CN103848828A - Application of oxadiazole derivatives in anti-cancer drugs - Google Patents
Application of oxadiazole derivatives in anti-cancer drugs Download PDFInfo
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- 150000004866 oxadiazoles Chemical class 0.000 title claims abstract description 15
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 7
- 229940126214 compound 3 Drugs 0.000 claims description 7
- 239000007795 chemical reaction product Substances 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims description 3
- BSVYLJCOTFYPSN-UHFFFAOYSA-N 5h-furo[3,2-c]pyrazole Chemical class N1=NC2=CCOC2=C1 BSVYLJCOTFYPSN-UHFFFAOYSA-N 0.000 claims description 3
- 150000001565 benzotriazoles Chemical class 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 235000010288 sodium nitrite Nutrition 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 20
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 208000019065 cervical carcinoma Diseases 0.000 abstract description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 abstract description 2
- 201000009030 Carcinoma Diseases 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 14
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 10
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 description 8
- 235000015097 nutrients Nutrition 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 238000013016 damping Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- -1 pHGF (HGF) Proteins 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 239000012737 fresh medium Substances 0.000 description 2
- 102000006495 integrins Human genes 0.000 description 2
- 108010044426 integrins Proteins 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- ILUJQPXNXACGAN-UHFFFAOYSA-N ortho-methoxybenzoic acid Natural products COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- MXNBDFWNYRNIBH-UHFFFAOYSA-N 3-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC(F)=C1 MXNBDFWNYRNIBH-UHFFFAOYSA-N 0.000 description 1
- TUXYZHVUPGXXQG-UHFFFAOYSA-N 4-bromobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1 TUXYZHVUPGXXQG-UHFFFAOYSA-N 0.000 description 1
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 1
- 102000013585 Bombesin Human genes 0.000 description 1
- 108010051479 Bombesin Proteins 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241001062009 Indigofera Species 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 208000033781 Thyroid carcinoma Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- DNDCVAGJPBKION-DOPDSADYSA-N bombesin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1NC2=CC=CC=C2C=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1NC(=O)CC1)C(C)C)C1=CN=CN1 DNDCVAGJPBKION-DOPDSADYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 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 1
- 238000012827 research and development Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention discloses an oxadiazole derivative. The oxadiazole derivative is characterized by having the general formula shown in the specification, wherein R is one of groups shown in the specification. The oxadiazole derivative disclosed by the invention has an obvious inhibitory effect on human cervical carcinoma cells (Hela) and hepatoma carcinoma cells (HepG2), so that the oxadiazole derivative disclosed by the invention can be applied in preparation of anti-cancer drugs. The invention discloses a preparation method of the oxadiazole derivative.
Description
Technical field
She of the present invention is Ji oxadiazole analog derivative and preparation method thereof and purposes.
background technology
Oxadiazole is a class raw material conventional on medicine industry, can derive furodiazole derivative.It has significant biological activity, is the focus of pharmaceutical chemistry area research always, is widely used in clinically the treatment of tumor disease.Selectively acting has become the important directions of current antitumor drug research and development in efficient, the low toxicity of specific target spot, the new type anticancer medicine of high specificity.So far, existing ten multiple protein tyrosine kinase inhibitors and antibody enter the I-II clinical trial phase stage, and individual other goes on the market, and obtained challenging treatment result.
FAK has expression in different tissues, and the expression in pernicious metastatic tumour is high especially.The expression of FAK in different tumor tissues is different, and in the generating process of prostate cancer, mammary cancer, colorectal carcinoma, ovarian cancer, oral carcinoma and thyroid carcinoma, the expression of FAK is improved.Especially in mammary cancer and colon cancer tissue, FAK expresses high.Bombesin, pHGF (HGF), prolactin antagonist etc. can stimulate the expression of FAK in tumour cell.FAK does not have classical cancer protein function, but it participates in all playing an important role in tumor development process and transfer process in integrin signaling transduction and integrin, this means that FAK may become for a target spot in malignant cell diverse development process
Summary of the invention
The object of the present invention is to provide Yi Lei oxadiazole analog derivative and their preparation method and purposes.
Technical scheme of the present invention is as follows:
1. a class oxadiazole analog derivative, is characterized in that it has following general formula:
In formula, R is:
A method for making for Shang Shu oxadiazole analog derivative, it is made up of the following step:
Step 1. adds O-Phenylene Diamine and appropriate organic solvent in reaction vessel, stirring makes it to dissolve, add again appropriate Sodium Nitrite, reflux for some time (follows the tracks of and reacts with TLC, until at least one raw material does not seldom even have), the PH of product is adjusted to 4.4-4.6 with 40% sodium hydroxide solution, then with sodium chloride solution washing, last recrystallization obtains compound 2 benzotriazoles.
Step 2. is by synthetic above compound 2 and ethyl chloroacetate, salt of wormwood mixes to join in appropriate organic solvent and dissolves, and reflux for some time, (follows the tracks of and reacts with TLC, have two kinds of products) boil off machine solvent with Rotary Evaporators, use column chromatography and obtain compound 3
Step 3. is dissolved in synthetic compound 3 in organic solvent, drips hydrazine hydrate in ice-water bath, stirs 2～10 hours in ice bath, and adularescent solid is separated out, and white solid is filtered out and obtains compound 4.
Step 4. is dissolved in compound 4 in organic solvent, then adds wherein the toluylic acid containing various different substituents, reflux 5～10 hours.Reaction product solution is adjusted to suitable pH value with solution of potassium carbonate, has solid to separate out, filtration can obtain end product.
Oxadiazole analog derivative of the present invention has obvious restraining effect to cervical cancer cell (Hela) and liver cancer cell (HepG2), and therefore oxadiazole analog derivative of the present invention can be applied to and prepare antitumor drug.
Embodiment
Embodiment mono-: 2-((1H-benzo[d] [1,2,3] triazol-1-yl) methyl)-5-(3-chlorophenyl)-1,3, the preparation of 4-oxadiazole (compound 1)
Step 1. adds O-Phenylene Diamine and appropriate organic solvent in reaction vessel, stirring makes it to dissolve, add again appropriate Sodium Nitrite, reflux for some time (follows the tracks of and reacts with TLC, until at least one raw material does not seldom even have), the PH of product is adjusted to 4.4-4.6 with 40% sodium hydroxide solution, then with sodium chloride solution washing, last recrystallization obtains compound 2 benzotriazoles.
Step 2. is by synthetic above compound 2 and ethyl chloroacetate, salt of wormwood mixes to join in appropriate organic solvent and dissolves, and reflux for some time, (follows the tracks of and reacts with TLC, have two kinds of products) boil off machine solvent with Rotary Evaporators, use column chromatography and obtain compound 3
Step 3. is dissolved in synthetic compound 3 in organic solvent, drips hydrazine hydrate in ice-water bath, stirs 5～6 hours in ice bath, and adularescent solid is separated out, and white solid is filtered out and obtains compound 4.
Step 4. is dissolved in compound 4 in organic solvent, then adds m-chlorobenzoic acid wherein, reflux 7～8 hours.Reaction product solution is adjusted to suitable pH value with solution of potassium carbonate, has solid to separate out, filtration can obtain end product.Mp?240-242℃.
1H-NMR(300MHz，DMSO，δppm)：6.09(s，2H)，6.45(d，J＝15.64Hz，1H)，7.09-7.15(m，3H)，7.17-7.44(m，3H)，7.82(d，J＝8.14，2H)，12.04(s，1H).MS(ESI)：332.05([M+H]
+).Anal.calc.for?C
16H
13NO
5S：C，58.00；H，3.95；N，4.23％；found：C，58.02；H，3.97；N，4.26％。
Embodiment bis-: 2-((1H-benzo[d] [1,2,3] triazol-1-yl) methyl)-5-(3-fluorophenyl)-1,3, the preparation of 4-oxadiazole (compound 2)
Preparation method is with embodiment mono-.So that m-fluorobenzoic acid is replaced to m-chlorobenzoic acid, obtain white powder target compound.Productive rate 61%.Mp?230-232℃.
1H-NMR(300MHz，DMSO，δppm)：5.6303(s，2H)，7.3920-7.4664(m，2H)，7.5493-7.6298(m，3H)，7.7078-7.7334(m，1H)，8.0437-8.0717(m，2H).MS(ESI)：346.37([M+H]+).Anal.calc.for?C15H10FN5O，C，61.02；H，3.41；F，6.43；N，23.72；O，5.42％。found：C，61.04；H，3.39；N，23.74％。
Embodiment tri-: 2-((1H-benzo[d] [1,2,3] triazol-1-yl) methyl)-5-(3-methoxyphenyl)-1,3, the preparation of 4-oxadiazole (compound 3)
Preparation method is with embodiment mono-.Replace m-chlorobenzoic acid with a methoxy benzoic acid, obtain white powder target compound.Productive rate 62%.Mp?235-237℃.
1H-NMR(300MHz，DMSO，δppm)：3.4522-3.5814(m，2H)，3.5814-3.7381(m，3H)，5.4303-56065(m，2H)，6.7770-6.8026(m，1H)，7.1677-7.2195(m，1H)，7.2195-7.5274(m，1H)，7.5755-7.7895(m，1H).MS(ESI)：307.31([M+H]
+).Anal.calc.for?C16H13N5O2：C，62.53；H，4.26；N，22.79；O，10.41％；found：C，62.54；H，4.24；N，22.80％。
Embodiment tetra-: 2-((1H-benzo[d] [1,2,3] triazol-1-yl) methyl)-5-(4-nitrophenyl)-1,3, the preparation of 4-oxadiazole (compound 4)
Preparation method is with embodiment mono-.Replace m-chlorobenzoic acid with p-nitrobenzoic acid, obtain white powder target compound.Productive rate 63%.Mp?240-242℃.
1H-NMR(300MHz，DMSO，δppm)：7.4225-7.8163(m，5H)，7.816-7.8663(m，4H)，8.80498-8.80778(m，1H).MS(ESI)：366.01([M+H]
+).Anal.calc.for?C15H10N6O3：C，55.90；H，3.13；N，26.08；O，14.89％；found：C，55.92；H，3.15；N，26.30％。
Embodiment five: 2-((1H-benzo[d] [1,2,3] triazol-1-yl) methyl)-5-(4-bromophenyl)-1,3, the preparation of 4-oxadiazole (compound 5)
Preparation method is with embodiment mono-.Replace m-chlorobenzoic acid with parabromobenzoic acid, obtain white powder target compound.Productive rate 63%.Mp?240-242℃.
1H-NMR(300MHz，DMSO，δppm)：6.3795(s，2H)，7.2750-7.3163(m，2H)，7.4237-7.4597(m，3H)，7.4719-7.4963(m，1H)，7.4963-7.5115(m，1H)；8.0754-8.1034(m，1H).MS(ESI)：411.96([M+H]
+).Anal.calc.for?C15H10BrN5O：C，50.58；H，2.83；Br，22.43；N，19.66；O，4.49％；found：C，50.57；H，2.85；N，19.68％。
Embodiment six: 2-((1H-benzo[d] [1,2,3] triazol-1-yl) methyl)-5-(2-methoxyphenyl)-1,3, the preparation of 4-oxadiazole (compound 7)
Preparation method is with embodiment mono-.Replace m-chlorobenzoic acid with adjacent methoxy benzoic acid, replace benzsulfamide with para toluene sulfonamide, obtain white powder target compound.Productive rate 64%.Mp?230-232℃.
1H-NMR(300MHz，DMSO，δppm)：6.3953-6.4868(m，3H)，7.1208-7.2336(m，1H)，7.2336-74451(m，4H)，7.5585-7.7541(m，2H)，7.7797-7.9687(m，1H)，7.9407-7.9687(m，1H)，8.1010-8.1284(m，1H).MS(ESI)：307.31([M+H]
+).Anal.calc.for?C16H13N5O2：C，62.53；H，4.26；N，22.79；O，10.41％；found：C，62.55；H，4.28；N，22.80％。
Embodiment seven: oxadiazole analog derivative anti tumor activity in vitro researchs
Adopt MTT[3-(4,5)-bis-methyl-2-thiazole-(2,5)-phenyl bromination tetrazole indigo plant] method measures the half-inhibition concentration (IC of oxadiazoles azole derivative to cervical cancer cell strain (Hela) and hepatoma cell strain (HepG2)
50).
(1) preparation of nutrient solution (every liter): 1. suspension cell: RPMI-1640 cultivates one bag, powder (10.4g), new-born calf serum 100ml, penicillin solution (200,000 U/ml) 0.5ml, Streptomycin sulphate solution (200,000 U/ml) 0.5ml, add after tri-distilled water dissolving, with 5.6% NaHCO
3solution adjusts pH value to 7.2-7.4, is finally settled to 1000ml.Filtration sterilization.2. attached cell: the same, then add NaHCO
32.00g, HEPES 2.38g.
(2) preparation of D-Hanks damping fluid (every liter): NaCl 8.00g, KCl 0.40g, Na
2hPO
412 H
2o 0.06g, KH
2pO
40.06g, NaHCO
30.35g.Autoclaving.
(3) preparation of trypsin solution: utilizing D-Hanks damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(4) preparation of experiment liquid: test sample is dissolved and is made into storing solution with a small amount of tri-distilled water, general by 10 times of preparation storing solutions of experiment maximum concentration.According to compound dissolution difference, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, then adds tri-distilled water and dissolve.The concentration of DMSO in nutrient solution is unsuitable excessive, and in the every porocyte suspension after dosing, the final concentration of DMSO is generally no more than 0.05%-0.1%.Storing solution is stored in-20 DEG C of refrigerators for subsequent use.
(5) cultivation of human cervical carcinoma cell Hela and liver cancer cell HepG: be adherent growth cell, cellar culture is (containing 10% foetal calf serum, 100U/ml Streptomycin sulphate) in DMEM nutrient solution, is placed in 37 DEG C, 5%CO
2in incubator, cultivate, went down to posterity once every 1-2 days.While going down to posterity, nutrient solution in former bottle is transferred in centrifuge tube, the centrifugal 5min of 1000rpm, discard original fluid, add equivalent fresh medium, piping and druming evenly, pipette in right amount to fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(6) cell is hatched: the tumour cell in the vegetative period of taking the logarithm, tune concentration of cell suspension is 1-1.5 × 10
5individual ml
-1.In 96 well culture plates, every hole adds cell suspension 100 μ l, puts 37 DEG C, 5%CO
2in incubator, cultivate 24h.Cultivate after 24h, add liquid by design respectively.
(8) dosing: test liquid is joined respectively in each hole according to the concentration gradient of ultimate density, and each concentration is established 6 parallel holes.Experiment is divided into drug test group (adding respectively the test medicine of different concns), 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).96 orifice plates after dosing are placed in to 37 DEG C, 5%CO
2in incubator, cultivate 48h.The activity of positive control medicine is measured according to the method for test sample.
(9) mensuration of survivaling cell: having cultivated in 96 orifice plates after 24h, every hole adds MTT 40 μ l (being made into 4mg/ml with D-Hanks damping fluid).Place after 4h at 37 DEG C, remove supernatant liquor.Every hole adds 150 μ l DMSO, and vibration 5min, makes formazan dissolving crystallized.Finally, utilize automatic microplate reader to detect the optical density(OD) (OD value) in each hole at 570nm wavelength place.
The calculating of inhibiting rate: the inhibiting rate of Growth of Cells calculates according to the following formula:
Growth inhibition ratio=(1-survival rate) × 100%=[1-(OD
experiment-OD
blank)/(OD
contrast-OD
blank)] × 100% (OD
experimentrepresent the average optical of testing drug group, OD
contrastrepresent the average optical of control group, OD
blankrepresent the average optical of control group).
Half-inhibition concentration (IC
50) be defined as the drug level in the time of the survival of 50% tumour cell.According to the optical density(OD) (OD value) of measuring, make the typical curve of inhibitory rate of cell growth, on typical curve, try to achieve its corresponding drug level.
The IC recording
50be shown in Table 1.
The inhibition IC to tumour cell of the listed sulfonamides compound of table 1 the present invention
50value (μ g/ml)
Claims (3)
1. a class oxadiazole analog derivative, is characterized in that it has following general formula:
In formula, R is:
2. a method for making for furodiazole derivative claimed in claim 1, is characterized in that it is made up of the following step:
Step 1. adds O-Phenylene Diamine and appropriate organic solvent in reaction vessel, stirring makes it to dissolve, add again appropriate Sodium Nitrite, reflux for some time (follows the tracks of and reacts with TLC, until at least one raw material does not seldom even have), the PH of product is adjusted to 4.4-4.6 with 40% sodium hydroxide solution, then with sodium chloride solution washing, last recrystallization obtains compound 2 benzotriazoles.
Step 2. is by synthetic above compound 2 and ethyl chloroacetate, salt of wormwood mixes to join in appropriate organic solvent and dissolves, and reflux for some time, (follows the tracks of and reacts with TLC, have two kinds of products) boil off machine solvent with Rotary Evaporators, use column chromatography and obtain compound 3
Step 3. is dissolved in synthetic compound 3 in organic solvent, in ice-water bath, drip hydrazine hydrate, in ice bath, stir 5～6 hours, adularescent solid is separated out, white solid is filtered out and obtains compound 4. steps 4. compound 4 is dissolved in organic solvent, add wherein again the toluylic acid containing various different substituents, reflux 7～8 hours.Reaction product solution is adjusted to suitable pH value with solution of potassium carbonate, has solid to separate out, filtration can obtain end product.
According to the furodiazole derivative described in claim in the application of preparing in antitumor drug.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110872299B (en) * | 2019-11-19 | 2022-09-30 | 广州中医药大学(广州中医药研究院) | P-benzoquinone-bis-triazole core skeleton derivative and preparation method and application thereof |
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