CN102020598A - Gronwell naphthaquinone derivative, preparation method of gronwell naphthaquinone derivative and application of gronwell naphthaquinone derivative serving as anticarcinoma drug - Google Patents
Gronwell naphthaquinone derivative, preparation method of gronwell naphthaquinone derivative and application of gronwell naphthaquinone derivative serving as anticarcinoma drug Download PDFInfo
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- 150000002791 naphthoquinones Chemical class 0.000 title claims abstract description 28
- 239000003814 drug Substances 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims description 6
- 230000001093 anti-cancer Effects 0.000 title abstract description 5
- 229940079593 drug Drugs 0.000 title abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 24
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical group SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims abstract description 18
- 235000004256 Buglossoides arvense Nutrition 0.000 claims description 22
- 241000118841 Lithospermum incisum Species 0.000 claims description 22
- 229930192627 Naphthoquinone Natural products 0.000 claims description 21
- -1 substituted-phenyl Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 239000012434 nucleophilic reagent Substances 0.000 claims description 4
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- 239000002246 antineoplastic agent Substances 0.000 claims description 3
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- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
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- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
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- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
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- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 2
- 239000003560 cancer drug Substances 0.000 claims 1
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- UNNKKUDWEASWDN-UHFFFAOYSA-N alkannin Natural products CC(=CCC(O)c1cc(O)c2C(=O)C=CC(=O)c2c1O)C UNNKKUDWEASWDN-UHFFFAOYSA-N 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- BXAVKNRWVKUTLY-UHFFFAOYSA-N 4-sulfanylphenol Chemical compound OC1=CC=C(S)C=C1 BXAVKNRWVKUTLY-UHFFFAOYSA-N 0.000 description 1
- NEZONWMXZKDMKF-UHFFFAOYSA-N C.I. Natural Red 20 Chemical compound C1=CC(O)=C2C(=O)C(C(O)CC=C(C)C)=CC(=O)C2=C1O NEZONWMXZKDMKF-UHFFFAOYSA-N 0.000 description 1
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- NBOMNTLFRHMDEZ-UHFFFAOYSA-N thiosalicylic acid Chemical compound OC(=O)C1=CC=CC=C1S NBOMNTLFRHMDEZ-UHFFFAOYSA-N 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to the field of organic chemistry, in particular to a gronwell naphthaquinone derivative and an application of the gronwell naphthaquinone derivative serving as an anticarcinoma drug. People discover that a compound with arysulfydryl group substituted by a substituent group is introduced in a parent body of beta, beta-dimethylacrylalkannin, wherein the anticancer activity and the toxicity of the compound is respectively higher and lower than those of a compound introducing a thiophenol substituent group, thus the gronwell naphthaquinone derivative has preferable clinic application value. The gronwell naphthaquinone derivative has a structure as shown in the formula (I), wherein R1 is the arysulfydryl having at least one substituent group; R2 is H or the arysulfydryl having at least one substituent group, and R3 is H or the arysulfydryl having at least one substituent group. As the preferable compound, the aryl in the arysulfydryl is a substituted phenyl group, a napheyl, a five-element heterocylic ring having 1-2 heteroatoms or a six-element heterocylic ring having 1-3 heteroatoms.
Description
Technical field
The present invention relates to organic chemistry filed, be specifically related to a kind of Asian puccoon naphthoquinone derivatives and as the application of antitumor drug.
Technical background
Cancer is current to one of maximum disease of human health and quality of life harm, and the exploitation of cancer therapy drug is the focus that scientist studies always.Quinones is widespread in nature, and has multiple physiologically active.American National ICRs in 1974 have been announced the anticancer The selection result of 1500 synthetic and natural quinoness, find that this compounds has notable antitumor activity to tumour cell, have caused the concern of scientist to quinones.
And contained naphthoquinone compound has been found that to have certain anti-tumor activity in the plurality of Chinese, but as from the isolating beta-hydroxyisovalerylshiderivative inducing leukemia of gromwell root root HL-60 apoptosis; Another Asian puccoon composition β, beta-dimethyl-acryl A Kaning also be proved to Human Prostate Cancer Cells (DU145, PC-3, LNCaD) inhibited; And to the existing history that surpasses more than 20 years of the research of Radix Arnebiae extract antitumous effect, just their anti-tumor activity of isolating natural product is not high enough from Asian puccoon, still fails at present to use in clinical.Therefore the natural product that obtains from Radix Arnebiae extract is carried out structure of modification, it is higher therefrom to obtain activity, and toxicity is lower, the compound that is more suitable for using clinically.We are with β in the early time; beta-dimethyl-acryl A Kaning is a lead compound; it is carried out structure of modification; active testing result from a series of derivatives; in parent compound, introduce the thiophenol substituting group cytotoxic activity of compound is greatly improved, strong tens times to the specific activity parent compound of tumour cell.Further experimentation on animals shows, this compound can significantly suppress solid tumor in the mouse, and the generation of xenotransplantation knurl, growth and diffusion significantly suppress the microvascular generation of tumour, and do not see in the experimentation that significant toxic side effect appears in mouse, show the excellent development prospect.This result of study has also been given us very big prompting, and we guess that the introducing of fragrant sulfydryl may play a part very crucial to the activity raising of compound.For many years, we are absorbed in the research, and higher in the hope of obtaining activity, toxicity is lower, and the Asian puccoon naphthoquinone derivatives compound that is more suitable for using clinically is for the mankind's anticancer cause contributes.Summary of the invention
In years of researches; we find at β; it is higher that the antitumour activity of introducing the compound of the aryl mercapto groups with substituting group replacement on the parent of beta-dimethyl-acryl A Kaning compares the activity of introducing thiophenol substituting group compound, and toxicity is lower, has clinical value preferably.
The invention provides a kind of Asian puccoon naphthoquinone derivatives, and disclose the application of this derivative on the preparation antitumor drug.This derivative has as shown in the formula the structure shown in (I),
Wherein, R1 has the aryl sulfydryl that 1 substituting group replaces at least; R2 is H or has the aryl sulfydryl that 1 substituting group replaces at least; R3 is H or has the aryl sulfydryl that 1 substituting group replaces at least.
As preferred compound, the aryl in the described aryl sulfydryl is substituted-phenyl, naphthyl, contains 1-2 heteroatomic five-membered ring or contain 1-3 heteroatomic hexa-member heterocycle.
Described five-membered ring is furan nucleus, pyrrole ring or thiphene ring.
Described hexa-member heterocycle is pyridine ring or pyrimidine ring.
Aryl substituent in the described aryl sulfydryl is alkyl amide, C1-C4 alkyloyl, nitro, cyano group, halogen, trihalomethyl group, carboxyl or the C1-C4 alkoxy acyl of C1-4 alkyl, C1-4 alkoxyl group, amino, the single replacement of C1-6 or two replacement alkylamino radical, C1-C4.
Aryl substituent in the described aryl sulfydryl is specially methyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino, diethylin, kharophen, ethanoyl, fluorine, bromine, chlorine, trifluoromethyl, methoxy acyl group or ethoxy acyl group.
Aryl substituent in the described aryl sulfydryl is 1-3.
Prove that by experiment above-mentioned Asian puccoon naphthoquinone derivatives or its salt all have stronger anti-tumor activity, can be applied to preparing anti-tumor medicine.Such medicine contains Asian puccoon naphthoquinone derivatives of the present invention or salt, also can comprise the still acceptable auxiliary of pharmacy.This medicine can be made formulations such as injection, tablet, emulsion, pill, suppository, capsule or suspension agent.
Asian puccoon naphthoquinone derivatives of the present invention can obtain by the method for chemosynthesis, and common Asian puccoon naphthoquinone derivatives of the present invention can obtain by following prepared in reaction.
In organic solvent, with β, beta-dimethyl-acryl A Kaning; be that formula (II) compound is a raw material,, refer to that mainly the aryl thiophenol derivatives reaction that replaces obtains compound (I) with nucleophilic reagent; temperature of reaction is-40-100 ℃, and optimal reaction temperature is a room temperature.R1 in the reaction formula, R2, the definition cotype (I) of R3
Starting material compound can be with reference to Zhi-Shu Huang, etc, and European Journal ofMedicinal Chemistry, 39, (2004), 755-764 extracts preparation.
According to this synthetic method, but synthetic compound is as shown in table 1:
The structure and the title of table 1 gained compound
To above-mentioned other Gronwell naphthaquinone derivatives of mentioning of the present invention, can utilize the method for this chemosynthesis to obtain.
Asian puccoon naphthoquinone derivatives of the present invention is carried out biological active testing, the result shows: introduce substituted aryl thiophenol substituting group in parent compound the cytotoxic activity of compound is greatly improved, the raising degree is relevant with substituent character, it is less that electron-withdrawing substituent, alkyl substituent and halogen replace the active degree of raising, strong power supplying groups is strong tens times to the specific activity parent compound of tumour cell as hydroxyl, amino, kharophen etc.Further experimentation on animals shows, this compound can significantly suppress solid tumor in the mouse, and the generation of xenotransplantation knurl, growth and diffusion significantly suppress the microvascular generation of tumour, and do not see in the experimentation that significant toxic side effect appears in mouse.This result of study has also been given us very big prompting, and the introducing of substituted aroma sulfydryl plays a part very crucial to the activity raising of compound.Therefore we introduce various substituted aroma mercapto groups at β on the parent of beta-dimethyl-acryl A Kaning, and present result shows that the anti-tumor activity of improved compound significantly strengthens than the active of benzene sulfhydryl compound, has the excellent development prospect.
Embodiment
Embodiment 1 ZC-5a, ZC-5b's is synthetic
0.11g (0.3mmol) A Kaning is dissolved in the 10ml methyl alcohol, adds 0.075g (0.6mmol) p-aminophenyl thiophenol, stirring at room reaction 24h.TLC monitors reaction.Reaction removes reaction solvent under reduced pressure after finishing, and column chromatography obtains the mixture of a pair of isomer ZC-5a and ZC-5b.
With the aryl thiophenol nucleophilic reagent of following different replacement, adopt the method identical with embodiment 1, can synthesize corresponding compound, as shown in table 2:
The pairing Compound I of the different substituted aryl thiophenols of table 2
Hydrogen is composed, mass-spectrometric data is as shown in table 4.
Embodiment 2:ZC-1a, ZC-1b's is synthetic
0.11g (0.3mmol) A Kaning is dissolved in the 10ml methyl alcohol, adds 0.087g (0.6mmol), stirring at room reaction 24h chlorothio-phenol.TLC monitors reaction.Reaction is separated out solid after finishing, and suction filtration obtains the mixture 0.105g of a pair of isomer ZC-1a and ZC-1b, productive rate 63%.
With the aryl thiophenol nucleophilic reagent of following different replacement, adopt the method identical with embodiment 2, can synthesize corresponding compound, as shown in table 3:
The pairing Compound I I of the different substituted aryl thiophenols of table 3
Hydrogen spectrum, mass-spectrometric data such as table 4.
Embodiment 3:ZC-3a, ZC-3b's is synthetic
0.11g (0.3mmol) A Kaning is dissolved in the 10ml acetone, adds 0.074g (0.6mmol), stirring at room reaction 24h the methylbenzene thiophenol.TLC monitors reaction.Reaction removes reaction solvent under reduced pressure after finishing, and column chromatography obtains the mixture 0.108g of a pair of isomer ZC-3a and ZC-3b, productive rate 70%.
Embodiment 4:ZC-6a, ZC-6b's is synthetic
0.11g (0.3mmol) A Kaning is dissolved in the 10ml acetonitrile, adds 0.077g (0.6mmol), stirring at room reaction 24h fluoro thiophenol.TLC monitors reaction.Reaction removes reaction solvent under reduced pressure after finishing, and column chromatography obtains the mixture 0.086g of a pair of isomer ZC-4a and ZC-4b, productive rate 55%.
Embodiment 5:ZC-8a, ZC-8b's is synthetic
0.11g (0.3mmol) A Kaning is dissolved in the 10ml ethyl acetate, adds 0.075g (0.6mmol) thiohydroquinone, stirring at room reaction 24h.TLC monitors reaction.Reaction removes reaction solvent under reduced pressure after finishing, and column chromatography obtains the mixture 0.095g of a pair of isomer ZC-4a and ZC-4b, productive rate 61%.
Embodiment 6:ZC-21a, ZC-21b's is synthetic
0.11g (0.3mmol) A Kaning is dissolved in the 10ml toluene, adds 0.084g (0.6mmol), stirring at room reaction 24h methoxybenzenethiol.TLC monitors reaction.Reaction removes reaction solvent under reduced pressure after finishing, and column chromatography obtains the mixture 0.1 of a pair of isomer ZC-4a and ZC-4b, productive rate 63%.
Embodiment 7:10c's is synthetic
0.11g (0.3mmol) A Kaning is dissolved in the 10ml methyl alcohol, adds 0.092g (0.6mmol) to Thiosalicylic acid ,-30 ℃ of stirring reaction 48h.TLC monitors reaction.Reaction removes reaction solvent under reduced pressure after finishing, and column chromatography obtains the mixture 0.038g of a pair of isomer ZC-4a and ZC-4b, productive rate 30%.
Embodiment 8:ZC-11a, ZC-11b's is synthetic
0.11g (0.3mmol) A Kaning is dissolved in the 10ml methyl alcohol, adds 0.1g (0.6mmol) acetparaminosalol thiophenol, 100 ℃ of stirring reaction 12h.TLC monitors reaction.Reaction removes reaction solvent under reduced pressure after finishing, and column chromatography obtains the mixture 0.076g of a pair of isomer ZC-4a and ZC-4b, productive rate 42%.
Table 4 gained compound hydrogen spectrum data
Embodiment 9: the anti-tumor activity test
National People's Congress's pneumonocyte cancer cells (SMMC-7721), human liver cancer cell (NCIH-460) is by the guarantor's strain of going down to posterity of Zhongshan University institute of oncology.
With the anti-tumor activity of mtt assay test compounds, the cell suspension of the corresponding cell strain in the vegetative period of taking the logarithm (making cell detachment) 0.5-1.0 * 10 through 0.25% tryptic digestion
5/ ml, be sub-packed in 96 well culture plates, 195 μ l/ holes, cultivate 24h, after treating cell attachment, the medicine or the test solution that add the corresponding different concns of 5 μ l respectively, experiment are established negative control group (physiological saline), solvent control group (it is 0.5 ‰ that adding 2%DMSO makes final concentration) and 6 different concns administration groups.Establish 4 parallel holes for every group.Put constant temperature 5%CO
2Incubator was cultivated 48 hours for 37 ℃, finish preceding 4 hours every holes in experiment and add 20 μ lMTT liquid (5mg/ml), draw nutrient solution after 4 hours, every hole adds 0.1ml DMSO, dull and stereotyped shaking table jolts the rearmounted enzyme connection of 5min dissolving to be crystallized detector, survey the OD value in each hole in the 570nm wavelength,, and obtain half-inhibition concentration IC with the Bliss method by the following formula long inhibiting rate of seeking survival
50
Medicine has passed through to cell in vitro poison experiment test the anti-tumor activity of compound to inhibition rate of tumor cell=(the average OD value of the average OD value/control group of 1-medication group) * 100%.The result is as shown in table 5:
Table 5: the cytotoxic activity of Asian puccoon naphthoquinone derivatives
Several compounds, especially ZC-5, ZC-11, ZC-22 are to the cytotoxicity IC of SMMC-7721 and NCIH-460
50All reached the level of 5 μ M, wherein ZC-11 has also reached the level of nM level to SMMC-7721.Its cytotoxic activity all has the meaning of further research.
Claims (10)
1. Asian puccoon naphthoquinone derivatives or its salt with general formula (I) structure,
It is characterized in that:
R1 has the aryl sulfydryl that 1 substituting group replaces at least;
R2 is H or has the aryl sulfydryl that 1 substituting group replaces at least;
R3 is H or has the aryl sulfydryl that 1 substituting group replaces at least.
2. Asian puccoon naphthoquinone derivatives as claimed in claim 1 or its salt is characterized in that, the aryl in the described aryl sulfydryl is substituted-phenyl, naphthyl, contains 1-2 heteroatomic five-membered ring or contain 1-3 heteroatomic hexa-member heterocycle.
3. Asian puccoon naphthoquinone derivatives as claimed in claim 2 or its salt is characterized in that, described five-membered ring is furan nucleus, pyrrole ring or thiphene ring.
4. Asian puccoon naphthoquinone derivatives as claimed in claim 3 or its salt is characterized in that, described hexa-member heterocycle is pyridine ring or pyrimidine ring.
5. Asian puccoon naphthoquinone derivatives as claimed in claim 1 or its salt; it is characterized in that the aryl substituent in the described aryl sulfydryl is alkyl amide, C1-C4 alkyloyl, nitro, cyano group, halogen, trihalomethyl group, hydroxyl, carboxyl or the C1-C4 alkoxy acyl of C1-4 alkyl, C1-4 alkoxyl group, amino, the single replacement of C1-6 or two replacement alkylamino radical, C1-C4.
6. Asian puccoon naphthoquinone derivatives as claimed in claim 5 or its salt; it is characterized in that the aryl substituent in the described aryl sulfydryl is specially methyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino, diethylin, kharophen, ethanoyl, fluorine, bromine, chlorine, trifluoromethyl, methoxy acyl group or ethoxy acyl group.
7. Asian puccoon naphthoquinone derivatives as claimed in claim 1 or its salt is characterized in that, the aryl substituent in the described aryl sulfydryl is 1-3.
8. the described Asian puccoon naphthoquinone derivatives of claim 1 or its salt application in the preparation antitumor drug.
9. a treatment cancer drug that contains Asian puccoon naphthoquinone derivatives as claimed in claim 1 or its salt is characterized in that described medicine is made injection, tablet, emulsion, pill, suppository, capsule or suspension agent.
10. the preparation method of Asian puccoon naphthoquinone derivatives as claimed in claim 1; it is characterized by: with β; beta-dimethyl-acryl A Kaning (II) is a raw material; contain the aryl thiophenol that one or more substituting groups replace with nucleophilic reagent and react, wherein to the definition of R1, R2, R3 with claim 1.
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| CN102659661A (en) * | 2012-04-20 | 2012-09-12 | 南京大学 | Synthetic method and application of shikonin derivative |
| CN103113335A (en) * | 2011-11-17 | 2013-05-22 | 复旦大学 | Benzoquinone compound and use thereof for preparing anti-tumour drug |
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| CN106810430A (en) * | 2016-11-30 | 2017-06-09 | 浙江师范大学 | A kind of preparation method of the naphthoquinone derivatives of 2 trifluoromethyl 1,4 |
| CN107721893A (en) * | 2017-10-30 | 2018-02-23 | 黑龙江八农垦大学 | Naphthoquinone compound of 2 naphthalene sulfydryl, 5,8 dimethoxy 1,4 and preparation method thereof and the medicine containing it |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103113335A (en) * | 2011-11-17 | 2013-05-22 | 复旦大学 | Benzoquinone compound and use thereof for preparing anti-tumour drug |
| CN103113335B (en) * | 2011-11-17 | 2015-06-17 | 复旦大学 | Benzoquinone compound and use thereof for preparing anti-tumour drug |
| CN102659661A (en) * | 2012-04-20 | 2012-09-12 | 南京大学 | Synthetic method and application of shikonin derivative |
| CN104130164A (en) * | 2014-07-09 | 2014-11-05 | 上海交通大学 | Racemic alkannin naphthazarin parent nucleus hydroxymethyl sodium sulfonate derivative |
| CN104130164B (en) * | 2014-07-09 | 2016-05-04 | 上海交通大学 | Racemic modification alkannin naphthazarine mother parent nucleus HM sodium sulfonate derivative |
| CN106810430A (en) * | 2016-11-30 | 2017-06-09 | 浙江师范大学 | A kind of preparation method of the naphthoquinone derivatives of 2 trifluoromethyl 1,4 |
| CN106810430B (en) * | 2016-11-30 | 2019-07-30 | 浙江师范大学 | A kind of 2- Trifluoromethyl-1, the preparation method of 4- naphthoquinone derivatives |
| CN107721893A (en) * | 2017-10-30 | 2018-02-23 | 黑龙江八农垦大学 | Naphthoquinone compound of 2 naphthalene sulfydryl, 5,8 dimethoxy 1,4 and preparation method thereof and the medicine containing it |
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