary of the invention
An object of the present invention is the tributyl tin 9-anthroic acid ester providing a kind of macrocyclic structure.
Two of the object of the invention is the preparation method of the tributyl tin 9-anthroic acid ester providing above-mentioned a kind of macrocyclic structure.
Three of the object of the invention is the application of tributyl tin 9-anthroic acid ester in medicine providing above-mentioned a kind of macrocyclic structure.
In order to realize foregoing invention object, the technical solution adopted in the present invention is:
A tributyl tin 9-anthroic acid ester for macrocyclic structure, the compound for following structural formula (1):
Wherein Bu is normal-butyl, and R is-C
14h
9(9-anthryl).
The compound of described structural formula (1) is crystalline structure, its crystallographic data: hexagonal system, spacer
a=2.06279 (13) nm, b=2.06279 (13) nm, c=3.2639 (2) nm, α=β=90 °, γ=120 °, Z=3, V=12.0276 (13) nm
3; Macrocyclic structure is formed by carboxyl oxygen bridging (tributyl) tin of 9-anthroic acid in molecule.
The preparation method of the tributyl tin 9-anthroic acid ester of macrocyclic structure: add 9-anthroic acid 1mmol, bis oxide (tributyl tin) 0.5 ~ 0.75mmol or tributyltin chloride 1 ~ 1.5mmol, sodium methylate 0 ~ 1.5mmol, solvent anhydrous methanol 15 ~ 50mL in reaction vessel in order successively, reacts 8 ~ 12h under stirring and refluxing; Cooling, filters; Under 25 ~ 35 DEG C of conditions, control solvent evaporates crystallization, obtain pale yellow crystals, be a kind of tributyl tin 9-anthroic acid ester of macrocyclic structure.
The tributyl tin 9-anthroic acid ester of applicant to above-mentioned a kind of macrocyclic structure has carried out anti tumor activity in vitro and has confirmed research, confirm that the tributyl tin 9-anthroic acid ester of this kind of macrocyclic structure has anti-tumor biological, that is the purposes of the tributyl tin 9-anthroic acid ester of above-mentioned a kind of macrocyclic structure is preparing the application in antitumor drug, is exactly specifically preparing the application in anti-cervical cancer or anti-breast cancer or anti-liver cancer or inhibitor against colon carcinoma cells or anti-lung-cancer medicament.
The tributyl tin 9-anthroic acid ester of a kind of macrocyclic structure of the present invention has good antitumour activity, it can prepare anti-cervical cancer, anti-breast cancer, anti-liver cancer, inhibitor against colon carcinoma cells, anti-lung-cancer medicament for raw material.Compared with the platinum-containing anticancer drug generally used at present, the tributyl tin 9-anthroic acid ester of a kind of macrocyclic 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 the tributyl tin 9-anthroic acid crystalline esters molecular structure of macrocyclic structure.
Specific implementation method
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:
A kind of preparation of tributyl tin 9-anthroic acid ester of macrocyclic structure:
In round-bottomed flask, add 9-anthroic acid 0.222g (1mmol), bis oxide (tributyl tin) 0.298g (0.5mmol), 15mL anhydrous methanol in order successively, under stirring and refluxing, react 8h; Cooling, filters; Under 25 ~ 35 DEG C of conditions, control solvent evaporates crystallization, obtain light yellow clear crystal, be the tributyl tin 9-anthroic acid ester of macrocyclic structure.Productive rate 73.8%.Fusing point: 148 ~ 150 DEG C.
Ultimate analysis (C
162h
216o
12sn
6): theoretical value: C63.43, H7.10; Measured value: C63.42, H7.12.
IR(KBr，cm
-1)：3053(w，ν
Ar-H)，2955，2920，2853(m，ν
C-H)，1555(vs，ν
asCOO)，1433(m，ν
C=C)，1391(s，ν
sCOO)，557(w，ν
Sn-C)，409(w，ν
Sn-O)。
1HNMR(CDCl
3，400MHz)，δ(ppm):8.45(s，6H，10-Ar-H)，8.19(d，J=8.4Hz，12H，1，8-Ar-H)，7.99(d，J=8.4Hz，12H，4，5-Ar-H)，7.48(m，24H，2，3，6，7-Ar-H)，1.40～1.90(m，108H，SnCH
2CH
2CH
2-)，0.97(t，J=7.2Hz，54H，-CH
3)。
13CNMR(CDCl
3，100MHz)，δ(ppm):14.66(-CH
3)，20.15(SnCH
2CH
2CH
2CH
3)，23.31(SnCH
2CH
2CH
2CH
3)，29.75(SnCH
2CH
2CH
2CH
3)，110.02，117.20，124.32，127.44，134.36，143.33，146.39，151.67(Ar-C)，166.11(-COO)。
Crystallographic data: hexagonal system, spacer
crystallographic parameter: a=2.06279 (13) nm, b=2.06279 (13) nm, c=3.2639 (2) nm, α=β=90 °, γ=120 °, Z=3, V=12.0276 (13) nm
3, D
c=1.270Mgm
-3, μ (MoK
α)=0.974mm
-1, F (000)=4752, R=0.0665, wR=0.2123.
Embodiment 2:
A kind of preparation of tributyl tin 9-anthroic acid ester of macrocyclic structure:
In round-bottomed flask, add 9-anthroic acid 0.222g (1mmol), bis oxide (tributyl tin) 0.328g (0.55mmol), 25mL anhydrous methanol in order successively, under stirring and refluxing, react 9h; Cooling, filters; Under 25 ~ 35 DEG C of conditions, control solvent evaporates crystallization, obtain light yellow clear crystal, be the tributyl tin 9-anthroic acid ester of macrocyclic structure.Productive rate 75.4%.Fusing point: 148 ~ 150 DEG C.
Ultimate analysis (C
162h
216o
12sn
6): theoretical value: C63.43, H7.10; Measured value: C63.42, H7.12.
IR(KBr，cm
-1)：3053(w，ν
Ar-H)，2955，2920，2853(m，ν
C-H)，1555(vs，ν
asCOO)，1433(m，ν
C=C)，1391(s，ν
sCOO)，557(w，ν
Sn-C)，409(w，ν
Sn-O)。
1HNMR(CDCl
3，400MHz)，δ(ppm):8.45(s，6H，10-Ar-H)，8.19(d，J=8.4Hz，12H，1，8-Ar-H)，7.99(d，J=8.4Hz，12H，4，5-Ar-H)，7.48(m，24H，2，3，6，7-Ar-H)，1.40～1.90(m，108H，SnCH
2CH
2CH
2-)，0.97(t，J=7.2Hz，54H，-CH
3)。
13CNMR(CDCl
3，100MHz)，δ(ppm):14.66(-CH
3)，20.15(SnCH
2CH
2CH
2CH
3)，23.31(SnCH
2CH
2CH
2CH
3)，29.75(SnCH
2CH
2CH
2CH
3)，110.02，117.20，124.32，127.44，134.36，143.33，146.39，151.67(Ar-C)，166.11(-COO)。
Crystallographic data: hexagonal system, spacer
crystallographic parameter: a=2.06279 (13) nm, b=2.06279 (13) nm, c=3.2639 (2) nm, α=β=90 °, γ=120 °, Z=3, V=12.0276 (13) nm
3, D
c=1.270Mgm
-3, μ (MoK
α)=0.974mm
-1, F (000)=4752, R=0.0665, wR=0.2123.
Embodiment 3:
A kind of preparation of tributyl tin 9-anthroic acid ester of macrocyclic structure:
In round-bottomed flask, add 9-anthroic acid 0.222g (1mmol), bis oxide (tributyl tin) 0.358g (0.6mmol), 35mL anhydrous methanol in order successively, under stirring and refluxing, react 10h; Cooling, filters; Under 25 ~ 35 DEG C of conditions, control solvent evaporates crystallization, obtain light yellow clear crystal, be a kind of tributyl tin 9-anthroic acid ester of macrocyclic structure.Productive rate 78.9%.Fusing point: 148 ~ 150 DEG C.
Ultimate analysis (C
162h
216o
12sn
6): theoretical value: C63.43, H7.10; Measured value: C63.42, H7.12.
IR(KBr，cm
-1)：3053(w，ν
Ar-H)，2955，2920，2853(m，ν
C-H)，1555(vs，ν
asCOO)，1433(m，ν
C=C)，1391(s，ν
sCOO)，557(w，ν
Sn-C)，409(w，ν
Sn-O)。
1HNMR(CDCl
3，400MHz)，δ(ppm):8.45(s，6H，10-Ar-H)，8.19(d，J=8.4Hz，12H，1，8-Ar-H)，7.99(d，J=8.4Hz，12H，4，5-Ar-H)，7.48(m，24H，2，3，6，7-Ar-H)，1.40～1.90(m，108H，SnCH2CH2CH2-)，0.97(t，J=7.2Hz，54H，-CH
3)。
13CNMR(CDCl
3，100MHz)，δ(ppm):14.66(-CH
3)，20.15(SnCH
2CH
2CH
2CH
3)，23.31(SnCH
2CH
2CH
2CH
3)，29.75(SnCH
2CH
2CH
2CH
3)，110.02，117.20，124.32，127.44，134.36，143.33，146.39，151.67(Ar-C)，166.11(-COO)。
Crystallographic data: hexagonal system, spacer
crystallographic parameter: a=2.06279 (13) nm, b=2.06279 (13) nm, c=3.2639 (2) nm, α=β=90 °, γ=120 °, Z=3, V=12.0276 (13) nm
3, D
c=1.270Mgm
-3, μ (MoK
α)=0.974mm
-1, F (000)=4752, R=0.0665, wR=0.2123.
Embodiment 4:
A kind of preparation of tributyl tin 9-anthroic acid ester of macrocyclic structure:
In round-bottomed flask, add 9-anthroic acid 0.222g (1mmol), bis oxide (tributyl tin) 0.447g (0.75mmol), 50mL anhydrous methanol in order successively, under stirring and refluxing, react 12h; Cooling, filters; Under 25 ~ 35 DEG C of conditions, control solvent evaporates crystallization, obtain light yellow clear crystal, be the tributyl tin 9-anthroic acid ester of a kind of macrocyclic structure of the present invention.Productive rate 84.3%.Fusing point: 148 ~ 150 DEG C.
Ultimate analysis (C
162h
216o
12sn
6): theoretical value: C63.43, H7.10; Measured value: C63.42, H7.12.
IR(KBr，cm
-1)：3053(w，ν
Ar-H)，2955，2920，2853(m，ν
C-H)，1555(vs，ν
asCOO)，1433(m，ν
C=C)，1391(s，ν
sCOO)，557(w，ν
Sn-C)，409(w，ν
Sn-O)。
1HNMR(CDCl
3，400MHz)，δ(ppm):8.45(s，6H，10-Ar-H)，8.19(d，J=8.4Hz，12H，1，8-Ar-H)，7.99(d，J=8.4Hz，12H，4，5-Ar-H)，7.48(m，24H，2，3，6，7-Ar-H)，1.40～1.90(m，108H，SnCH
2CH
2CH
2-)，0.97(t，J=7.2Hz，54H，-CH
3)。
13CNMR(CDCl
3，100MHz)，δ(ppm):14.66(-CH
3)，20.15(SnCH
2CH
2CH
2CH
3)，23.31(SnCH
2CH
2CH
2CH
3)，29.75(SnCH
2CH
2CH
2CH
3)，110.02，117.20，124.32，127.44，134.36，143.33，146.39，151.67(Ar-C)，166.11(-COO)。
Crystallographic data: hexagonal system, spacer
crystallographic parameter: a=2.06279 (13) nm, b=2.06279 (13) nm, c=3.2639 (2) nm, α=β=90 °, γ=120 °, Z=3, V=12.0276 (13) nm
3, D
c=1.270Mgm
-3, μ (MoK
α)=0.974mm
-1, F (000)=4752, R=0.0665, wR=0.2123.
Embodiment 5:
A kind of preparation of tributyl tin 9-anthroic acid ester of macrocyclic structure:
In round-bottomed flask, add 9-anthroic acid 0.222g (1mmol), tributyltin chloride 0.326g (1mmol), sodium methylate 0.054g (1mmol), 15mL anhydrous methanol in order successively, under stirring and refluxing, react 8h; Cooling, filters; Under 25 ~ 35 DEG C of conditions, control solvent evaporates crystallization, obtain light yellow clear crystal, be a kind of tributyl tin 9-anthroic acid ester of macrocyclic structure.Productive rate 70.1%.Fusing point: 148 ~ 150 DEG C.
Ultimate analysis (C
162h
216o
12sn
6): theoretical value: C63.43, H7.10; Measured value: C63.42, H7.12.
IR(KBr，cm
-1)：3053(w，ν
Ar-H)，2955，2920，2853(m，ν
C-H)，1555(vs，ν
asCOO)，1433(m，ν
C=C)，1391(s，ν
sCOO)，557(w，ν
Sn-C)，409(w，ν
Sn-O)。
1HNMR(CDCl
3，400MHz)，δ(ppm):8.45(s，6H，10-Ar-H)，8.19(d，J=8.4Hz，12H，1，8-Ar-H)，7.99(d，J=8.4Hz，12H，4，5-Ar-H)，7.48(m，24H，2，3，6，7-Ar-H)，1.40～1.90(m，108H，SnCH
2CH
2CH
2-)，0.97(t，J=7.2Hz，54H，-CH
3)。
13CNMR(CDCl
3，100MHz)，δ(ppm):14.66(-CH
3)，20.15(SnCH
2CH
2CH
2CH
3)，23.31(SnCH
2CH
2CH
2CH
3)，29.75(SnCH
2CH
2CH
2CH
3)，110.02，117.20，124.32，127.44，134.36，143.33，146.39，151.67(Ar-C)，166.11(-COO)。
Crystallographic data: hexagonal system, spacer
crystallographic parameter: a=2.06279 (13) nm, b=2.06279 (13) nm, c=3.2639 (2) nm, α=β=90 °, γ=120 °, Z=3, V=12.0276 (13) nm
3, D
c=1.270Mgm
-3, μ (MoK
α)=0.974mm
-1, F (000)=4752, R=0.0665, wR=0.2123.
Embodiment 6:
A kind of preparation of tributyl tin 9-anthroic acid ester of macrocyclic structure:
In round-bottomed flask, add 9-anthroic acid 0.222g (1mmol), tributyltin chloride 0.359g (1.1mmol), sodium methylate 0.059g (1.1mmol), 20mL anhydrous methanol in order successively, under stirring and refluxing, react 9h; Cooling, filters; Under 25 ~ 35 DEG C of conditions, control solvent evaporates crystallization, obtain light yellow clear crystal, be the tributyl tin 9-anthroic acid ester of macrocyclic structure.Productive rate 73.7%.Fusing point: 148 ~ 150 DEG C.
Ultimate analysis (C
162h
216o
12sn
6): theoretical value: C63.43, H7.10; Measured value: C63.42, H7.12.
IR(KBr，cm
-1)：3053(w，ν
Ar-H)，2955，2920，2853(m，ν
C-H)，1555(vs，ν
asCOO)，1433(m，ν
C=C)，1391(s，ν
sCOO)，557(w，ν
Sn-C)，409(w，ν
Sn-O)。
1HNMR(CDCl
3，400MHz)，δ(ppm):8.45(s，6H，10-Ar-H)，8.19(d，J=8.4Hz，12H，1，8-Ar-H)，7.99(d，J=8.4Hz，12H，4，5-Ar-H)，7.48(m，24H，2，3，6，7-Ar-H)，1.40～1.90(m，108H，SnCH2CH2CH2-)，0.97(t，J=7.2Hz，54H，-CH
3)。
13CNMR(CDCl
3，100MHz)，δ(ppm):14.66(-CH
3)，20.15(SnCH
2CH
2CH
2CH
3)，23.31(SnCH
2CH
2CH
2CH
3)，29.75(SnCH
2CH
2CH
2CH
3)，110.02，117.20，124.32，127.44，134.36，143.33，146.39，151.67(Ar-C)，166.11(-COO)。
Crystallographic data: hexagonal system, spacer
crystallographic parameter: a=2.06279 (13) nm, b=2.06279 (13) nm, c=3.2639 (2) nm, α=β=90 °, γ=120 °, Z=3, V=12.0276 (13) nm
3, D
c=1.270Mgm
-3, μ (MoK
α)=0.974mm
-1, F (000)=4752, R=0.0665, wR=0.2123.
Embodiment 7:
A kind of preparation of tributyl tin 9-anthroic acid ester of macrocyclic structure:
In round-bottomed flask, add 9-anthroic acid 0.222g (1mmol), tributyltin chloride 0.424g (1.3mmol), sodium methylate 0.070g (1.3mmol), 40mL anhydrous methanol in order successively, under stirring and refluxing, react 11h; Cooling, filters; Under 25 ~ 35 DEG C of conditions, control solvent evaporates crystallization, obtain light yellow clear crystal, be the tributyl tin 9-anthroic acid ester of macrocyclic structure.Productive rate 75.2%.Fusing point: 148 ~ 150 DEG C.
Ultimate analysis (C
162h
216o
12sn
6): theoretical value: C63.43, H7.10; Measured value: C63.42, H7.12.
IR(KBr，cm
-1)：3053(w，ν
Ar-H)，2955，2920，2853(m，ν
C-H)，1555(vs，ν
asCOO)，1433(m，ν
C=C)，1391(s，ν
sCOO)，557(w，ν
Sn-C)，409(w，ν
Sn-O)。
1HNMR(CDCl
3，400MHz)，δ(ppm):8.45(s，6H，10-Ar-H)，8.19(d，J=8.4Hz，12H，1，8-Ar-H)，7.99(d，J=8.4Hz，12H，4，5-Ar-H)，7.48(m，24H，2，3，6，7-Ar-H)，1.40～1.90(m，108H，SnCH
2CH
2CH
2-)，0.97(t，J=7.2Hz，54H，-CH
3)。
13CNMR(CDCl
3，100MHz)，δ(ppm):14.66(-CH
3)，20.15(SnCH
2CH
2CH
2CH
3)，23.31(SnCH
2CH
2CH
2CH
3)，29.75(SnCH
2CH
2CH
2CH
3)，110.02，117.20，124.32，127.44，134.36，143.33，146.39，151.67(Ar-C)，166.11(-COO)。
Crystallographic data: hexagonal system, spacer
crystallographic parameter: a=2.06279 (13) nm, b=2.06279 (13) nm, c=3.2639 (2) nm, α=β=90 °, γ=120 °, Z=3, V=12.0276 (13) nm
3, D
c=1.270Mgm
-3, μ (MoK
α)=0.974mm
-1, F (000)=4752, R=0.0665, wR=0.2123.
Embodiment 8:
A kind of preparation of tributyl tin 9-anthroic acid ester of macrocyclic structure:
In round-bottomed flask, add 9-anthroic acid 0.222g (1mmol), tributyltin chloride 0.489g (1.5mmol), sodium methylate 0.081g (1.5mmol), 50mL anhydrous methanol in order successively, under stirring and refluxing, react 12h; Cooling, filters; Under 25 ~ 35 DEG C of conditions, control solvent evaporates crystallization, obtain light yellow clear crystal, be the tributyl tin 9-anthroic acid ester of macrocyclic structure.Productive rate 83.4%.Fusing point: 148 ~ 150 DEG C.
Ultimate analysis (C
162h
216o
12sn
6): theoretical value: C63.43, H7.10; Measured value: C63.42, H7.12.
IR(KBr，cm
-1)：3053(w，ν
Ar-H)，2955，2920，2853(m，ν
C-H)，1555(vs，ν
asCOO)，1433(m，ν
C=C)，1391(s，ν
sCOO)，557(w，ν
Sn-C)，409(w，ν
Sn-O)。
1HNMR(CDCl
3，400MHz)，δ(ppm):8.45(s，6H，10-Ar-H)，8.19(d，J=8.4Hz，12H，1，8-Ar-H)，7.99(d，J=8.4Hz，12H，4，5-Ar-H)，7.48(m，24H，2，3，6，7-Ar-H)，1.40～1.90(m，108H，SnCH
2CH
2CH
2-)，0.97(t，J=7.2Hz，54H，-CH
3)。
13CNMR(CDCl
3，100MHz)，δ(ppm):14.66(-CH
3)，20.15(SnCH
2CH
2CH
2CH
3)，23.31(SnCH
2CH
2CH
2CH
3)，29.75(SnCH
2CH
2CH
2CH
3)，110.02，117.20，124.32，127.44，134.36，143.33，146.39，151.67(Ar-C)，166.11(-COO)。
Crystallographic data: hexagonal system, spacer
crystallographic parameter: a=2.06279 (13) nm, b=2.06279 (13) nm, c=3.2639 (2) nm, α=β=90 °, γ=120 °, Z=3, V=12.0276 (13) nm
3, D
c=1.270Mgm
-3, μ (MoK
α)=0.974mm
-1, F (000)=4752, R=0.0665, wR=0.2123.
Test example:
The tributyl tin 9-anthroic acid ester of a kind of macrocyclic 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-diphenyltetrazolium bromide.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 tributyl tin 9-anthroic acid ester of this kind of macrocyclic structure to the inhibit activities of human cervical carcinoma cell (Hela), human breast cancer cell (MCF7), human liver cancer cell (HepG2), human colon cancer cell (Colo205), human lung carcinoma cell (NCI-H460).
Cell strain and culture system: Hela, MCF7, HepG2, Colo205 and NCI-H460 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 GraphPadPrismversion5.0 program, and Compound I C50 carries out matching by the nonlinear regression model (NLRM) in program with S shape dose response and obtains.
With MTT analytical method, human cervical carcinoma cell (Hela) cell strain, human breast cancer cell (MCF7) cell strain, human liver cancer cell (HepG2) cell strain, human colon cancer cell (Colo205) cell strain, human lung carcinoma cell (NCI-H460) cell strain are analyzed, measure its IC
50value, result is as shown in table 1, conclusion is: from data in table, cancer therapy drug is used as with the tributyl tin 9-anthroic acid ester of a kind of macrocyclic structure of the present invention, higher to human cervical carcinoma, human breast carcinoma, people's liver cancer, human colon carcinoma, people's lung cancer activity, can be used as the candidate compound of cancer therapy drug.
The tributyl tin 9-anthroic acid ester cancer therapy drug external activity test data of table 1 macrocyclic structure
Claims (5)
1. a tributyl tin 9-anthroic acid ester for macrocyclic structure, is characterized in that, the compound for following structural formula (1):
Wherein Bu is normal-butyl, and R is 9-anthryl.
2. the tributyl tin 9-anthroic acid ester of a kind of macrocyclic structure as claimed in claim 1, is characterized in that, the compound of described structural formula (1) is crystalline structure, its crystallographic data: hexagonal system, spacer
a=2.06279 (13) nm, b=2.06279 (13) nm, c=3.2639 (2) nm, α=β=90 °, γ=120 °, Z=3, V=12.0276 (13) nm
3; Macrocyclic structure is formed by carboxyl oxygen bridging (tributyl) tin of 9-anthroic acid in molecule.
3. the preparation method of the tributyl tin 9-anthroic acid ester of a kind of macrocyclic structure described in claim 1 or 2, it is characterized in that, in reaction vessel, add 9-anthroic acid 1mmol, bis oxide (tributyl tin) 0.5 ~ 0.75mmol or tributyltin chloride 1 ~ 1.5mmol, sodium methylate 0 ~ 1.5mmol, solvent anhydrous methanol 15 ~ 50mL in order successively, under stirring and refluxing, react 8 ~ 12h; Cooling, filters; Under 25 ~ 35 DEG C of conditions, control solvent evaporates crystallization, obtain pale yellow crystals, be a kind of tributyl tin 9-anthroic acid ester of macrocyclic structure.
4. the tributyl tin 9-anthroic acid ester of a kind of macrocyclic structure described in claim 1 or 2 is preparing the application in antitumor drug.
5. application according to claim 4, wherein said tumour is human cervical carcinoma, mammary cancer, liver cancer, colorectal carcinoma, lung cancer.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0177785A2 (en) * | 1984-09-18 | 1986-04-16 | Yashima Chemical Industrial Co., Ltd. | Tris(beta,beta-dimethylphenethyl)tin compounds |
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2013
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0177785A2 (en) * | 1984-09-18 | 1986-04-16 | Yashima Chemical Industrial Co., Ltd. | Tris(beta,beta-dimethylphenethyl)tin compounds |
Non-Patent Citations (2)
| Title |
|---|
| 三苯基锡9-蒽甲酸酯的合成、表征、荧光、热稳定性及量子化学研究;庾江喜 等;《无机化学学报》;20131231;第29卷(第12期);第2688-2694页 * |
| 新型双大环二正丁基锡羧酸酯的合成、晶体结构及生物活性;王艳华 等;《高等学校化学学报》;20080930;第29卷(第9期);第1781-1785页 * |
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