CN102690313A - Cholic acid-naphthoylimine compounds and application thereof - Google Patents
Cholic acid-naphthoylimine compounds and application thereof Download PDFInfo
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Abstract
The invention discloses cholic acid-naphthoylimine antitumor lead compounds and application thereof, belonging to the field of pharmaceutical chemistry. The invention particularly relates to new naphthoylimine compounds which have the following chemical structure general formula. The compounds have strong inhibition activities for HepG2 liver cancer cells; and compared with the phase II clinical lead compounds Anfeinaite, part of the compounds have more excellent inhibition activities, and can be used for preparing antineoplastic drugs.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to one type of novel cholic acid-naphthalimide anti-tumor compounds and preparation method thereof and application.
Background technology
Malignant tumour serious threat human beings'health, human discovery malignant tumour has had the history in thousands of years.At aspects such as structure, function and metabolism, malignant cell is compared with normal cell has very big difference, and they have paranormal hyperplasia ability, and this hyperplasia and organism are not in tune.Malignant cell also has very strong aggressive and transitivity simultaneously.
The main method of treatment malignant tumour comprises at present: the chemotherapy of operative treatment, cancer therapy drug, radiotherapy and BRM and other treatment.Main method still is traditional radiotherapy and chemotherapy.Radiotherapy is to kill and wound cancer cells with radioactive rays: be about to cancer cells and burn to death.Chemotherapy is to use the chemicals kill cancer cell: be about to cancer cells and poison with poison.But for the solid tumor that accounts for tumour 90%; Chemicotherapy always is difficult to play the effect of radical cure tumour; Not only recurrence rate is very high; And chemicotherapy also can kill normal cell in kill cancer cell, and can cause toxic side effecties such as gastrointestinal dysfunction, bone marrow depression, especially destroys the human immune system.Can cause accompanying infection and function of human body depletion finally to cause death when serious.In addition, in secular cancer therapy, cancer cells tends to develop and resistance.Therefore, medicine that low toxicity highly selective, the resistance of research a new generation is low and improvement treat-ment become the task of top priority of treating malignant tumor, are key subjects and long-range tasks biological, the medical research field.
The target approach that with the cholic acid is carrier has significant advantage aspect above-mentioned.Cholic acid is synthetic by SUV in liver cell, is stored in the gall-bladder with bile then.Its very small amount in liver sausage round-robin process gets into blood; Show very high organ specificity; Have very high turn-over capacity, outstanding feature is that the absorption of cholic acid is that a kind of transhipment of active absorbs, and is that targeting vector can improve bioavailability of medicament with the cholic acid therefore; Have good bio-compatibility as endogenic natural aglucon cholic acid, thereby be suitable for carrier as targeted drug.Thereby realize the liver sausage target property of medicine, the specificity that improves medicine absorbs, and reduces Normocellular toxicity.
Summary of the invention
The object of the invention is to provide one type of cholic acid-naphthalimide new compound that anti-tumor activity is high, and another purpose is to provide its application aspect the preparation medicine.
The general structure of cholic acid-naphthoyl imide compounds provided by the invention is as follows:
Wherein: X is selected from H, Cl or Br; Y is selected from H or OH; N is 2 or 3.
The preparation method of cholic acid-naphthoyl imide compounds provided by the invention realizes through following reaction scheme:
(1) in the methanol solution of triethylamine, diamine compounds and tert-Butyl dicarbonate reaction obtain compound 2;
(2) under the nitrogen protection, compound 2 and naphthalic anhydride class reacting generating compound 3 in absolute ethyl alcohol;
(3) compound 3 is sloughed the protection base and is obtained compound 4 in the ethanolic soln of hydrogenchloride;
(4) compound 4 and cholic acid or Septochol be in anhydrous chloroform, N, and under the effect of N-carbonyl dimidazoles and triethylamine, condensation reaction generation target compound 5;
X is H, Cl or Br; Y is H or OH; N is 2 or 3.
Used diamine compounds is respectively quadrol or tn; Used naphthalic anhydride class is 1,8-naphthalic anhydride, 4-chloro-1,8-naphthalic anhydride or 4-bromo-1,8-naphthalic anhydride; Used cholic acid class is cholic acid or Septochol.
Advantage of the present invention and innovative point are: the present invention is a raw material with people's physical efficiency self synthetic material cholic acid; Synthesized cholic acid-naphthoyl imide compounds; This compounds has good anti tumor activity in vitro, and part of compounds is much better than control compound to the external activity of HepG2 human liver cancer cell and pacifies luxuriant and rich with fragrance Nat.Can realize the target efficient absorption of medicine, reduce, thereby realize selectively killing cancer cells to normal histiocytic toxicity.Its preparation method economy, simple, gentle has realized amino selective protection, and for follow-up synthesizing brought facility, yield is higher.
The chemical structure of synthetic part preferred compound of the present invention, infrared and nuclear magnetic data such as following table 1:
Embodiment
Below in conjunction with embodiment the present invention is done and to further describe.
Embodiment 1:
(1), preparation compound 2
Compound tn or quadrol 50 mmol are dissolved in the methanol solution of triethylamine of massfraction 10%, under the ice bath, vigorous stirring dropwise drips the tert-Butyl dicarbonate solution that 20 mmol are dissolved in methyl alcohol, and dropwise half a hour.The reaction nature rises to room temperature, stirred overnight.Reaction solution is creamy white, and decompression steams solvent, and residuum is dissolved in the chloroform, uses saturated Na
2CO
3Solution washing, anhydrous sodium sulfate drying filters, and decompression steams solvent, obtains faint yellow thickness oily liquids, is the tn or the quadrol of single Boc protection.
(2), preparation compound 3
With 1 of 1.98g (10mmol), the 8-naphthalic anhydride is dissolved in the absolute ethyl alcohol of 30mL, adds the tn of single Boc protection of 1.74g (10mmol) then, under the nitrogen protection, and refluxing and stirring, TLC monitoring reaction process.After reaction finishes; Decompression steams solvent; Column chromatography for separation (petrol ether/ethyl acetate volume ratio 5:1) obtains the white powder solid tertiary butyl-3-(1,3-dioxo-1H-benzo [de] isoquinoline 99.9-2 (3H)-yl) propyl carbamate (compound 3a) 2.83g.
(3), preparation compound 4
With the 10mmol compound tertiary butyl-3-(1; 3-dioxo-1H-benzo [de] isoquinoline 99.9-2 (3H)-yl) propyl carbamate is dissolved in the mixing solutions of ethanol and chloroform; Reaction solution is cooled to 0 ℃; Dropwise drip two equivalents of ethanolic soln of the hydrochloric acid of 4mol/L, drip off afterreaction liquid and rise to room temperature, magnetic agitation 2 hours.Reaction solution is creamy white, and has a large amount of solids to produce.Filter, with freezing absolute ethanol washing, drying obtains pressed powder 2-(3-aminopropyl)-1H-benzo [de] isoquinoline 99.9-1,3 (2H)-dione hydrochloride (compound 4a).
Adopt as above synthetic 3b-3f of method and 4b-4f compound, structure is following:
Embodiment 2: preparation compound 5a
0.5 the mmol cholic acid is dissolved in 20 mL anhydrous methylene chlorides, adds the N of 0.162 g (1 mmol) then, N-carbonyl dimidazoles (CDI) stirs.The compound 4a that adds 0.5 mmol again splashes into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After reaction finished, reaction solution added 30 mL methylene dichloride once more, uses the saturated common salt water washing, and organic layer is used anhydrous sodium sulfate drying, filtered, and column chromatography for separation (chloroform: the ethanol volume ratio is 8:1) gets faint yellow solid, is compound 5a.
Embodiment 3: preparation compound 5b
0.5 the mmol Septochol is dissolved in 20 mL anhydrous methylene chlorides, adds the N of 0.162 g (1 mmol) then, N-carbonyl dimidazoles (CDI) stirred one hour.The compound 4a that adds 0.5 mmol again splashes into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After reaction finished, reaction solution added 30 mL methylene dichloride once more, uses the saturated common salt water washing, and organic layer is used anhydrous sodium sulfate drying, filtered, and column chromatography for separation (chloroform: the ethanol volume ratio is 6:1) gets faint yellow solid, is compound 5b.
Embodiment 4: preparation compound 5c
0.5 the mmol cholic acid is dissolved in 20 mL anhydrous methylene chlorides, adds the N of 0.162 g (1 mmol) then, N-carbonyl dimidazoles (CDI) stirs.The compound 4b that adds 0.5 mmol again splashes into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After reaction finished, reaction solution added 30 mL methylene dichloride once more, uses the saturated common salt water washing, and organic layer is used anhydrous sodium sulfate drying, filtered, and column chromatography for separation (chloroform: the ethanol volume ratio is 6:1) gets faint yellow solid, is compound 5c.
Embodiment 5: preparation 5d
0.5 the mmol Septochol is dissolved in 20 mL anhydrous methylene chlorides, adds the N of 0.162 g (1 mmol) then, N-carbonyl dimidazoles (CDI) stirred one hour.The compound 4b that adds 0.5 mmol again splashes into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After reaction finished, reaction solution added 30 mL methylene dichloride once more, uses the saturated common salt water washing, and organic layer is used anhydrous sodium sulfate drying, filtered, and column chromatography for separation (chloroform: the ethanol volume ratio is 8:1) gets faint yellow solid, is compound 5d.
Embodiment 6: preparation compound 5e
0.5 the mmol cholic acid is dissolved in 20 mL anhydrous methylene chlorides, adds the N of 0.162 g (1 mmol) then, N-carbonyl dimidazoles (CDI) stirred one hour.The compound 4c that adds 0.5 mmol again splashes into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After reaction finished, reaction solution added 30 mL methylene dichloride once more, uses the saturated common salt water washing, and organic layer is used anhydrous sodium sulfate drying, filtered, and column chromatography for separation (chloroform: the ethanol volume ratio is 8:1) gets faint yellow solid, is compound 5e.
Embodiment 7: preparation compound 5f
0.5 the mmol Septochol is dissolved in 20 mL anhydrous methylene chlorides, adds the N of 0.162 g (1 mmol) then, N-carbonyl dimidazoles (CDI) stirred one hour.The compound 4c that adds 0.5 mmol again splashes into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After reaction finished, reaction solution added 30 mL methylene dichloride once more, uses the saturated common salt water washing, and organic layer is used anhydrous sodium sulfate drying, filtered, and column chromatography for separation (chloroform: the ethanol volume ratio is 8:1) gets faint yellow solid, is compound 5f.
Embodiment 8: preparation compound 5g
0.5 the mmol cholic acid is dissolved in 20 mL anhydrous methylene chlorides, adds the N of 0.162 g (1 mmol) then, N-carbonyl dimidazoles (CDI) stirred one hour.The compound 4d that adds 0.5 mmol again splashes into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After reaction finished, reaction solution added 30 mL methylene dichloride once more, uses the saturated common salt water washing, and organic layer is used anhydrous sodium sulfate drying, filtered, and column chromatography for separation (chloroform: the ethanol volume ratio is 8:1) gets faint yellow solid, is compound 5g.
Embodiment 9: preparation compound 5h
0.5 the mmol Septochol is dissolved in 20 mL anhydrous methylene chlorides, adds the N of 0.162 g (1 mmol) then, N-carbonyl dimidazoles (CDI) stirred one hour.The compound 4d that adds 0.5 mmol again splashes into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After reaction finished, reaction solution added 30 mL methylene dichloride once more, uses the saturated common salt water washing, and organic layer is used anhydrous sodium sulfate drying, filtered, and column chromatography for separation (chloroform: the ethanol volume ratio is 8:1) gets faint yellow solid, is compound 5h.
Embodiment 10: preparation compound 5i
0.5 the mmol cholic acid is dissolved in 20 mL anhydrous methylene chlorides, adds the N of 0.162 g (1 mmol) then, N-carbonyl dimidazoles (CDI) stirred one hour.The compound 4e that adds 0.5 mmol again splashes into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After reaction finished, reaction solution added 30 mL methylene dichloride once more, uses the saturated common salt water washing, and organic layer is used anhydrous sodium sulfate drying, filtered, and column chromatography for separation (chloroform: the ethanol volume ratio is 8:1) gets faint yellow solid, is compound 5i.
Embodiment 11: preparation compound 5j
0.5 the mmol Septochol is dissolved in 20 mL anhydrous methylene chlorides, adds the N of 0.162 g (1 mmol) then, N-carbonyl dimidazoles (CDI) stirred one hour.The compound 4e that adds 0.5 mmol again splashes into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After reaction finished, reaction solution added 30 mL methylene dichloride once more, uses the saturated common salt water washing, and organic layer is used anhydrous sodium sulfate drying, filtered, and column chromatography for separation (chloroform: the ethanol volume ratio is 8:1) gets faint yellow solid, is compound 5j.
Embodiment 12: preparation compound 5k
0.5 the mmol cholic acid is dissolved in 20 mL anhydrous methylene chlorides, adds the N of 0.162 g (1 mmol) then, N-carbonyl dimidazoles (CDI) stirred one hour.The compound 4f that adds 0.5 mmol again splashes into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After reaction finished, reaction solution added 30 mL methylene dichloride once more, uses the saturated common salt water washing, and organic layer is used anhydrous sodium sulfate drying, filtered, and column chromatography for separation (chloroform: the ethanol volume ratio is 8:1) gets faint yellow solid, is compound 5k.
Embodiment 13: preparation compound 5l
0.5 the mmol Septochol is dissolved in 20 mL anhydrous methylene chlorides, adds the N of 0.162 g (1 mmol) then, N-carbonyl dimidazoles (CDI) stirred one hour.The compound 4f that adds 0.5 mmol again splashes into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After reaction finished, reaction solution added 30 mL methylene dichloride once more, uses the saturated common salt water washing, and organic layer is used anhydrous sodium sulfate drying, filtered, and column chromatography for separation (chloroform: the ethanol volume ratio is 8:1) gets faint yellow solid, is compound 5l.
The mass spectrum of above synthetic compound, infrared and nuclear magnetic data are seen table.
Embodiment 14:
Synthetic midbody of the present invention and target compound have antitumor action, optimize 12 compounds, and pharmacological evaluation is following:
(1) experimental technique:
In order to investigate this series compound anti-tumor activity, adopt the MTT method to carry out preliminary screening, reference substance is Amonafide.
1. cell culture condition: get cell nursery stage, add and contain 10% calf serum, 2 mM L-L-glutamic acid, 100U/mL penicillium mould is in 50 μ g/mL Streptomycin sulphates, the 2 mM HYDRAZINE CARBOXIMIDAMIDE nutrient solutions, in 37 ° of C, 5% CO
2Cultivate in the environment.
2. cytotoxicity test: the HepG2 in the vegetative period of taking the logarithm (liver cancer cell) tumour cell, the adjustment cell count is 5 * 10
3Individual/mL, be added on and make its adherent spending the night in 96 well culture plates, add the sample liquid of concentration known after 24 hours, added MTT solution after 48 hours, every hole 100 μ L; Under 37 ° of C conditions, in incubator, cultivate 4 h, remove MTT solution, every porocyte crystal is dissolved with 150 μ L DMSO.More than be divided into branch sample sets, control group (not adding sample) and blank control group (having only substratum, acellular), on ELIASA, measure wavelength 570 nm places OD value.Calculate the inhibiting rate under the different sample concentrations by following formula after recording optical density(OD).
Growth of tumour cell inhibiting rate (%)=(OD contrast-OD experiment)/(OD contrast-OD is blank) * 100%
(2) experimental data and result
The anti-tumor activity following table 2 of 12 preferred compounds of the above-mentioned synthetic of the present invention:
Table?2 The?data?of?Inhibitory?rate?activity
Above-mentioned experimental result shows that compound according to the invention has good anti tumor activity in vitro; And a plurality of compounds are much better than control compound to the external activity that supplies the examination cancer cells and pacify luxuriant and rich with fragrance Nat; Be used to prepare new antitumor drug as active ingredient with The compounds of this invention, have the potential using value.
Claims (3)
1. cholic acid-naphthoyl imide compounds, this compounds has following general formula: wherein: X is selected from H, Cl or Br; Y is selected from H or OH; N is 2 or 3,
.
2. cholic acid-naphthoyl imide compounds according to claim 1 is characterized in that, is following compound:
。
3. like claim 1 or the application of 2 described cholic acid-naphthoyl imide compounds in the preparation medicine, it is characterized in that, it is applied to prepare in the antitumor drug as active ingredient.
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| CN105801662A (en) * | 2016-04-07 | 2016-07-27 | 河南省科学院化学研究所有限公司 | Bile acid-alpha-hydroxyphosphonate derivatives and synthetic method thereof |
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| CN101575315A (en) * | 2009-06-09 | 2009-11-11 | 北京大学 | New naphthalimide derivative, preparation method and application thereof |
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| CN101575315A (en) * | 2009-06-09 | 2009-11-11 | 北京大学 | New naphthalimide derivative, preparation method and application thereof |
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| 梅子厚等: "萘酰亚胺-多胺缀合物的合成及体外抗癌活性", 《药学学报》 * |
| 王文等: "以胆酸为载体的肝靶向抗肿瘤药物的研究", 《中国新药杂志》 * |
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| CN105801662A (en) * | 2016-04-07 | 2016-07-27 | 河南省科学院化学研究所有限公司 | Bile acid-alpha-hydroxyphosphonate derivatives and synthetic method thereof |
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