CN101602707B - Naphthaline lactam derivative and application thereof in propagation suppression of tumor cells - Google Patents
Naphthaline lactam derivative and application thereof in propagation suppression of tumor cells Download PDFInfo
- Publication number
- CN101602707B CN101602707B CN2009100122506A CN200910012250A CN101602707B CN 101602707 B CN101602707 B CN 101602707B CN 2009100122506 A CN2009100122506 A CN 2009100122506A CN 200910012250 A CN200910012250 A CN 200910012250A CN 101602707 B CN101602707 B CN 101602707B
- Authority
- CN
- China
- Prior art keywords
- derivative
- naphthaline
- indoles
- benzo
- fork
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- -1 Naphthaline lactam Chemical class 0.000 title claims abstract description 17
- 210000004881 tumor cell Anatomy 0.000 title claims abstract description 17
- 230000001629 suppression Effects 0.000 title abstract description 5
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 43
- 230000004663 cell proliferation Effects 0.000 claims description 8
- 230000005764 inhibitory process Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 abstract description 26
- 206010006187 Breast cancer Diseases 0.000 abstract description 7
- 208000026310 Breast neoplasm Diseases 0.000 abstract description 7
- 238000002474 experimental method Methods 0.000 abstract description 7
- 238000000034 method Methods 0.000 abstract description 7
- 208000005718 Stomach Neoplasms Diseases 0.000 abstract description 6
- 206010017758 gastric cancer Diseases 0.000 abstract description 6
- 201000011549 stomach cancer Diseases 0.000 abstract description 6
- 125000003831 tetrazolyl group Chemical group 0.000 abstract description 6
- 230000004071 biological effect Effects 0.000 abstract description 3
- 208000019065 cervical carcinoma Diseases 0.000 abstract description 3
- 238000009833 condensation Methods 0.000 abstract description 3
- 230000005494 condensation Effects 0.000 abstract description 3
- 238000010189 synthetic method Methods 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 abstract description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000007336 electrophilic substitution reaction Methods 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 150000002466 imines Chemical class 0.000 abstract description 2
- 239000004215 Carbon black (E152) Substances 0.000 abstract 1
- 125000003277 amino group Chemical group 0.000 abstract 1
- 230000002349 favourable effect Effects 0.000 abstract 1
- 229930195733 hydrocarbon Natural products 0.000 abstract 1
- 150000002430 hydrocarbons Chemical class 0.000 abstract 1
- 150000003951 lactams Chemical class 0.000 abstract 1
- 201000007270 liver cancer Diseases 0.000 abstract 1
- 208000014018 liver neoplasm Diseases 0.000 abstract 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 1
- 125000002560 nitrile group Chemical group 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 52
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000012043 crude product Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 239000013078 crystal Substances 0.000 description 11
- 150000002475 indoles Chemical class 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 238000001291 vacuum drying Methods 0.000 description 9
- 238000010792 warming Methods 0.000 description 9
- 238000013019 agitation Methods 0.000 description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 6
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- RUEKPBLTWGFBOD-UHFFFAOYSA-N bromoethyne Chemical group BrC#C RUEKPBLTWGFBOD-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 4
- 235000014347 soups Nutrition 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 201000010881 cervical cancer Diseases 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 230000009036 growth inhibition Effects 0.000 description 3
- VJMRKWPMFQGIPI-UHFFFAOYSA-N n-(2-hydroxyethyl)-5-(hydroxymethyl)-3-methyl-1-[2-[[3-(trifluoromethyl)phenyl]methyl]-1-benzothiophen-7-yl]pyrazole-4-carboxamide Chemical compound OCC1=C(C(=O)NCCO)C(C)=NN1C1=CC=CC2=C1SC(CC=1C=C(C=CC=1)C(F)(F)F)=C2 VJMRKWPMFQGIPI-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 0 *CCN(c1cccc2c1c1ccc2)C1=C(C#N)C#N Chemical compound *CCN(c1cccc2c1c1ccc2)C1=C(C#N)C#N 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- PBVZQAXFSQKDKK-UHFFFAOYSA-N 3-Methoxy-3-oxopropanoic acid Chemical class COC(=O)CC(O)=O PBVZQAXFSQKDKK-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- VSPPAHXSTYFAGO-UHFFFAOYSA-N N#CC(C#N)=C1Nc2cccc3cccc1c23 Chemical compound N#CC(C#N)=C1Nc2cccc3cccc1c23 VSPPAHXSTYFAGO-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- PWSKHLMYTZNYKO-UHFFFAOYSA-N heptane-1,7-diamine Chemical compound NCCCCCCCN PWSKHLMYTZNYKO-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- PWXJULSLLONQHY-UHFFFAOYSA-N phenylcarbamic acid Chemical compound OC(=O)NC1=CC=CC=C1 PWXJULSLLONQHY-UHFFFAOYSA-N 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- ZRRGOUHITGRLBA-UHFFFAOYSA-N stattic Chemical compound [O-][N+](=O)C1=CC=C2C=CS(=O)(=O)C2=C1 ZRRGOUHITGRLBA-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
Landscapes
- Indole Compounds (AREA)
Abstract
The invention relates to a naphthaline lactam derivative and application thereof in the propagation suppression of tumor cells, belonging to the technical field of pharmaceutical chemistry. N aphthaline lactam is taken as a parent for the naphthaline lactam derivative takes, and a derivative with high biological activity base groups, such as acetylene bonds, nitrile groups, amine groups or acylamide structures, and the like is obtained respectively by synthetic methods of firstly using different alkylogen hydrocarbon to carry out dehydrogenating condensation to two-position carbonyl and a compound with active methylene, introducing different electrophilic substitution base groups by six positions and then carrying out substitution to the active hydrogen of one-position imine. An experiment of the naphthaline lactam derivative for the propagation suppression of tumor cells selects a tetrazolium reduction method and is carried out aiming at 7721 human body liver cancer cells, MCF-7 human body mammarycancer cells, Hela human body cervical carcinoma cells or BGC-823 human body stomach cancer cells; and a result indicates that the naphthaline lactam derivative has favorable activity and selectivity in the propagation suppression of the tumor cells.
Description
Technical field
The present invention relates to a class naphthalene lactam derivatives and the application on tumor cell proliferation suppresses thereof, belong to the pharmaceutical chemistry technical field.
Background technology
The naphthalene lactan has special biological activity with its special lactan structure, attracts bio-organic scholars' interest and concern always.Mari ' a L.Lo ' pez-Rodri ' guez etc. replace naphthalene lactan and 5-HT7R receptor acting with the N-of composition optimizes, its pKi value all less than 7.3 (mari ' a L.Lo ' pez-Rodri ' guez, et al.J.Med.Chem.2003,46,5638-5650).Yansong Gu etc. introduce 1 of alkyl replacement in 6 in naphthalene lactan, and 4-encircles heptamethylene diamine, has synthesized to be used to regulate 5-HT
2The naphthalene lactan series derivates of the disorderly or shortage of C acceptor (Gu et al.U.S.Patent 6,667,303B1).
Yet the inherent structure based on the naphthalene lactan is not easy to modify, though it has extensive and good biological activity, the naphthalene lactam derivatives quantity that has been seen in report at present is still limited.
Summary of the invention
In order to overcome deficiency of the prior art, the invention provides a class naphthalene lactam derivatives and the application on tumor cell proliferation suppresses thereof.With the naphthalene lactan is that parent is done further modification, in the hope of filtering out the novel derivative with stronger tumor cell proliferation inhibition activity.
Technical scheme of the present invention is: a class naphthalene lactam derivatives has chemical structure of general formula and is:
Wherein:
R
1For=C (CN)
2,=C (COOCH
3)
2,
R
2For-H ,-Cl ,-Br ,-CN or-NO
2
R
3For-CH
2CH
2C ≡ CH ,-CH
2CH
2Br ,-CH
2CH
2NH
2,
-CH
2CH
2NHCH
2CH
2N(CH
3)
2、-CH
2CH
2NHCH
2CH
2N(CH
2CH
3)
2、
-CH
2CH
2NCH
2CH
2CH
2CH
3Or
Described naphthalene lactam derivatives is mixed with the soup with different concns, with the tetrazolium reduction method 7721 human hepatoma cells, MCF-7 human breast cancer cell, Hela human body cervical cancer or BGC-823 Human Gastric Cancer cell are tested, method is by different tumor growth rates, the tumour cell that some amount is in logarithmic phase is inoculated in the 96 hole microtest plates with 90 μ l/ holes, add the soup 10 μ l/ holes that prepare after cultivating 24h, to each cell strain, each concentration is three multiple holes.Other establishes acellular zeroing hole.If the soup for preparing has color will do the acellular zeroing of corresponding liquor strength hole.Tumour cell is at 37 ℃, 5%CO
2Cultivate after 48 hours under the condition, add 5mg/ml tetrazole saline solution 20 μ l/ holes with the physiological saline preparation; Continue to cultivate after 4 hours, add three liquid, 50 μ l/ holes, in CO by 10% sodium laurylsulfonate-5% isopropylcarbinol-0.01mol/lHCl preparation
2Spend the night in the incubator.Survey the OD570 value with microplate reader then.Calculate the inhibiting rate of described naphthalene lactam derivatives by following formula to growth of cancer cells:
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value * 100%.
Described derivative is as follows: 2-[(1-propargyl-benzo [c, d] indoles)-2 (1H)-fork] propane dinitrile (derivative 1), 2-[(1-bromotrifluoromethane-benzo [c, d] indoles)-2 (1H)-fork] propane dinitrile (derivative 2), the 2-{[(2-amino-ethyl)-benzo [c, d] indoles]-2 (1H)-fork } propane dinitrile (derivative 3), (E)-N-{[1-(2-amino-ethyl)-benzo [c, d] indoles]-2 (1H)-fork }-4-N-methyl-p-nitroaniline (derivative 4), (E)-N-[(1-propargyl-benzo [c, d] indoles)-2 (1H)-fork]-4-N-methyl-p-nitroaniline (derivative 5), (E)-N-{[1-(2-amino-ethyl)-benzo [c, d] indoles]-2 (1H)-fork }-4-carboxyl aniline (derivative 6), (E)-N-[(1-propargyl-benzo [c, d] indoles)-2 (1H)-fork]-4-carboxyl aniline (derivative 7), 2-[(1-propargyl-benzo [c, d] indoles)-2 (1H)-fork] dimethyl malonate (derivative 8), 2-{[2-(N, N '-dimethyl-quadrol)-ethyl-benzo [c, d] indoles]-2 (1H)-fork } propane dinitrile (derivative 9), 2-{[2-(N, N '-diethyl-quadrol)-ethyl-benzo [c, d] indoles]-2 (1H)-fork } propane dinitrile (derivative 10), 2-[(2-butylamine-ethyl-benzo [c, d] indoles)-2 (1H)-fork] propane dinitrile (derivative 11), 2-[(2-piperazine-ethyl-benzo [c, d] indoles)-2 (1H)-fork] propane dinitrile (derivative 12), 2-[benzo [c, d] indoles-2 (1H)-fork] propane dinitrile (derivative 13), 2-[6-chloro-benzo [c, d] indoles-2 (1H)-fork] propane dinitrile (derivative 14), 2-[6-bromo-benzo [c, d] indoles-2 (1H)-fork] propane dinitrile (derivative 15), 2-[6-cyano group-benzo [c, d] indoles-2 (1H)-fork] propane dinitrile (derivative 16), 2-[6-nitro-benzo [c, d] indoles-2 (1H)-fork] propane dinitrile (derivative 17), (E)-N-[benzo [c, d] indoles-2 (1H)-fork]-4-N-methyl-p-nitroaniline (derivative 18), (E)-N-[6-nitro-benzo [c, d] indoles-2 (1H)-fork]-4-N-methyl-p-nitroaniline (derivative 19), (E)-N-[6-cyano group-benzo [c, d] indoles-2 (1H)-fork]-4-N-methyl-p-nitroaniline (derivative 20).
The synthetic method of described naphthalene lactam derivatives is as follows:
Derivative 1-8 synthetic was divided into for two steps and carries out:
Be raw material promptly, as solvent, add 1mLPOCl with benzene, toluene or chlorobenzene with the naphthalene lactan
3As dewatering agent, temperature of reaction selects to have the propane dinitrile or the propanedioic acid methyl esters of active methylene radical respectively between 100-120 ℃, perhaps has the aromatic primary amine of electron withdrawing group such as p-Nitroaniline or carboxyl aniline is carried out dehydrating condensation, the corresponding intermediate that obtains.Wherein, obtain derivative 13, obtain derivative 18 with the reaction of p-Nitroaniline with the reaction of propane dinitrile.
Above-mentioned intermediate with halogenated alkane such as bromine ethamine, bromoacetylene or ethylene dibromide reaction, is taken off the HBr product through behind the purifying accordingly, and reaction environment carries out complexity according to reaction and selects acetonitrile/t-BuOK system or DMF/NaOCH
3System.
Derivative 9-12 is to be raw material with derivative 2, and alkaline condition catalysis refluxes in acetonitrile with corresponding amine respectively, takes off HBr and obtains corresponding product.
Derivative 14-20 synthetic route is:
Be raw material still, respectively with SO with the naphthalene lactan
2Cl
2In acetate 50 ℃ down reaction 0-5h, with liquid Br
21, in the 2-ethylene dichloride 50 ℃ down reaction 0.5h or with dense HNO
3At dense H
2SO
4Middle ice bath is reaction 3h down, obtains R
2For-Cl ,-Br ,-NO
2Intermediate.
Above-mentioned intermediate and propane dinitrile/POCl
3100 ℃ of reactions, promptly get derivative 14,15,17.
6-nitro-1 in the above-mentioned intermediate, 8-naphthalene lactan is with p-Nitroaniline/POCl
3120 ℃ of reactions, promptly get derivative 19.
6-bromo-1 in the above-mentioned intermediate, 8-naphthalene lactan and CuCN react 4h under 130 ℃ in N-Methyl pyrrolidone (NMP), obtain 6-cyano group-1,8-naphthalene lactan.
6-cyano group-1,8-naphthalene lactan and propane dinitrile/POCl
3100 ℃ of reactions, promptly get derivative 16.
6-cyano group-1,8-naphthalene lactan and p-Nitroaniline/POCl
3120 ℃ of reactions, promptly get derivative 20.
(microculture tetrozolium, MTT) reduction method is carried out body outer suppressioning test to 7721 human hepatoma cells, MCF-7 human breast cancer cell, Hela human body cervical carcinoma cell and BGC-823 Human Gastric Cancer cell to derivative to tumour cell vitro inhibition growth activity experiment employing tetrazolium.
The invention has the beneficial effects as follows: this analog derivative is to be parent with the naphthalene lactan, respectively by earlier 2 carbonyls and the compound with active methylene radical being carried out dehydrogenative condensation with different halogenated alkanes, and 6 different electrophilic substitution groups of introducing, the synthetic method that the reactive hydrogen of 1 imines is replaced obtains the derivative that a class has acetylene bond, cyano group, amido or the contour biological active moiety of amide structure then.The experiment that this analog derivative suppresses tumor cell proliferation, be to select the tetrazolium reduction method for use, carry out at 7721 human hepatoma cells, MCF-7 human breast cancer cell, Hela human body cervical cancer or BGC-823 Human Gastric Cancer cell, the result shows that such naphthalene lactam derivatives has good activity and selectivity to suppressing tumor cell proliferation.
Embodiment
The present invention is described further below by embodiment.
Embodiment 1
2-[(1-propargyl-benzo [c, d] indoles)-2 (1H)-fork] propane dinitrile (derivative 1) synthetic:
(1) 1.69g naphthalene lactan (0.01mol), 0.6g propane dinitrile (0.01mol), 1.1mLPOCl
3Join in the 25mL two-mouth bottle, add 15mL toluene, be heated to 100 ℃ under the magnetic agitation, behind the isothermal reaction 4h, reaction solution is poured in the methyl alcohol, the cooling back is suction filtration directly, obtains the brown solid crude product.After the vacuum-drying, column chromatography separates crude product, obtains yellow continuous shape crystal 1.82g, productive rate 83%, fusing point:＞300 ℃.
ESI-HRMS (m/z): calculated value: 217.064, experimental value: 217.0639.
1HNMR(d6-DMSO，400MHz)：δ(ppm)：5.30(s，1H)，7.21(d，J＝7.2Hz，1H)，7.58(t，J
1＝7.6Hz，J
2＝8.0Hz，1H)，7.68(d，J＝8.0Hz，1H)，7.83(t，J
1＝8.0Hz，J
2＝7.2Hz，1H)，8.17(d，J＝8.0Hz，1H)，8.55(d，J＝8.0Hz，1H)。
(2) 0.217g derivative 13 (1mmol) is dissolved in 10mLDMF, add 0.067gNaOCH
3(1.2mmol), be warming up to 60 ℃ under the magnetic agitation after, drip the 1mL bromoacetylene, the thin plate chromatography is followed the tracks of reaction, behind about 45min, reacts completely.In refrigerative reaction solution impouring 150mL frozen water, with methylene dichloride water is extracted, use anhydrous MgSO
4After the dry organic phase, rotary evaporation obtains crude product.Column chromatography purification obtains golden yellow crystal 0.18g, productive rate 71%.Fusing point:＞300 ℃.
ESI-HRMS (m/z): calculated value: 255.0796, experimental value: 255.0797.
1HNMR(d6-DMSO，400MHz)：δ(ppm)：2.50(s，1H)，5.23(s，2H)，7.23(d，J＝7.2Hz，1H)，7.62(t，J
1＝8.0Hz，J
2＝7.2Hz，1H)，7.70(d，J＝8.4Hz，1H)，7.81(t，J
1＝8.0Hz，J
2＝8.4Hz，1H)，8.14(d，J＝8.0Hz，2H)，8.69(d，J＝7.6Hz，1H)。
Embodiment 2
2-[(1-bromotrifluoromethane-benzo [c, d] indoles)-2 (1H)-fork] propane dinitrile (derivative 2) synthetic:
(1mmol) is dissolved in the 10mL anhydrous acetonitrile with 0.217g derivative 13, adds 0.2g K
2CO
3, the 1mL ethylene dibromide, be heated to backflow under the magnetic agitation, the 5h afterreaction is complete, direct vacuum evaporation obtains solid crude product, washing final vacuum drying obtains yellow solid.Column chromatography purification obtains yellow crystals 0.175g, productive rate 80%, fusing point: 232.3 ℃.
ESI-HRMS (m/z): calculated value: 323.0058, experimental value: 323.0067.
1HNMR(CDCl3，400MHz)：δ(ppm)：3.83(t，J
1＝6.4Hz，J
2＝6.8Hz，2H)，4.85(t，J
1＝6.4Hz，J
2＝6.8Hz，2H)，7.25(d，J＝7.6Hz，1H)，7.61(t，J
1＝8.0Hz，J
2＝7.6Hz，1H)，7.70(d，J＝8.0Hz，1H)，7.82(t，J
1＝8.0Hz，J
2＝7.6Hz，1H)，8.15(d，J＝8.4Hz，2H)，8.71(d，J＝7.6Hz，1H)。
Embodiment 3
The 2-{[(2-amino-ethyl)-and benzo [c, d] indoles]-2 (1H)-fork } propane dinitrile (derivative 3) synthetic:
(1mmol) dissolves in 10mLDMF with 0.217g derivative 13, adds 0.134gNaOCH
3(2.4mmol), be warming up to 100 ℃, after reaction half hour, add the hydrobromate (1.2mmol) of 0.243g bromine ethamine, back flow reaction 4h.In refrigerative reaction solution impouring 150mL frozen water, with methylene dichloride water is extracted, use anhydrous MgSO
4After the dry organic phase, rotary evaporation obtains crude product.Column chromatography purification obtains yellow crystals 0.176g, productive rate 68%, fusing point: 213.2 ℃.
1HNMR(d6-DMSO，400MHz)：δ(ppm)：1.84(t，NH
2，2H)，2.54(m，NCH
2CH
2N，2H)，2.87(m，NCH
2CH
2N，2H)，6.32(d，J＝7.6Hz，1H)，6.54(t，J
1＝7.6Hz，J
2＝8.8Hz，1H)，7.54(d，J＝8.8Hz，1H)，7.34(d，J＝7.6Hz，1H)，7.35(t，J
1＝7.6Hz，J
2＝7.2Hz，1H)，7.82(d，J＝7.2Hz，1H)。
ESI-HRMS (m/z): calculated value: 260.1062, experimental value: 260.1045.
Embodiment 4
(E)-and N-{[1-(2-amino-ethyl)-benzo [c, d] indoles]-2 (1H)-fork }-4-N-methyl-p-nitroaniline (derivative 4) synthetic:
(1) 1.69g naphthalene lactan (0.01mol), 1.65g p-Nitroaniline (0.012mol) join in the 25mL two-mouth bottle, add the 10mL chlorobenzene, are heated to 120 ℃ under the magnetic agitation.In the reaction system that stirs, drip 1.1mLPOCl
3, behind the isothermal reaction 2h, it is brown that solution is, and behind the cool to room temperature, drips 2mL methyl alcohol to reaction solution, and after mixing and cooling off, directly suction filtration is washed with a large amount of methyl alcohol, washes, and obtains the red solid crude product.After the vacuum-drying, use the acetate recrystallization, obtain red crystals 2.62g, productive rate 90%.
(2) 0.289g derivative 18 (1mmol) is dissolved in the 10mL acetonitrile, add 0.269gt-BuOK (2.4mmol), be warming up to backflow, after reaction half hour, add the hydrobromate (1.2mmol) of 0.243g bromine ethamine, back flow reaction 5h.In refrigerative reaction solution impouring 150mL frozen water, suction filtration, vacuum-drying obtains crude product.Column chromatography purification obtains reddish-brown crystal 2 00mg, productive rate 60%, fusing point: 152.3-153.6 ℃.
1HNMR(d6-DMSO，400MHz)：δ(ppm)：2.05(t，NH
2，2H)，2.94(m，NCH
2CH
2N，2H)，3.07(m，NCH
2CH
2N，2H)，6.85(d，J＝7.6Hz，1H)，7.10(d，J＝7.6Hz，1H)，7.24(d，J＝8.4Hz，2H)，7.428(t，J
1＝8.0Hz，J
2＝7.6Hz，1H)，7.46(d，J＝7.6Hz，1H)，7.51(t，J
1＝7.6Hz，J
2＝8.4Hz，1H)，7.89(d，J＝8.0Hz，1H)，8.31(d，J＝8.4Hz，2H)。
ESI-HRMS (m/z): calculated value: 332.1273, experimental value: 332.1258.
Embodiment 5
E)-and N-[(1-propargyl-benzo [c, d] indoles)-2 (1H)-fork]-4-N-methyl-p-nitroaniline (derivative 5) synthetic:
(1mmol) dissolves in 10mLDMF with 0.289g derivative 18, adds 0.067gNaOCH
3(1.2mmol), be warming up to 80 ℃ under the magnetic agitation after, drip the 1mL bromoacetylene, the thin plate chromatography is followed the tracks of reaction, behind the 2h, reacts completely.In refrigerative reaction solution impouring 150mL frozen water, with methylene dichloride water is extracted, use anhydrous MgSO
4After the dry organic phase, rotary evaporation obtains crude product.Column chromatography purification obtains brown particle crystal 0.27g, productive rate 70%, fusing point: 170.5-171.8 ℃.
ESI-HRMS (m/z): calculated value: 327.1008, experimental value: 327.0988.
1HNMR(CDCl3，400MHz)：δ(ppm)：2.31(s，2H)，4.90(s，2H)，6.96(d，J＝7.2Hz，1H)，7.07(d，J＝7.2Hz，1H)，7.22(d，J＝8.8Hz，2H)，7.38(t，J
1＝7.6Hz，J
2＝8.0Hz，1H)，7.46(d，J＝8.4Hz，1H)，7.51(t，J
1＝8.8Hz，J
2＝7.2Hz，1H)，7.89(d，J＝8.0Hz，1H)，8.31(d，J＝8.8Hz，2H)。
Embodiment 6
(E)-and N-{[1-(2-amino-ethyl)-benzo [c, d] indoles]-2 (1H)-fork }-4-carboxyl aniline (derivative 6) synthetic:
(1) 1.69g naphthalene lactan (0.01mol), 1.63g para-amino benzoic acid (0.012mol) join in the 25mL two-mouth bottle, add the 10mL chlorobenzene, drip 1.1mLPOCl in the reaction system that stirs
3, under the magnetic agitation, behind the back flow reaction 4h. cool to room temperature, drip 2mL methyl alcohol to reaction solution, after mixing and cooling off, directly suction filtration is washed with a large amount of methyl alcohol, washes, and obtains the brown solid crude product.After the vacuum-drying, use the acetate recrystallization, obtain brown solid 1.7g, productive rate 59%.
(2) 0.288g step (1) gained intermediate (1mmol) is dissolved in the 10mL acetonitrile, add 0.269g t-BuOK (2.4mmol), be warming up to backflow, after reaction half hour, add the hydrobromate (1.2mmol) of 0.243g bromine ethamine, back flow reaction 5h.In refrigerative reaction solution impouring 150mL frozen water, use dichloromethane extraction, rotary evaporation obtains the brown crude product.Column chromatography purification obtains brown crystal 150mg, productive rate 45%, fusing point: 176.8-178.1 ℃.
ESI-HRMS (m/z): calculated value: 331.1231, experimental value: 331.1274.
1HNMR(d6-DMSO，400MHz)：δ(ppm)：2.14(t，NH
2，2H)，2.84(m，NCH
2CH
2N，2H)，2.98(t，NCH
2CH
2N，2H)，6.86(d，J＝7.2Hz，1H)，7.08(d，J＝7.2Hz，1H)，7.12(d，J＝8.8Hz，2H)，7.28(t，J
1＝8.0Hz，J
2＝7.2Hz，1H)，7.42(d，J＝8.4Hz，1H)，7.53(t，J
1＝7.2Hz，J
2＝8.4Hz，1H)，7.89(d，J＝8.0Hz，1H)，8.31(d，J＝8.8Hz，2H)，8.44(s，OH，1H)。
Embodiment 7
(E)-and N-[(1-propargyl-benzo [c, d] indoles)-2 (1H)-fork]-4-carboxyl aniline (derivative 7) synthetic:
The intermediate 0.288g (1mmol) of gained in derivative 6 steps (1) is dissolved in the 10mL acetonitrile, add 0.269gt-BuOK (2.4mmol), be warming up to backflow, after reaction half hour, drip the 1mL bromoacetylene, reaction 3h.In refrigerative reaction solution impouring 150mL frozen water, use dichloromethane extraction, rotary evaporation obtains brown crude product.Column chromatography purification obtains brown crystal 170mg, productive rate 52%.
ESI-HRMS (m/z): calculated value: 326.1055, experimental value: 326.1089.
1HNMR(d6-DMSO，400MHz)：δ(ppm)：2.31(s，1H)，4.89(s，NCH
2，2H)，6.96(d，J＝7.6Hz，1H)，7.07(d，J＝7.2Hz，1H)，7.22(d，J＝8.8Hz，2H)，7.38(t，J
1＝8.0Hz，J
2＝7.6Hz，1H)，7.46(d，J＝8.4Hz，1H)，7.51(t，J
1＝7.2Hz，J
2＝8.4Hz，1H)，7.89(d，J＝8.0Hz，1H)，8.31(d，J＝8.4Hz，2H)，8.5(s，OH，1H)。
Embodiment 8
2-[(1-propargyl-benzo [c, d] indoles)-2 (1H)-fork] dimethyl malonate (derivative 8) synthetic:
(1) 1.69g naphthalene lactan (0.01mol), 1.32g propanedioic acid two formicesters (0.01mol) join in the 25mL two-mouth bottle, add 15mL toluene, are heated to 120 ℃ under the magnetic agitation.In reaction system, dropwise drip 1.1mLPOCl
3, behind the isothermal reaction 4h, adding in the 2mL methyl alcohol to reaction system, after the cooling, directly suction filtration is washed with a large amount of methyl alcohol, and washing obtains the brown solid crude product.After the vacuum-drying, column chromatography separates crude product, obtains yellow crystals 1.55g, productive rate 54%.
(2) gained intermediate 0.283g (1mmol) dissolves in 10mLDMF in the step (1), adds 0.067gNaOCH
3(1.2mmol), be warming up to 100 ℃ under the magnetic agitation after, drip the 1mL bromoacetylene, reaction 2h.In refrigerative reaction solution impouring 150mL frozen water, suction filtration, vacuum-drying obtains crude product.Column chromatography purification obtains yellow crystals 0.2g, productive rate 63%, fusing point: 257.6 ℃.
1HNMR(d6-DMSO，400MHz)：δ(ppm)：1.88(s，1H)，3.75(s，NCH
2，2H)，6.58(d，J＝7.8Hz，1H)，7.15(t，J
1＝6.8Hz，J
2＝6.3Hz，1H)，7.17(d，J＝6.3Hz，1H)，7.52(d，J＝7.2Hz，1H)，7.45(t，J
1＝7.2Hz，J
2＝7.6Hz，1H)，7.63(d，J＝7.6Hz，1H)，4.76(s，OCH
3，6H)。
ESI-HRMS (m/z): calculated value: 321.1001, experimental value: 321.1045.
Embodiment 9
2-{[2-(N, N '-dimethyl-quadrol)-ethyl-benzo [c, d] indoles]-2 (1H)-fork } propane dinitrile (derivative 9), 2-{[2-(N, N '-diethyl-quadrol)-ethyl-benzo [c, d] indoles]-2 (1H)-fork } propane dinitrile (derivative 10), 2-[(2-butylamine-ethyl-benzo [c, d] indoles)-2 (1H)-fork] propane dinitrile (derivative 11), 2-[(2-piperazine-ethyl-benzo [c, d] indoles)-2 (1H)-fork] propane dinitrile (derivative 12) synthetic:
Get 0.324g derivative 2 (1mmol) and dissolve in the 10mL acetonitrile, add corresponding amine 2mmol and 2mL triethylamine, 60 ℃ of backflows, thin-layer chromatography is followed the tracks of reaction to fully, generally needs 20-30h.After having reacted, the refrigerative reaction solution is poured in the 150mL frozen water, used dichloromethane extraction, the anhydrous MgSO of organic phase
4Revolve after the drying to steam and obtain crude product.After the vacuum-drying, crude product obtains corresponding pure target derivative through column chromatography purification.
Derivative 9:
1HNMR (d6-DMSO, 400MHz): δ (ppm): 2.31 (s, NCH
3, 6H), 2.52 (t, NCH
2CH
2N, 2H), 2.70 (m, NCH
2CH
2N, 2H), 4.0 (m, NH, 1H), 2.82 (m, NCH
2CH
2N, 2H), 3.22 (t, NCH
2CH
2N, 2H), 7.32 (d, J=7.6Hz, 1H), 7.10 (t, J
1=7.6Hz, J
2=7.6Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.34 (d, J=8.8Hz, 1H), 7.17 (t, J
1=7.6Hz, J
2=8.0Hz, 1H), 7.75 (d, J=8.4Hz, 1H).
ESI-HRMS (m/z): calculated value: 331.1797, experimental value: 331.1763.
Derivative 10:ESI-HRMS (359.2145m/z), derivative 11:ESI-HRMS (316.1662m/z), derivative 12:ESI-HRMS (329.168m/z).
Embodiment 10
2-[6-chloro-benzo [c, d] indoles-2 (1H)-fork] propane dinitrile (derivative 14) synthetic:
(1) 1.69g naphthalene lactan (0.01mol) is dissolved in 25mL acetate fully, is warming up to 50 ℃, 0.8mLSO
2Cl
2(0.01mol) slowly drop to reaction solution, temperature of reaction system raises, and flavescence suddenly generates a large amount of solids, continues to stir 0.5h, direct suction filtration, exsiccant glassy yellow solid 1.90g, productive rate 94%.
(2) experimental technique is with the step (1) of derivative 1, productive rate 78%.
Derivative 12:ESI-HRMS (251.027m/z), fusing point＞300 ℃.
Embodiment 11
2-[6-bromo-benzo [c, d] indoles-2 (1H)-fork] propane dinitrile (derivative 15) synthetic:
(1) 1.69g naphthalene lactan (0.01mol) is dissolved in 20mL1, the 2-ethylene dichloride.Get 0.51mL liquid bromine (0.01mol) and be dissolved in 10mL1, the 2-ethylene dichloride.With this Br
2-ClCH
2CH
2The Cl system drops to reaction system, slowly is warming up to 50 ℃, reaction 3h.Cooling is left standstill, and directly suction filtration obtains yellow solid 2.05g, productive rate 83%, fusing point: 254.9 ℃.
(2) experimental technique is with the step (1) of derivative 1, productive rate 82%.
1HNMR(d6-DMSO，400MHz)：δ(ppm)：7.77(d，J＝7.6Hz，1H)，7.92(t，J
1＝7.6Hz，J
2＝8.4Hz，1H)，8.60(d，J＝8.0Hz，1H)，8.29(d，J＝8.4Hz，1H)，7.03(d，J＝8.0Hz，1H)，9.88(s，NH，1H)。
ESI-HRMS (m/z): calculated value: 297.9745, experimental value: 297.9711.
Embodiment 12
2-[6-cyano group-benzo [c, d] indoles-2 (1H)-fork] propane dinitrile (derivative 16) synthetic:
(1) with derivative 15 synthesis steps (1) gained intermediate 6-bromo-1,8-naphthalene lactan 1.24g (5mmol) is dissolved in 15mLN-methyl-2-pyrrolidone (NMP), stirs to add 0.627g cuprous cyanide (7mmol) down 130 ℃ of reactions of constant temperature 4h.In the reaction solution cooling back impouring 200mL frozen water, suction filtration is washed light green off with ammoniacal liquor, and drying obtains yellow solid 0.91g, productive rate 94%.
(2) experimental technique is with the step (1) of derivative 1, productive rate 75%.
1HNMR(d6-DMSO，400MHz)：δ(ppm)：7.82(d，J＝7.6Hz，1H)，7.99(t，J
1＝7.6Hz，J
2＝8.4Hz，1H)，8.63(d，J＝7.6Hz，1H)，8.34(d，J＝8.4Hz，1H)，7.12(d，J＝7.6Hz，1H)，9.95(s，NH，1H)。
ESI-HRMS (m/z): calculated value: 242.0592, experimental value: 242.0574.
Embodiment 13
2-[6-nitro-benzo [c, d] indoles-2 (1H)-fork] propane dinitrile (derivative 17) synthetic:
(1) 1.69g naphthalene lactan (0.01mol) is dissolved in the 10mL vitriol oil, ice-water bath makes temperature control be lower than 10 ℃, after stirring, drip the 2.4mL concentrated nitric acid to it, solution colour shoals, behind the reaction 3h, in reaction solution impouring frozen water, separate out yellow solid, suction filtration, vacuum-drying gets solid 19.0g, productive rate 89%.
(2) experimental technique is with the step (1) of derivative 1, productive rate 78%.
ESI-HRMS (m/z): calculated value: 262.0491, experimental value: 262.0434.
Embodiment 14
(E)-N-[6-nitro-benzo [c, d] indoles-2 (1H)-fork]-4-N-methyl-p-nitroaniline (derivative 19) synthetic:
Get derivative 17 synthesis steps (1) gained intermediate 6-nitro-1,8-naphthalene lactan, experimental implementation such as derivative 4 synthesis steps (1), productive rate 72%.
ESI-HRMS (m/z): calculated value: 334.0702, experimental value: 334.0775.
Embodiment 15
(E)-N-[6-cyano group-benzo [c, d] indoles-2 (1H)-fork]-4-N-methyl-p-nitroaniline (derivative 20) synthetic:
Get derivative 16 synthesis steps (1) gained intermediate 6-cyano group-1,8-naphthalene lactan, experimental implementation such as derivative 4 synthesis steps (1), productive rate 68%.
ESI-HRMS (m/z): calculated value: 314.0804, experimental value: 314.0844.
1HNMR(d6-DMSO，400MHz)：δ(ppm)：4.31(s，1H)，6.56(d，J＝7.2Hz，1H)，7.67(d，J＝7.2Hz，1H)，7.28(d，J＝8.8Hz，2H)，7.50(d，J＝8.4Hz，1H)，7.57(t，J
1＝7.6Hz，J
2＝8.4Hz，1H)，7.85(d，J＝8.0Hz，1H)，8.41(d，J＝8.8Hz，2H)。
Embodiment 16
Measure the extracorporeal suppression tumor cell growth activity of derivative:
(microculture tetrozolium, MTT) reduction method is carried out body outer suppressioning test to 7721 human hepatoma cells, MCF-7 human breast cancer cell, Hela human body cervical carcinoma cell and BGC-823 Human Gastric Cancer cell with tetrazolium.
The concrete operations of tetrazolium (MTT) reduction method are: by different tumor growth rates, the tumour cell 90 μ l/ holes that some amount are in logarithmic phase are inoculated in the 96 hole microtest plates, add soup 10 μ l/ holes after cultivating 24h, to each cell strain, each concentration is three multiple holes.Other establishes acellular zeroing hole.If medicine has color will do the acellular zeroing of relative medicine concentration hole.Tumour cell is at 37 ℃, 5%CO
2Cultivate after 48 hours under the condition, add MTT (Sigma) liquid 5mg/ml and prepare 20 μ l/ holes with physiological saline; Continue to cultivate after 4 hours, (the 50 μ l/ holes of 10%SDS-5% isopropylcarbinol-0.01mol/lHCl) are in CO to add three liquid
2Spend the night in the incubator.Survey the OD570 value with microplate reader then.Calculate the inhibiting rate of analyte by following formula to growth of cancer cells:
Tumor control rate=(control group OD value-treatment group OD value)/control group OD value * 100%
From table data as can be seen, derivative 3,4,9,19 shows good inhibition tumor cell proliferation activity, and 7 pairs 7721 human hepatoma cells of derivative, 11 couples of MCF-7 human breast cancer cells of derivative present optionally inhibited proliferation.
Table 1. derivative is to the growth inhibition ratio of 7721 human hepatoma cells
Table 2. derivative is to MCF-7 human breast cancer cell's growth inhibition ratio
Table 3. derivative is to the growth inhibition ratio of Hela human body cervical cancer
Table 4. derivative is to the growth inhibition ratio of BGC-823 Human Gastric Cancer cell
Claims (2)
1. a class naphthalene lactam derivatives, it is characterized in that: this analog derivative has chemical structure of general formula and is:
Wherein:
R
1For=C (CN)
2,=C (COOCH
3)
2,
R
2For-H ,-Cl ,-Br ,-CN or-NO
2
R
3For-CH
2CH
2C ≡ CH ,-CH
2CH
2Br ,-CH
2CH
2NH
2,-CH
2CH
2NHCH
2CH
2N (CH
3)
2,-CH
2CH
2NHCH
2CH
2N (CH
2CH
3)
2,-CH
2CH
2NCH
2CH
2CH
2CH
3Or
2. according to the application of the described class naphthalene lactam derivatives of claim 1 in preparation inhibition tumor cell proliferation medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100122506A CN101602707B (en) | 2009-06-23 | 2009-06-23 | Naphthaline lactam derivative and application thereof in propagation suppression of tumor cells |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100122506A CN101602707B (en) | 2009-06-23 | 2009-06-23 | Naphthaline lactam derivative and application thereof in propagation suppression of tumor cells |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101602707A CN101602707A (en) | 2009-12-16 |
| CN101602707B true CN101602707B (en) | 2011-08-31 |
Family
ID=41468622
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100122506A Expired - Fee Related CN101602707B (en) | 2009-06-23 | 2009-06-23 | Naphthaline lactam derivative and application thereof in propagation suppression of tumor cells |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101602707B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104072485B (en) * | 2014-06-04 | 2016-08-24 | 大连理工大学 | Containing triazole side chain benzo [c, d] indole-2 (1H)-one compounds and application thereof |
| CN106432219B (en) * | 2015-08-04 | 2019-04-05 | 大连理工大学 | Benzo [c, d] indoles -2 (1H) -one analog derivative of benzothiazole, preparation method and application |
| CN114349684B (en) * | 2022-01-19 | 2023-03-28 | 西南林业大学 | Synthetic method of benzo [ c, d ] indole imine derivative |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6667303B1 (en) * | 2001-07-30 | 2003-12-23 | Wyeth | Aryl substituted 1,4-diazepanes and method of use thereof |
-
2009
- 2009-06-23 CN CN2009100122506A patent/CN101602707B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6667303B1 (en) * | 2001-07-30 | 2003-12-23 | Wyeth | Aryl substituted 1,4-diazepanes and method of use thereof |
Non-Patent Citations (6)
| Title |
|---|
| ´ |
| a L.Lo´ |
| guez,et al.Optimization of the Pharmacophore Model for 5-HT7R Antagonism. Design and Synthesis of New Naphtholactam and Naphthosultam Derivatives.《Journal of Medicinal Chemistry》.2003,第46卷(第26期),5638-5650. |
| Marı |
| Marı´a L.Lo´pez-Rodrıguez,et al.Optimization of the Pharmacophore Model for 5-HT7R Antagonism. Design and Synthesis of New Naphtholactam and Naphthosultam Derivatives.《Journal of Medicinal Chemistry》.2003,第46卷(第26期),5638-5650. * |
| pez-Rodrı |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101602707A (en) | 2009-12-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106749282B (en) | A kind of preparation method for treating ovarian cancer Rucaparib intermediate | |
| CN106167490B (en) | Imidazo naphthalimide analog derivative and its synthesis and application of the one kind containing indoles | |
| CN106632379B (en) | A kind of Bergenin azepine cinnamate derivative compound and its synthetic method having anti-tumor activity | |
| CN110627801B (en) | HDAC inhibitor and application thereof | |
| CN104292170A (en) | Quinazolinyl-aryl urea derivatives with antitumor function and application thereof | |
| CN104072493B (en) | One class contains 2-mercaptobenzothiazole and the naphthalimide compound of triazole heterocycle, its preparation method and application thereof | |
| CN106432259B (en) | A kind of Bergenin analog derivative and its synthetic method and application | |
| CN101602707B (en) | Naphthaline lactam derivative and application thereof in propagation suppression of tumor cells | |
| CN114133390A (en) | Harmine derivative and preparation method and application thereof | |
| CN106831793A (en) | A kind of synthesis technique for treating ovarian cancer Rucaparib intermediates | |
| CN102321033A (en) | Preparation method of tarceva | |
| CN104262283B (en) | Application of 1,2-oxa-cyclic compound derivative for preparing myeloma treamtnet medicine | |
| CN106748989A (en) | A kind of diaryl urea compound with antitumor activity and its preparation method and application | |
| CN106188049B (en) | Dibenzo naphthyridones compound and its preparation method and application | |
| CN105924390B (en) | A kind of synthetic method of Mei Tafeini | |
| CN105693609B (en) | Polysubstituted phenyl alkylamino acridone -4- amides compound and its preparation method and application | |
| CN110963981B (en) | Benzothiazole aryl compound derivatives and preparation method thereof | |
| CN106478449A (en) | A kind of γ glutamic acid transferring enzyme fluorescent probe and its preparation and application | |
| CN108164469A (en) | A kind of method for preparing trione compounds | |
| CN109867709B (en) | Preparation method and application of glycyrrhetinic acid series derivatives (TOGA-X) with anti-tumor effect | |
| CN104844607A (en) | Tryptanthrin bromo derivative with antineoplastic activity and synthetic method therefor | |
| CN110526854A (en) | A kind of ɑ, alpha, beta-unsaturated ketone derivative, preparation method and the purposes as drug | |
| CN106588690B (en) | The preparation method of Holotrichia trichophora A prime Abrusamide | |
| CN105753864B (en) | A kind of 3 (hetero) aryl indole piperazine carboxamides derivatives and its preparation method and application | |
| CN103435574B (en) | Mercapto benzothiazole substituent acenaphtho-heterocycle compound and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110831 Termination date: 20140623 |
|
| EXPY | Termination of patent right or utility model |