CN103113277B - Selenium-containing compound as well as preparation method and pharmaceutical composition thereof - Google Patents
Selenium-containing compound as well as preparation method and pharmaceutical composition thereof Download PDFInfo
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- CN103113277B CN103113277B CN201310069965.1A CN201310069965A CN103113277B CN 103113277 B CN103113277 B CN 103113277B CN 201310069965 A CN201310069965 A CN 201310069965A CN 103113277 B CN103113277 B CN 103113277B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 80
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 title claims abstract description 57
- 239000011669 selenium Substances 0.000 title claims abstract description 56
- 229910052711 selenium Inorganic materials 0.000 title claims abstract description 56
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 239000003814 drug Substances 0.000 claims description 42
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 28
- 229910052697 platinum Inorganic materials 0.000 claims description 26
- 238000011282 treatment Methods 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 231100000331 toxic Toxicity 0.000 description 9
- 230000002588 toxic effect Effects 0.000 description 9
- 238000011275 oncology therapy Methods 0.000 description 8
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 238000010025 steaming Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000002296 dynamic light scattering Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 229960004562 carboplatin Drugs 0.000 description 3
- 190000008236 carboplatin Chemical compound 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000003255 drug test Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- YWDUZLFWHVQCHY-UHFFFAOYSA-N 1,3,5-tribromobenzene Chemical compound BrC1=CC(Br)=CC(Br)=C1 YWDUZLFWHVQCHY-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical class CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011785 micronutrient Substances 0.000 description 1
- 235000013369 micronutrients Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 150000003342 selenium Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- MVDRXYIEGOGRAI-UHFFFAOYSA-N tribromomethylbenzene Chemical compound BrC(Br)(Br)C1=CC=CC=C1 MVDRXYIEGOGRAI-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a selenium-containing compound as well as a preparation method and a pharmaceutical composition thereof, wherein the selenium-containing compound has a structure shown as formula I. The selenium-containing compound can be used for preparing a drug carrier.
Description
Technical field
The present invention relates to medical technical field.In particular to selenium-containing compound and preparation method thereof, pharmaceutical composition.
Background technology
Medicine, in treatment disease, often has larger toxic side effect, and such as cis-platinum, carboplatin, oxaliplatin etc. are widely used as a kind of effective cancer therapy drug always, but its high toxicity and non-selectivity have limited its use.People are attempting being improved drug effect and being reduced the toxic side effect of medicine by various means always, than with attempting to utilize medicine-carried system to reach this object.
Yet current medicine and medicine-carried system all still have much room for improvement.
Summary of the invention
The present invention is intended at least solve one of technical problem existing in prior art.For this reason, the present invention proposes a kind of selenium-containing compound and method thereof, and the application of selenium-containing compound.
The following discovery of the present invention based on contriver completes:
Cancer therapy drug, as cis-platinum, be widely used clinically, but its high toxicity and non-selectivity have limited its result for the treatment of always, although and selenium can be alleviated chemotherapy side effect as a kind of human body micronutrient element, selenium is but difficult to directly use as pharmaceutical carrier.In view of this, the present invention is intended to synthetic a kind of selenium-containing compound and forms a kind of medicine-carried system, to when guaranteeing or improving curative effect of medication, can also reduce the toxic side effect of medicine.The present inventor is surprised to find, and by technical scheme of the present invention, can effectively solve for example above-mentioned technical problem.Following part is described the feature and advantage of technical solution of the present invention being done further.
In one aspect of the invention, the present invention proposes a kind of selenium-containing compound.According to embodiments of the invention, this selenium-containing compound has structure as shown in Equation 1:
Utilization is according to the selenium-containing compound of the embodiment of the present invention, can be for the preparation of pharmaceutical carrier, the micella carrier system of cancer therapy drug for example, neither affect the result for the treatment of of medicine, can effectively reduce the toxic side effect of medicine again, selenium-containing compound itself does not have toxicity yet, thereby can be widely used in field of medicaments, has huge medical applications and is worth and market popularization value.Selenium-containing compound of the present invention is except being effectively applied to field of medicaments technical field, and person skilled can certainly be extended to other field, does not repeat them here, and these are all within the scope of the present invention.
In another aspect of the present invention, the present invention proposes a kind of method of preparing selenium-containing compound (being compound shown in formula 1) described in above embodiment.
With reference to following synthetic route
Step 1:
Step 3:
According to embodiments of the invention, the method comprises:
1) will contact with compound shown in formula 2 methyl sulfuryl chloride, so that compound shown in acquisition formula 3,
2) compound shown in described formula 3 is contacted with sub-sodium selenide, so that compound shown in acquisition formula 4,
and
3) by compound shown in described formula 4 and sodium borohydride and the contact of 1,3,5-tribromo-benzene, so that the selenium-containing compound described in acquisition formula 1,
Utilization can be prepared selenium-containing compound effectively according to the method for preparing selenium-containing compound of the embodiment of the present invention, this preparation method has no bibliographical information, and this preparation technology is simple, and combined coefficient is high, thereby be more suitable for extensive, suitability for industrialized production selenium-containing compound.Prepared selenium-containing compound can be for the preparation of pharmaceutical carrier, the micella carrier system of cancer therapy drug for example, neither affect the result for the treatment of of medicine, selenium-containing compound can effectively reduce the toxic side effect of medicine again, thereby can be widely used in field of medicaments, there is huge medical applications and be worth and market popularization value.
In addition, according to the method for preparing selenium-containing compound of the embodiment of the present invention, can also there is following additional technical characterictic:
According to embodiments of the invention, in step 1), in triethylamine solution, by described, methyl sulfuryl chloride is contacted with compound shown in described formula 2, to obtain compound shown in described formula 3.Thus, can further improve the efficiency of compound shown in preparation formula 1.
According to embodiments of the invention, in step 1), getting compound shown in formula 2 described in 40mmol mixes with the triethylamine of 5.56ml, the round-bottomed flask that adds 100ml, under ice-water bath, stir, 48mmol Tosyl chloride is dissolved in to 20ml methylene dichloride, with constant pressure funnel, slowly add, after adding, withdraw from ice-water bath, under 30 degrees Celsius of oil baths, confined reaction is 3 hours, and separatory, revolves steaming, after dry, with the solution that the volume ratio of methylene dichloride and ethyl acetate is 4:1, make developping agent and cross pillar, to obtain compound shown in described formula 3; In step 2) in, get 15mmol sodium borohydride and 15mmol selenium powder, the round-bottomed flask that is placed in 100ml adds 15ml water, confined reaction 20min after uncovered reaction 2.5min, then add with compound shown in formula 3 described in the 15mmol of 20ml acetonitrile dissolving, 75 degrees Celsius of oil bath confined reactions 2 hours, to obtain compound shown in described formula 4; And in step 3), get the sodium borohydride of 22mmol, add the sodium hydroxide one of 0.05g to reinstate 10ml water dissolution, slowly add in flask, reaction 10min, dissolves 1 of 5mmol with 5ml acetonitrile, 3,5-trisbromomethyl benzene, reacts separatory 5 hours, revolve steaming, after dry, with the solution that the volume ratio of ether and methyl alcohol is 12:1, as developping agent, cross pillar, to obtain compound shown in described formula 1, its structure as shown in Figure 1.Thus, compound shown in preparation formula 1 effectively, and technique is simple, combined coefficient is high, raw materials usedly easily from market, buys.Thereby be conducive to reduce production costs.
Of the present invention, aspect another, the present invention proposes a kind of pharmaceutical composition.According to embodiments of the invention, this pharmaceutical composition comprises: carrier, and described carrier is formed by the selenium-containing compound described in above embodiment; And activeconstituents, described activeconstituents is attached on described carrier.
In the present invention, medicine can combine with carrier, and can effectively be discharged.For example according to a particular embodiment of the invention, as shown in Figure 2, described medicine is that cis-platinum, carboplatin and other metal are cancer therapy drug, is preferably cis-platinum, and such medicine can be combined with carrier by coordination, then by competitive coordination effect, is discharged.
Utilization is according to the pharmaceutical composition of the embodiment of the present invention, can effectively be used for the treatment of and preventing disease, cancer for example, this pharmaceutical composition both can be treated and preventing disease effectively, its toxic side effect can access again greatly and reduce, thereby can be widely used in field of medicaments, there is huge medical applications and be worth and market popularization value.
In addition, according to the pharmaceutical composition of the embodiment of the present invention, can also there is following additional technical characterictic:
According to embodiments of the invention, the kind of described activeconstituents is not particularly limited.For example according to a particular embodiment of the invention, described activeconstituents is cis-platinum.Select in the present invention cis-platinum to be because at field of medicaments, cis-platinum is a kind of clinical application cancer therapy drug widely, and metallic element platinum wherein can reach medicine carrying object with selenium-containing compound coordination, certainly, activeconstituents of the present invention can also be the platinum series cancer therapy drug of other type, as carboplatin and oxaliplatin, and can also be other metal types cancer therapy drug, as class of metallocenes complex compound and ruthenium complexe.Thus, medicament selection scope can be effectively widened, the result for the treatment of of pharmaceutical composition can be further improved.
The inventor finds under study for action, if the mol ratio ratio of described selenium-containing compound and described cis-platinum is too high, the toxicity of medicine can be larger, if ratio is too low, the curative effect of medicine can be lower.According to some embodiments of the present invention, the mol ratio of described selenium-containing compound and described cis-platinum is 3:2～1:2.Can further improve the result for the treatment of of described pharmaceutical composition thus.
According to embodiments of the invention, described carrier is the micella being formed by the selenium-containing compound described in above embodiment.Can further improve the result for the treatment of of described pharmaceutical composition thus.
According to embodiments of the invention, described pharmaceutical composition is used for the treatment of or preventing cancer.Can further improve the result for the treatment of of described pharmaceutical composition thus.
The present inventor is surprised to find, the growth that pharmaceutical composition of the present invention can anticancer, but for normal cell, there is no restraining effect, toxic side effect is little.Can further improve the result for the treatment of of described pharmaceutical composition thus.
According to the embodiment of the present invention, the present invention can realize following advantages one of at least:
1, according to the selenium-containing compound of the embodiment of the present invention, can be for the preparation of pharmaceutical carrier, neither affect the result for the treatment of of medicine, can effectively reduce the toxic side effect of medicine again, selenium-containing compound itself does not have toxicity yet, thereby can be widely used in field of medicaments, there is huge medical applications and be worth and market popularization value;
2, according to the method for preparing selenium-containing compound of the embodiment of the present invention, having no bibliographical information, be world's the first, and combined coefficient is high, and the purity of prepared selenium-containing compound is also higher, can be effectively for the preparation of pharmaceutical carrier;
3,, according to the method for preparing selenium-containing compound of the embodiment of the present invention, raw material and reagent used are easily buied from market, thereby are conducive to reduce production costs;
4, according to the method for preparing selenium-containing compound of the embodiment of the present invention, technique is simple, with short production cycle, thereby is more suitable for extensive, suitability for industrialized production selenium-containing compound.
5, according to the pharmaceutical composition of the embodiment of the present invention, this pharmaceutical composition both can be treated and preventing disease effectively, and for example cancer, can reduce the toxic side effect of chemotherapy again greatly, thereby is suitable for being widely used in medical treatment field.
The term that used in this article " contact " should be interpreted broadly, and it can be any mode that can make at least two kinds of reactant generation chemical reactions, for example, can be that two kinds of reactants are mixed under suitable condition.In this article, " compound N " in this article sometimes also referred to as " compound shown in formula N ", the arbitrary integer that N is 1-13 in this article, and for example " compound 2 " also can be called " compound shown in formula 2 " in this article.
The similar descriptions such as the term that used in this article " first ", " second " are only for describing object, and can not be interpreted as indication or hint relative importance or the implicit quantity that indicates indicated technical characterictic.Thus, one or more these features can be expressed or impliedly be comprised to the feature that is limited with " first ", " second ".In description of the invention, except as otherwise noted, the implication of " a plurality of " is two or more, unless separately there is clear and definite restriction.
Additional aspect of the present invention and advantage in the following description part provide, and part will become obviously from the following description, or recognize by practice of the present invention.
Accompanying drawing explanation
Above-mentioned and/or additional aspect of the present invention and advantage accompanying drawing below combination obviously and is easily understood becoming the description of embodiment, wherein:
Fig. 1 is the structural representation of selenium-containing compound according to an embodiment of the invention; And
Fig. 2 has shown cis-platinum and carrier combination and the structural representation discharging according to an embodiment of the invention;
Fig. 3 has shown the fluorescence emission spectrogram of micella according to an embodiment of the invention;
Fig. 4 has shown the Electronic Speculum figure of micella according to an embodiment of the invention;
Fig. 5 has shown the structural representation that cis-platinum and carrier bag carry according to an embodiment of the invention;
Fig. 6 has shown that bag carries cis-platinum and is dynamic light scattering size distribution (DLS) figure that bag carries cis-platinum according to an embodiment of the invention;
Fig. 7 has shown the structural representation that cis-platinum and carrier discharge according to an embodiment of the invention;
Fig. 8 has shown the cell counting figure of cell culture experiments according to an embodiment of the invention.
Embodiment
Describe embodiments of the invention below in detail, it should be noted that the embodiment the following describes is exemplary, only for explaining the present invention, and can not be interpreted as limitation of the present invention.In addition, if do not clearly not stated, all reagent of adopting are in the following embodiments can be buied on market, or can according to herein or known method synthetic, for the reaction conditions of not listing, be also that those skilled in the art easily obtain.
General method
1,, in the following example, the method for preparing selenium-containing compound comprises following key step:
1) getting compound shown in 40mmol formula 2 mixes with the triethylamine of 5.56ml, the round-bottomed flask that adds 100ml, stirs under ice-water bath, and 48mmol Tosyl chloride is dissolved in to 20ml methylene dichloride, with constant pressure funnel, slowly add, after adding, withdraw from ice-water bath, under 30 degrees Celsius of oil baths, confined reaction is 3 hours, separatory, revolve steaming, after dry, with the solution that the volume ratio of methylene dichloride and ethyl acetate is 4:1, make developping agent and cross pillar, so that compound shown in acquisition formula 3
2) get 15mmol sodium borohydride and 15mmol selenium powder, the round-bottomed flask that is placed in 100ml adds 15ml water, confined reaction 20min after uncovered reaction 2.5min, then add compound shown in the 15mmol formula 3 of dissolving with 20ml acetonitrile, 75 degrees Celsius of oil bath confined reactions 2 hours, so that compound shown in acquisition formula 4
and
3) get the sodium borohydride of 22mmol, add the sodium hydroxide one of 0.05g to reinstate 10ml water dissolution, slowly add in flask, reaction 10min, with 5ml acetonitrile, dissolve 1,3 of 5mmol, 5-trisbromomethyl benzene, react 5 hours, separatory, revolves steaming, crosses pillar after dry with the solution that the volume ratio of ether and methyl alcohol is 12:1 as developping agent, so that compound shown in acquisition formula 1
2,, in the following example, prepare micella and comprise following key step:
1) measurement of micelle-forming concentration (CMC): utilize water configuration selenium-containing compound solution, the saturated acetone soln that adds 1 volume % pyrene, after supersound process, measure the fluorescence emission spectrum of pyrene, as shown in Figure 3, the micelle-forming concentration that can see selenium-containing compound 1 is 1.68mg/ml to detected result.
2) get the methyl alcohol of selenium-containing compound or the solution of other organic solvents, be spin-dried for final vacuum and dry, more than adding water to micelle-forming concentration, make selenium-containing compound micella.
3,, in the following example, bag medicine carrying thing comprises following key step:
Get selenium-containing compound micella and mix with pharmaceutical aqueous solution, stir, ultrasonic, standing.
4,, in the following example, discharge drug test and comprise following key step:
To wrapping in the selenium-containing compound micellar solution of medicine carrying thing, carry out dialysis treatment, use respectively pure water and the gsh aqueous solution, with AES, measure the Pt content of solution outside dialysis membrane.
5,, in the following example, cell experiment comprises following key step:
The solution that the release drug treating of learning from else's experience is crossed adds substratum, respectively normal cell, cancer cells etc. is cultivated, and counts observation of cell survival rate under microscope.
Embodiment 1:
Getting compound shown in 40mmol formula 2 mixes with the triethylamine of 5.56ml, the round-bottomed flask that adds 100ml, under ice-water bath, stir, 48mmol Tosyl chloride is dissolved in to 20ml methylene dichloride, with constant pressure funnel, slowly add, after adding, withdraw from ice-water bath, under 30 degrees Celsius of oil baths, confined reaction is 3 hours, and separatory, revolves steaming, after dry, with the solution that the volume ratio of methylene dichloride and ethyl acetate is 4:1, make developping agent and cross pillar, so that compound shown in acquisition formula 3.
1H-NMR(300MHz,CDCl
3)δ(ppm)：7.78(2H，Ph-H)，7.34(2H，Ph-H)，4.15(2H，SO
2O-CH
2)，3.76(2H,SO
2O-CH
2-CH
2)，3.54-3.68(8H，O(CH
2)
2O(CH
2)
2OCH
3)，3.71(3H，OCH
3)，2.45(2H，Ph-CH
3)。
Embodiment 2:
Get the sodium borohydride of 22mmol, add the sodium hydroxide one of 0.05g to reinstate 10ml water dissolution, slowly add in flask, reaction 10min, with 5ml acetonitrile, dissolve 1 of 5mmol, 3,5-trisbromomethyl benzene, reacts 5 hours, separatory, revolve steaming, with the solution that the volume ratio of ether and methyl alcohol is 12:1, as developping agent, cross pillar after dry, so that compound shown in acquisition formula 1.
1H-NMR(300MHz,CDCl
3)δ(ppm)：7.07(3H，Ph-H)，3.76(6H，Ph-CH
2)，3.62-3.67(24H，O(CH
2)
2O(CH
2)
2OCH
3)，3.55(6H，Se-CH
2-CH
2)，3.37(9H，OCH
3)，2.64-2.69(6H，Se-CH
2-CH
2)。
Embodiment 3: prepare micella
After the selenium-containing compound methanol solution that is 3mg/mL by concentration is spin-dried for, adding water to concentration is that 3mg/mL makes selenium-containing compound micella.By scanning electronic microscope observation result as shown in Figure 4, can see that selenium-containing compound is assembled into particle diameter at the micella of 400-500nm left and right.
Embodiment 4: bag medicine carrying thing
The selenium-containing compound methanol solution of getting 0.95mL concentration and be 4.73mg/mL is spin-dried for final vacuum dries, the cisplatin aqueous solution that add respectively 0.223,0.335,0.502, the concentration of 0.670mL is 5mg/mL, add again 1.277,1.165,0.998, the water of 0.830mL, stir, ultrasonic, within standing 2 days, can obtain the molar ratio that the bag ratio of carrying is respectively 3:2,1:1,2:3,1:2(selenium-containing compound micella and cis-platinum) solution.Wherein, the molar ratio of selenium-containing compound micella and cis-platinum be 1:1 micella scanning electronic microscope detection figure result as shown in Figure 4, after can seeing bag medicine carrying thing, still can form micella assembly, unentrapped cis-platinum and different bags carry cis-platinum ratio micellar solution dynamic light scattering size distribution (DLS) figure as shown in Figure 6, can see that bag carries the particle diameter of micella after cis-platinum and had obvious reduction.
Embodiment 5: discharge drug test
The selenium-containing compound micella of 1 volume is dialysed in the dialysis membrane of 3500 molecular weight with the pure water of 60 times of volumes, in 24h, change 4 water.The structure of observing under its scanning electronic microscope after discharging as shown in Figure 5, can see that the micella after bag medicine carrying thing still can keep the structure of micella under diluted ambient, and circulation can keep certain stability in vivo.
Embodiment 6: cell culture experiments
Carrying out cell culture experiments cell used is liver cancer cell and normal liver cell, also can take cancer cells and the normal cell of its hetero-organization.The solution dilution of respectively process release drug treating being crossed to the molar ratio of selenium-containing compound micella and cis-platinum is 3:2,1:1,2:3,1:2, then in the process of preparation substratum, is added, and does not change other nutrition content of substratum.Result as shown in Figure 8, wherein, 1:1 refers to blank group, can see that bag carries the bag medicine carrying objects system that ratio (molar ratio of selenium-containing compound micella and cis-platinum) is 3:2,1:1,2:3,1:2 and all liver cancer cell shown to higher selectivity, can when brute force is killed and wounded cancer cells, but to normal liver cell, cause very little injury, and simple cis-platinum can also kill normal cell when killing cancer cells.
In the description of this specification sheets, the description of reference term " embodiment ", " some embodiment ", " illustrative examples ", " example ", " concrete example " or " some examples " etc. means to be contained at least one embodiment of the present invention or example in conjunction with specific features, structure, material or the feature of this embodiment or example description.In this manual, the schematic statement of above-mentioned term is not necessarily referred to identical embodiment or example.And the specific features of description, structure, material or feature can be with suitable mode combinations in any one or more embodiment or example.
Although illustrated and described embodiments of the invention above; be understandable that; above-described embodiment is exemplary; can not be interpreted as limitation of the present invention; those of ordinary skill in the art can change above-described embodiment within the scope of the invention in the situation that not departing from principle of the present invention and aim, modification, replacement and modification, and these all drop on the scope of the present invention.
Claims (2)
1. a pharmaceutical composition, is characterized in that, comprising:
Carrier, described carrier is the micella being formed by the selenium-containing compound shown in formula 1; And
Cis-platinum, described cis-platinum is attached on described carrier, and forms with described selenium-containing compound the structure being shown below:
Wherein, the mol ratio of described selenium-containing compound and described cis-platinum is 3:2～1:2.
2. the purposes of pharmaceutical composition claimed in claim 1 in preparing medicine, described medicine is used for the treatment of or preventing cancer.
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| CN102327620A (en) * | 2011-07-29 | 2012-01-25 | 暨南大学 | Application of nano-selenium in antineoplastic drug carrier |
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