CN103483256A - (-)-4-(2,3-dihydroxypropxyl)-methanamide-6-azabenzanthrone as well as synthesis method and application thereof - Google Patents
(-)-4-(2,3-dihydroxypropxyl)-methanamide-6-azabenzanthrone as well as synthesis method and application thereof Download PDFInfo
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Abstract
The invention discloses a chiral derivative of the oxoaporphinoid of a new single enantiomer, namely (-)-4-(2,3-dihydroxypropxyl)-methanamide-6-azabenzanthrone. A synthesis method for the (-)-4-(2,3-dihydroxypropxyl)-methanamide-6-azabenzanthrone comprises the steps as follows: weighing and dissolving 4-carboxyl-6-azabenzanthrone and (-)-3-amino-1,2-propanediol in N,N-dimethylacetamide; performing an amidation reaction under the catalysis of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP); loading a reaction product onto a silicon gel column to perform chromatography; eluting the reaction product by using a mixed solvent prepared from chloroform and methanol at the volume ratio of (10-200):1; evaporating and drying the mixed solvent with an eluant, and obtaining the (-)-4-(2,3-dihydroxypropxyl)-methanamide-6-azabenzanthrone. An applicant for the invention discovers that the (-)-4-(2,3-dihydroxypropxyl)-methanamide-6-azabenzanthrone has activity of inhibiting the propagation of various human tumor cell lines, particularly has the most remarkable antitumor activity in vitro to the BEL-7404, has higher potential medicinal value, and is likely to be used for preparing antitumor medicines. The structural formula of the (-)-4-(2,3-dihydroxypropxyl)-methanamide-6-azabenzanthrone is shown in the specification.
Description
Technical field
The present invention relates to medical technical field, be specifically related to a kind of chiral derivatives of oxidation aporphine alkaloid---(-)-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone and synthetic method and application.
Background technology
Oxoaporphinoid belongs to natural isoquinoline alkaloid, and it has physiologically active widely, has antitumor, anti-oxidant, antibiotic, antiviral isoreactivity, has good development prospect.At present, from the medicinal plants such as Magnoliaceae, Hernandiaceae, Rutaceae, annonaceae, isolate tens of kinds of natural oxidation aporphine alkaloids both at home and abroad, and its pharmacologically active is all remarkable.
Because the content of oxidation aporphine alkaloid in natural phant is extremely low, be unfavorable for carrying out further further investigation and exploitation.Therefore, the artificial organic synthesis research for the oxidation aporphine alkaloid is of great significance with regard to tool.The oxidation aporphine alkaloid the earliest by Schlittler in 1949, be synthesized (Schlittler E., Lindemann A.Helvetica Chimica Acta, 1949,32,1880-1891).In recent years, for pharmacologically active or the bioactivity research of oxidation aporphine alkaloid, carry out gradually both at home and abroad.(the Tang H. such as Tang Huang, Wei Y.B., Zhang C., Ning F.X., Qiao W., Huang S.L., Ma L., Huang Z.S., Gu L.Q.Eur.J.Med.Chem.2009,44,2523-2532) the oxidation aporphine alkali derivant that a series of 4-replace has been synthesized in design, and adopts mtt assay to test the oxidation aporphine derivative of synthesized to the NCI-H460(human lung carcinoma cell line), the GLC-82(human lung adenocarcinoma cell line), the strain of MCF-7(human breast cancer cell) anti tumor activity in vitro of three kinds of tumor lines.The experimental result demonstration, the half-inhibition concentration of majority of compounds is IC
50value is less than 10 μ mol/L, to the strain of MCF-7(human breast cancer cell) even reach 1 μ mol/L, show stronger cytotoxicity.
On the other hand, chirality is the essential characteristic of biosystem.Many endogenous material, comprise that enzyme, acceptor, carrier etc. all have chirality.The chiral environment of human body and special enantiomorph interact, and cause the stereoselective difference of enantiomers of chiral drugs on pharmacokinetics and pharmacodynamics, make the clinical application chiral drug complicacy occur.For example (+)-third oxygen sweet smell has analgesic effect, and (-)-third oxygen sweet smell has antitussive effect.Tranquilizer peptamine piperidone (Thalidomide, reaction stop) for pregnant antiemetic, but makes 6000 routine fetuses disable (sea dog) in west.Research is afterwards found, this is because this medicine comprises a pair of chirality enantiomorph, its stereoselectivity causes: the R-type has sedative effect, two meta-bolitess in S-type and body thereof have serious embryotoxicity and teratogenesis (Purser S., Moore P.R., Swallow S., Gouverneur V., Chem.Soc.Rev.2007,37,320.).In recent years, chiral drug is applied its single enantiomer medicine has clinically become trend.In view of situations such as the inherent pharmacologically actives of pharmaceutical production technology, cost and medicine, although should not require utterly all racemic drugs all to split into the single enantiomer medicine clinical on medicinal, should not deny that the single enantiomer medicine demonstrates the advantages such as security of better curative effect and Geng Gao than racemic modification.Yet there are no (-)-4-the relevant report of (2,3-dihydroxypropyl)-methane amide-this single enantiomer of 6-azepine benzanthrone and its synthetic method.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of chiral derivatives of oxidation aporphine alkaloid of new single enantiomer, i.e. (-)-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone, and its synthetic method and application.
(-) of the present invention-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone, its structural formula is shown below:
Above-mentioned (-)-4-(2, the synthetic method of the 3-dihydroxypropyl)-methane amide-6-azepine benzanthrone is: take 4-carboxyl-6-azepine benzanthrone and (-)-3-amino-1, the 2-propylene glycol, be dissolved in N, in the N-N,N-DIMETHYLACETAMIDE, carry out amidate action under the katalysis of phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl, silica gel column chromatography on reaction product, the mixed solvent wash-out that the chloroform that to use by volume ratio be 10～200:1 and methyl alcohol form, the elutriant solvent evaporated, obtain (-)-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone.
More specifically (-)-4-(2, the synthetic method of the 3-dihydroxypropyl)-methane amide-6-azepine benzanthrone is: the mol ratio by 1:0.5～4.0:0.5～5.0 takes 4-carboxyl-6-azepine benzanthrone, (-)-3-amino-1, 2-propylene glycol and phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl, by 4-carboxyl-6-azepine benzanthrone, (-)-3-amino-1, the 2-propylene glycol is dissolved in N, in the N-N,N-DIMETHYLACETAMIDE, slowly add wherein phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl, under 20～90 ℃ of conditions, stirring reaction is to complete, reaction solution removes N under reduced pressure, the N-N,N-DIMETHYLACETAMIDE, reaction product is used saturated sodium carbonate solution successively, methanol wash, silica gel column chromatography on residue, the mixed solvent wash-out that the chloroform that to use by volume ratio be 10～200:1 and methyl alcohol form, the elutriant solvent evaporated, obtain (-)-4-(2, the 3-dihydroxypropyl)-methane amide-6-azepine benzanthrone.
In synthetic method of the present invention, as raw material, use the 4-carboxyl-6-azepine benzanthrone can be with reference to existing document (Tang H., Wei Y.B., Zhang C., Ning F.X., Qiao W., Huang S.L., Ma L., Huang Z.S., Gu L.Q.Eur.J.Med.Chem.2009,44,2523-2532) method of middle report is synthesized.
In above-mentioned synthetic method, described N, the consumption of N-N,N-DIMETHYLACETAMIDE is can dissolve 4-carboxyl-6-azepine benzanthrone and (-)-3-amino-1, the 2-propylene glycol is advisable, generally, (-)-3-amino-1,2-PD of the 4-carboxyl of 1mol-6-azepine benzanthrone and 0.5～4.0mol dissolves by the N,N-dimethylacetamide of 50～200mL.In concrete dissolving step, after 4-carboxyl-6-azepine benzanthrone and (-)-3-amino-1,2-PD can being dissolved by N,N-dimethylacetamide respectively, remix reacts together; Also can dissolve after 4-carboxyl-6-azepine benzanthrone and (-)-3-amino-1,2-PD mixing, adding again N,N-dimethylacetamide.
To containing 4-carboxyl-6-azepine benzanthrone, (-)-3-amino-1, the 2-propylene glycol is dissolved in N, while adding phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl to be reacted in the N-N,N-DIMETHYLACETAMIDE, too violent for fear of reaction, normally by phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl N, the N-N,N-DIMETHYLACETAMIDE slowly adds after dissolving wiring solution-forming again, as long as the N,N-dimethylacetamide consumption is for can dissolve phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl.Too fierce and bring more by product in order to prevent from heating rear reaction, can allow 4-carboxyl-6-azepine benzanthrone and (-)-3-amino-1, the 2-propylene glycol is at solvent N, at room temperature first react for some time (being generally 10～120min) after mixing in the N-N,N-DIMETHYLACETAMIDE, and then carry out reacting by heating.
In above-mentioned synthetic method, the mol ratio of described 4-carboxyl-6-azepine benzanthrone, (-)-3-amino-1,2-PD and phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl is preferably 1:0.5～3.0:0.5～3.0.
In above-mentioned synthetic method, whether reaction can adopt thin-layer chromatography to follow the tracks of is fully detected, and under above-mentioned qualifications, reaction is to fully approximately needing 0.5～8h.Preferably, reaction is carried out at 40～60 ℃.
In above-mentioned synthetic method, for the mixed solvent of wash-out, the volume ratio of chloroform and methyl alcohol is 20～100:1.
The present invention also comprises with above-mentioned (-)-4-(2, the 3-dihydroxypropyl)-methane amide-application of 6-azepine benzanthrone in preparing antitumor drug.
It is antitumor drug prepared by effective constituent that the present invention further comprises (-)-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone.
Compared with prior art, total synthesis method of the present invention is synthetic obtains a kind of chiral derivatives---(-)-4-(2 of oxidation aporphine alkaloid of new single enantiomer, the 3-dihydroxypropyl)-methane amide-6-azepine benzanthrone, and investigated its proliferation inhibition activity to various human tumor cell lines such as BEL-7404, A549, SK-OV-3, HeLa229 and NCI-H460, result shows that it has the most significant anti tumor activity in vitro to BEL-7404, there is potential pharmaceutical use preferably, be expected to the preparation for antitumor drug.
The accompanying drawing explanation
The infrared spectra spectrogram that Fig. 1 is the final product that makes of the embodiment of the present invention 2;
The proton nmr spectra that Fig. 2 is the final product that makes of the embodiment of the present invention 2;
The carbon-13 nmr spectra that Fig. 3 is the final product that makes of the embodiment of the present invention 2;
The electrospray ionization mass spectrum spectrogram that Fig. 4 is the final product that makes of the embodiment of the present invention 2;
The ultraviolet-visible spectrum spectrogram that Fig. 5 is the final product that makes of the embodiment of the present invention 2;
The configurational identification CD spectrum spectrogram that Fig. 6 is the final product that makes of the embodiment of the present invention 2.
Embodiment
Below with embodiment, the invention will be further described, but the present invention is not limited to these embodiment.
In following embodiment, the concrete chemical name of the abbreviation of appearance is as follows:
DMAD: butine dioctyl phthalate dimethyl ester;
KOH: potassium hydroxide;
PyBOP: phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl;
DMA:N, the N-N,N-DIMETHYLACETAMIDE.
Synthesizing of embodiment 1:4-carboxyl-6-azepine benzanthrone
Synthetic route is as follows:
Concrete synthetic method comprises the following steps:
Synthesizing of (1) 4,5-dioctyl phthalate methyl esters-6-azepine benzanthrone
Take 9 of 1.0mol, the 10-phenanthrenequione, (pyridine: the volume ratio 1:6 of dehydrated alcohol), stirring and refluxing, slowly drip the 150mL ethanolic soln of 1.5mol methoxamine hydrochloride, and after dropwising, reaction refluxes 3.0 hours to add the pyridine of 300mL and dehydrated alcohol.Cooling, underpressure distillation is except desolventizing, and residue adds chloroform 350mL, distilled water wash, and anhydrous sodium sulfate drying, chloroform is removed in reduced pressure distillation, and residue is dissolved in 500mL toluene, adds 1.5mol DMAD, and under 120 ℃ of conditions, stirring and refluxing is 6～12 days.After completion of the reaction, cooling, separate out a large amount of yellow solids, suction filtration, filter cake toluene wash.Thick product Gossypol recrystallized from chloroform, obtain orange-yellow needle-like crystal (productive rate 50%).
Synthesizing of (2) 4,5-dicarboxyls-6-azepine benzanthrone
Taking orange-yellow needle-like crystal that the step (1) of 1.0mol makes and the KOH of 0.2mol joins in methanol/water (volume ratio=3:7) solution 250mL, under 65 ℃ of conditions, stir 12 hours, methyl alcohol is removed in reduced pressure distillation, and the aqueous solution is adjusted to pH=1～2, suction filtration with the hydrochloric acid of 6mol/L, filter cake washs with frozen water, cryodrying, thick product oil of mirbane recrystallization, obtain yellow needle-like crystal (productive rate 95%).
(3) 4-carboxyl-6-azepine benzanthrone is synthetic
Take the yellow needle-like crystal that the step (2) of 1.0mol makes, add phenyl ether 150mL, stir 3.0 hours at 200 ℃ of temperature, cooling, suction filtration, filter cake washs with anhydrous diethyl ether, thick product oil of mirbane recrystallization, obtain brown color solid (productive rate 85%).
Brown color solid to above-mentioned gained carries out proton nmr spectra and Electrospray Ionization Mass Spectrometry, and concrete data are as follows:
1H?NMR(DMSO-d
6,500MHz):δH7.62(t,1H,J=7.4Hz),7.84(t,1H,J=7.4Hz),8.01(t,1H,J=8.4Hz),8.23(d,1H,J=7.8Hz),8.50(d,1H,J=8.0Hz),8.71(d,1H,J=7.4Hz),8.87(d,1H,J=8.6Hz),9.36(s,1H);
ESI-MS?m/z:273.88[M-H]
-.
Therefore, the brown color solid that can determine above-mentioned gained is 4-carboxyl-6-azepine benzanthrone.
The 4-carboxyl of using in following embodiment 2～6-6-azepine benzanthrone is synthesized by the described method of above-described embodiment 1.
Embodiment 2:(-) synthesizing of-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone
Taking the 4-carboxyl of 1.0mol-6-azepine benzanthrone joins in the round-bottomed flask that fills the anhydrous DMA of 150mL, stir 80min (dissolving raw material) under 50 ℃ of conditions, (-)-3-amino-1 that adds 1.0mol, the 2-propylene glycol, stir 40min, slowly splash into the DMA solution that contains 1.5mol PyBOP, after dropwising, under 60 ℃ of conditions, stirring reaction is to complete (about 4.0h), reaction solution removes DMA under reduced pressure, residue adds saturated sodium carbonate solution (removing unnecessary PyBOP etc.), underpressure distillation is except anhydrating, add again 250mL anhydrous methanol (removing sodium carbonate), filter, steam except methyl alcohol, column chromatography on residue, the mixed solvent wash-out that the chloroform that to use by volume ratio be 50:1 and methyl alcohol form, the elutriant solvent evaporated, obtain yellow solid product, productive rate approximately 85%.
Above-mentioned gained yellow solid product is identified, data are as follows:
(1) infrared spectra, its spectrogram as shown in Figure 1:
IR(KBr):3284,2923,2879,1980,1843,1639,1484,1465,1432,1385,1273,1226,1204,1163,1102,1068,1042,934,839,803,772,749,696,603cm
-1.
(2) proton nmr spectra, its spectrogram as shown in Figure 2:
1H?NMR(500MHz,DMSO)δ9.05(s,1H),8.96–8.94(m,1H),8.79(d,J=7.2Hz,1H),8.58(d,J=7.9Hz,1H),8.37(d,J=8.5Hz,1H),8.31(d,J=7.8Hz,1H),8.02(t,J=7.9Hz,1H),7.90–7.87(m,1H),7.69–7.66(m,1H),4.99(s,1H),4.70(s,1H),4.38(t,J=4.9Hz,1H),3.76(s,1H),3.58–3.54(m,1H).
(3) carbon-13 nmr spectra, its spectrogram as shown in Figure 3:
13C?NMR(125MHz,DMSO)δ181.7,166.5,147.0,143.6,135.2,135.1,134.1,132.5,131.3,129.9,128.4,128.3,127.3,126.4,124.7,124.1,70.7,64.5,43.6.
(4) electrospray ionization mass spectrum, its spectrogram as shown in Figure 4:
ESI-MS?m/z:371.11[M+Na]
+.
(5) ultraviolet-visible spectrum, its spectrogram as shown in Figure 5.
(6) CD spectrum, its spectrogram as shown in Figure 6: from the long wavelength to short wavelength's direction, a negative peak first occurs, the rear posivtive spike that occurs, have negative peak at the 445nm place, at the 290nm place, posivtive spike arranged, and can judge it is the single enantiomer compound of (-) configuration.
Therefore, can determine that the yellow solid product of above-mentioned gained is (-)-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone, its structural formula is shown below:
Embodiment 3:(-) synthesizing of-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone
Taking the 4-carboxyl of 1.0mol-6-azepine benzanthrone joins in the round-bottomed flask that fills the anhydrous DMA of 50mL, stir 10min under 25 ℃ of conditions, (-)-3-amino-1 that adds 0.5mol, the 2-propylene glycol, stir 10min, slowly splash into the DMA solution that contains 1.5mol PyBOP, after dropwising, under 30 ℃ of conditions, stirring reaction is to complete (about 0.5h), reaction solution removes DMA under reduced pressure, residue adds saturated sodium carbonate solution, underpressure distillation is except anhydrating, add again the 50mL anhydrous methanol, filter, steam except methyl alcohol, column chromatography on residue, the mixed solvent wash-out that the chloroform that to use by volume ratio be 10:1 and methyl alcohol form, the elutriant solvent evaporated, obtain yellow solid product, productive rate approximately 40%.The yellow solid product of gained is carried out structure determination through infrared spectra, proton nmr spectra, carbon-13 nmr spectra, electrospray ionization mass spectrum, ultraviolet-visible spectrum and CD spectrum, be defined as target product (-)-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone.
Embodiment 4:(-) synthesizing of-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone
Taking the 4-carboxyl of 1.0mol-6-azepine benzanthrone joins in the round-bottomed flask that fills the anhydrous DMA of 500mL, stir 180min under 70 ℃ of conditions, (-)-3-amino-1 that adds 4.0mol, the 2-propylene glycol, stir 10min, slowly splash into the DMA solution that contains 5.0mol PyBOP, after dropwising, under 90 ℃ of conditions, stirring reaction is to complete (about 8.0h), reaction solution removes DMA under reduced pressure, residue adds saturated sodium carbonate solution, underpressure distillation is except anhydrating, add again the 500mL anhydrous methanol, filter, steam except methyl alcohol, column chromatography on residue, the mixed solvent wash-out that the chloroform that to use by volume ratio be 200:1 and methyl alcohol form, the elutriant solvent evaporated, obtain yellow solid product, productive rate approximately 75%.The yellow solid product of gained is carried out structure determination through infrared spectra, proton nmr spectra, carbon-13 nmr spectra, electrospray ionization mass spectrum, ultraviolet-visible spectrum and CD spectrum, be defined as target product (-)-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone.
Embodiment 5:(-) synthesizing of-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone
Taking the 4-carboxyl of 1.0mol-6-azepine benzanthrone joins in the round-bottomed flask that fills the anhydrous DMA of 320mL, stir 65min under 35 ℃ of conditions, (-)-3-amino-1 that adds 2.0mol, the 2-propylene glycol, stir 60min, slowly splash into the DMA solution that contains 2.5mol PyBOP, after dropwising, under 55 ℃ of conditions, stirring reaction is to complete (about 4.0h), reaction solution removes DMA under reduced pressure, residue adds saturated sodium carbonate solution, underpressure distillation is except anhydrating, add again the 300mL anhydrous methanol, filter, steam except methyl alcohol, column chromatography on residue, the mixed solvent wash-out that the chloroform that to use by volume ratio be 80:1 and methyl alcohol form, the elutriant solvent evaporated, obtain yellow solid product, productive rate approximately 55%.The yellow solid product of gained is carried out structure determination through infrared spectra, proton nmr spectra, carbon-13 nmr spectra, electrospray ionization mass spectrum, ultraviolet-visible spectrum and CD spectrum, be defined as target product (-)-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone.
Embodiment 6:(-) synthesizing of-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone
Taking the 4-carboxyl of 1.0mol-6-azepine benzanthrone joins in the round-bottomed flask that fills the anhydrous DMA of 280mL, stir 35min under 55 ℃ of conditions, (-)-3-amino-1 that adds 2.5mol, the 2-propylene glycol, stir 85min, slowly splash into the DMA solution that contains 1.0mol PyBOP, after dropwising, under 68 ℃ of conditions, stirring reaction is to complete (about 5.5h), reaction solution removes DMA under reduced pressure, residue adds saturated sodium carbonate solution, underpressure distillation is except anhydrating, add again the 300mL anhydrous methanol, filter, steam except methyl alcohol, column chromatography on residue, the mixed solvent wash-out that the chloroform that to use by volume ratio be 150:1 and methyl alcohol form, the elutriant solvent evaporated, obtain yellow solid product, productive rate approximately 68%.The yellow solid product of gained is carried out structure determination through infrared spectra, proton nmr spectra, carbon-13 nmr spectra, electrospray ionization mass spectrum, ultraviolet-visible spectrum and CD spectrum, be defined as target product (-)-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone.
In order to absolutely prove (-) of the present invention-4-(2, the 3-dihydroxypropyl)-methane amide-purposes of 6-azepine benzanthrone (hereinafter to be referred as (-)-FABA) in pharmacy, the applicant has carried out the anti tumor activity in vitro experiment test to (-)-FABA, and precursor synthetic with it-4-carboxyl-6-azepine benzanthrone and clinically contrast with the cancer therapy drug cis-platinum.
One, the proliferation inhibition activity experiment of (-)-FABA to the various human tumor cell line:
1, cell strain and cell cultures
5 kinds of human tumor cell lines such as BEL-7404, A549, SK-OV-3, HeLa229 and NCI-H460 are selected in this experiment.
The all cells strain is all cultivated in the RPMI-1640 nutrient solution containing the little ox blood of 10wt%, 100U/mL penicillin, 100U/mL Streptomycin sulphate, puts 37 ℃ containing volumetric concentration 5%CO
2in incubator, cultivate.
2, the preparation of testing compound
The purity of (-) used-FABA >=95% (making by the described method of embodiment 2), after being diluted with physiological buffer, its DMSO liquid storage is mixed with the whole solution of 20 μ mol/L, wherein the final concentration of solubility promoter DMSO≤1%, test the inhibition degree of compound to various growth of tumour cell under this concentration.
3, cell growth inhibition test (mtt assay)
(1) tumour cell of taking the logarithm vegetative period, after tryptic digestion, be mixed with the nutrient solution containing 10% calf serum the cell suspension that concentration is 5000/ml, be inoculated in 96 well culture plates with every hole 180 μ L, make cell density to 1000 to be measured～10000 holes (marginal pore is filled with aseptic PBS);
(2) 5%CO
2, hatch 24h for 37 ℃, be paved with the medicine 20 μ L that Di，Mei hole, hole adds the finite concentration gradient to cell monolayer, each concentration gradient is established 4 multiple holes;
(3) 5%CO
2, hatch 48 hours, observe under inverted microscope for 37 ℃;
(4) every hole adds the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L, continues to cultivate 4h;
(5) stop cultivating, carefully suck nutrient solution in hole, every hole adds the DMSO of 100 μ L fully to dissolve first a ceremonial jade-ladle, used in libation precipitation, after vibrator mixes, at the microplate reader wavelength, is 570nm, and reference wavelength is the optical density value that 450nm measures each hole;
(6) zeroing hole (substratum, MTT, DMSO), control wells (the medicine dissolution medium of cell, same concentrations, nutrient solution, MTT, DMSO) are set simultaneously.
(7) according to the optical density value (OD value) recorded, judge viable cell quantity, the OD value is larger, and cytoactive is stronger.Utilize formula:
Calculate the inhibiting rate of medicine to growth of tumour cell, then calculate respectively the IC of each test-compound to several tumor cell lines with the Bliss method
50value.Its result as shown in the following Table 1.
Table 1:(-) IC of-FABA to different tumor cell lines
50value (μ M)
From based on IC
50the external activity test result, (-)-FABA all has significant proliferation inhibition activity, IC to five kinds of human tumor cell lines
50the value scope is 10.5～31.5 μ M; Wherein human liver cancer cell BEL-7404 is had to the highest restraining effect, its IC
50value is 10.5 ± 0.8 μ M, only is about cis-platinum IC
501/10 of value (98.0 ± 7.5 μ M).With cis-platinum contrast, (-)-FABA to the inhibition activity of HeLa229 and two kinds of cell strains of A549 also higher than cis-platinum; Its proliferation inhibition activity to Proliferation of Human Ovarian Cell SK-OV-3 and human lung carcinoma cell NCI-H460 is far below cis-platinum.
By the above results, can be found out, oxidation aporphine of the present invention chiral derivatives-(-)-FABA, aggregate performance has gone out the anti tumor activity in vitro of wide spectrum, has certain potential pharmaceutical use, is expected to the preparation for various antitumor drugs.
Claims (8)
1. (-)-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone, its structural formula is shown below:
2. (-) claimed in claim 1-4-(2, the synthetic method of the 3-dihydroxypropyl)-methane amide-6-azepine benzanthrone, it is characterized in that: take 4-carboxyl-6-azepine benzanthrone and (-)-3-amino-1, the 2-propylene glycol, be dissolved in N, in the N-N,N-DIMETHYLACETAMIDE, carry out amidate action under the katalysis of phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl, silica gel column chromatography on reaction product, the mixed solvent wash-out that the chloroform that to use by volume ratio be 10～200:1 and methyl alcohol form, the elutriant solvent evaporated, obtain (-)-4-(2, the 3-dihydroxypropyl)-methane amide-6-azepine benzanthrone.
3. synthetic method according to claim 2, it is characterized in that: the mol ratio by 1:0.5～4.0:0.5～5.0 takes 4-carboxyl-6-azepine benzanthrone, (-)-3-amino-1, 2-propylene glycol and phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl, by 4-carboxyl-6-azepine benzanthrone, (-)-3-amino-1, the 2-propylene glycol is dissolved in N, in the N-N,N-DIMETHYLACETAMIDE, slowly add wherein phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl, under 20～90 ℃ of conditions, stirring reaction is to complete, reaction solution removes N under reduced pressure, the N-N,N-DIMETHYLACETAMIDE, reaction product is used saturated sodium carbonate solution successively, methanol wash, silica gel column chromatography on residue, the mixed solvent wash-out that the chloroform that to use by volume ratio be 10～200:1 and methyl alcohol form, the elutriant solvent evaporated, obtain (-)-4-(2, the 3-dihydroxypropyl)-methane amide-6-azepine benzanthrone.
4. according to the described synthetic method of claim 2 or 3, it is characterized in that: the mol ratio of described 4-carboxyl-6-azepine benzanthrone, (-)-3-amino-1,2-PD and phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole alkyl is 1:0.5～3.0:0.5～3.0.
5. according to the described synthetic method of claim 2 or 3, it is characterized in that: the temperature of stirring reaction is 40～60 ℃.
6. according to the described synthetic method of claim 2 or 3, it is characterized in that: for the mixed solvent of wash-out, the volume ratio of chloroform and methyl alcohol is 20～100:1.
7. (-) claimed in claim 1-4-(2, the 3-dihydroxypropyl)-methane amide-application of 6-azepine benzanthrone in preparing antitumor drug.
8. with (-) claimed in claim 1-4-(2,3-dihydroxypropyl)-methane amide-6-azepine benzanthrone, be antitumor drug prepared by effective constituent.
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