CN102690313B - 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 pharmaceutical chemistry field, be specifically related to the novel cholic acid-naphthalimide of class anti-tumor compounds and preparation method thereof and application.
Background technology
The malignant tumour serious threat mankind's health, the mankind find that malignant tumour has had the history of thousands of years.At aspects such as structure, function and metabolism, malignant cell is compared tool with normal cell and is very different, and they have paranormal Reproductive activity, and this hyperplasia and organism are not in tune.Malignant cell also has very strong aggressive and transitivity simultaneously.
The main method for the treatment of malignant tumour comprises at present: chemotherapy, radiotherapy and the biological response modifier of operative treatment, cancer therapy drug and other treatment.Main method is still traditional radiotherapy and chemotherapy.Radiotherapy is to kill and wound cancer cells with radioactive rays: burn to death by cancer cells.Chemotherapy is to kill cancer cells with chemicals: poison with poison by cancer cells.But for accounting for the solid tumor of tumour 90%, chemicotherapy is always difficult to play the effect of radical cure tumour, not only recurrence rate is very high, and chemicotherapy also can kill normal cell in killing cancer cells, and can cause the toxic side effects such as gastrointestinal dysfunction, bone marrow depression, especially destroy human immune system.When serious, can cause accompanying infection and function of human body exhaustion finally to cause death.In addition, in long-term cancer therapy, cancer cells tends to develop resistance.Therefore, studying the medicine that low toxicity highly selective, resistance of new generation are low and improving methods for the treatment of becomes the task of top priority for the treatment of malignant tumor, is key subjects and long-range task biological, medical research field.
Target approach taking cholic acid as carrier has significant advantage aspect above-mentioned.Cholic acid by cholesterol biosynthesis, is then stored in gall-bladder with bile in liver cell.It seldom measures and enters blood in the process of liver sausage circulation, 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 therefore can improve the bioavailability of medicine taking cholic acid as targeting vector; There is good bio-compatibility as endogenic natural aglucon cholic acid, thereby be suitable for the carrier as targeted drug.Thereby realize the liver sausage targeting of medicine, the specificity that improves medicine absorbs, and reduces Normocellular toxicity.
Summary of the invention
Cholic acid-naphthalimide the new compound that provides a class anti-tumor activity high is provided the object of the invention, and another object is to provide it in the application of preparing aspect 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 by following reaction scheme:
(1), in the methanol solution of triethylamine, diamine compounds and tert-Butyl dicarbonate reaction, obtain compound 2;
(2) under nitrogen protection, compound 2 and naphthalic anhydride class reacting generating compound 3 in dehydrated alcohol;
(3) compound 3 is sloughed protecting group 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 generates target compound 5;
X is H, Cl or Br; Y is H or OH; N is 2 or 3.
Diamine compounds used is respectively quadrol or propylene diamine; Naphthalic anhydride class used is that 1,8-naphthalic anhydride, 4-are chloro-1, and 8-naphthalic anhydride or 4-are bromo-1,8-naphthalic anhydride; Cholic acid class used is cholic acid or Septochol.
Advantage of the present invention and innovative point are: the present invention is taking the synthetic material cholic acid of people's physical efficiency self as raw material, synthesize 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 the toxicity of normal tissue cell, thereby realize the selectively killing to cancer cells.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 the synthetic part preferred compound of the present invention, infrared and nuclear magnetic data are as following table 1:
Embodiment
Below in conjunction with embodiment, the present invention is described further.
Embodiment 1:
(1), prepare compound 2
Compound propylene diamine or quadrol 50 mmol are dissolved in the methanol solution of triethylamine of massfraction 10%, and under ice bath, vigorous stirring, dropwise drips 20 mmol and is dissolved in the tert-Butyl dicarbonate solution of methyl alcohol, and dropwise half an hour.Reaction nature rises to room temperature, and stirring is spent the night.Reaction solution is creamy white, and decompression steams solvent, and residuum is dissolved in chloroform, uses saturated Na
2cO
3solution washing, anhydrous sodium sulfate drying, filters, and decompression steams solvent, obtains faint yellow thickness oily liquids, is propylene diamine or the quadrol of single Boc protection.
(2), prepare compound 3
By 1.98g(10mmol) 1,8-naphthalic anhydride is dissolved in the dehydrated alcohol of 30mL, then adds the propylene diamine of the single Boc protection of 1.74g (10mmol), under nitrogen protection, return stirring, TLC monitors reaction process.After completion of the reaction, 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), prepare compound 4
By 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 DEG C, dropwise drip two equivalents of ethanolic soln of the hydrochloric acid of 4mol/L, drip off rear reaction solution 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, dry, obtain pressed powder 2-(3-aminopropyl)-1H-benzo [de] isoquinoline 99.9-1,3(2H)-dione hydrochloride (compound 4a).
Adopt the as above synthetic 3b-3f of method and 4b-4f compound, structure is as follows:
Embodiment 2: prepare compound 5a
0.5 mmol cholic acid is dissolved in 20 mL anhydrous methylene chlorides, then adds 0.162 g(1 mmol) N, N-carbonyl dimidazoles (CDI), stir.Add again the compound 4a of 0.5 mmol, splash into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After completion of the reaction, reaction solution adds 30 mL methylene dichloride again, uses saturated common salt water washing, and organic layer anhydrous sodium sulfate drying filters, and column chromatography for separation (chloroform: ethanol volume ratio is 8:1), obtains faint yellow solid, is compound 5a.
Embodiment 3: prepare compound 5b
0.5 mmol Septochol is dissolved in 20 mL anhydrous methylene chlorides, then adds 0.162 g(1 mmol) N, N-carbonyl dimidazoles (CDI), stirs one hour.Add again the compound 4a of 0.5 mmol, splash into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After completion of the reaction, reaction solution adds 30 mL methylene dichloride again, uses saturated common salt water washing, and organic layer anhydrous sodium sulfate drying filters, and column chromatography for separation (chloroform: ethanol volume ratio is 6:1), obtains faint yellow solid, is compound 5b.
Embodiment 4: prepare compound 5c
0.5 mmol cholic acid is dissolved in 20 mL anhydrous methylene chlorides, then adds 0.162 g(1 mmol) N, N-carbonyl dimidazoles (CDI), stir.Add again the compound 4b of 0.5 mmol, splash into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After completion of the reaction, reaction solution adds 30 mL methylene dichloride again, uses saturated common salt water washing, and organic layer anhydrous sodium sulfate drying filters, and column chromatography for separation (chloroform: ethanol volume ratio is 6:1), obtains faint yellow solid, is compound 5c.
Embodiment 5: preparation 5d
0.5 mmol Septochol is dissolved in 20 mL anhydrous methylene chlorides, then adds 0.162 g(1 mmol) N, N-carbonyl dimidazoles (CDI), stirs one hour.Add again the compound 4b of 0.5 mmol, splash into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After completion of the reaction, reaction solution adds 30 mL methylene dichloride again, uses saturated common salt water washing, and organic layer anhydrous sodium sulfate drying filters, and column chromatography for separation (chloroform: ethanol volume ratio is 8:1), obtains faint yellow solid, is compound 5d.
Embodiment 6: prepare compound 5e
0.5 mmol cholic acid is dissolved in 20 mL anhydrous methylene chlorides, then adds 0.162 g(1 mmol) N, N-carbonyl dimidazoles (CDI), stirs one hour.Add again the compound 4c of 0.5 mmol, splash into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After completion of the reaction, reaction solution adds 30 mL methylene dichloride again, uses saturated common salt water washing, and organic layer anhydrous sodium sulfate drying filters, and column chromatography for separation (chloroform: ethanol volume ratio is 8:1), obtains faint yellow solid, is compound 5e.
Embodiment 7: prepare compound 5f
0.5 mmol Septochol is dissolved in 20 mL anhydrous methylene chlorides, then adds 0.162 g(1 mmol) N, N-carbonyl dimidazoles (CDI), stirs one hour.Add again the compound 4c of 0.5 mmol, splash into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After completion of the reaction, reaction solution adds 30 mL methylene dichloride again, uses saturated common salt water washing, and organic layer anhydrous sodium sulfate drying filters, and column chromatography for separation (chloroform: ethanol volume ratio is 8:1), obtains faint yellow solid, is compound 5f.
Embodiment 8: prepare compound 5g
0.5 mmol cholic acid is dissolved in 20 mL anhydrous methylene chlorides, then adds 0.162 g(1 mmol) N, N-carbonyl dimidazoles (CDI), stirs one hour.Add again the compound 4d of 0.5 mmol, splash into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After completion of the reaction, reaction solution adds 30 mL methylene dichloride again, uses saturated common salt water washing, and organic layer anhydrous sodium sulfate drying filters, and column chromatography for separation (chloroform: ethanol volume ratio is 8:1), obtains faint yellow solid, is compound 5g.
Embodiment 9: prepare compound 5h
0.5 mmol Septochol is dissolved in 20 mL anhydrous methylene chlorides, then adds 0.162 g(1 mmol) N, N-carbonyl dimidazoles (CDI), stirs one hour.Add again the compound 4d of 0.5 mmol, splash into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After completion of the reaction, reaction solution adds 30 mL methylene dichloride again, uses saturated common salt water washing, and organic layer anhydrous sodium sulfate drying filters, and column chromatography for separation (chloroform: ethanol volume ratio is 8:1), obtains faint yellow solid, is compound 5h.
Embodiment 10: prepare compound 5i
0.5 mmol cholic acid is dissolved in 20 mL anhydrous methylene chlorides, then adds 0.162 g(1 mmol) N, N-carbonyl dimidazoles (CDI), stirs one hour.Add again the compound 4e of 0.5 mmol, splash into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After completion of the reaction, reaction solution adds 30 mL methylene dichloride again, uses saturated common salt water washing, and organic layer anhydrous sodium sulfate drying filters, and column chromatography for separation (chloroform: ethanol volume ratio is 8:1), obtains faint yellow solid, is compound 5i.
Embodiment 11: prepare compound 5j
0.5 mmol Septochol is dissolved in 20 mL anhydrous methylene chlorides, then adds 0.162 g(1 mmol) N, N-carbonyl dimidazoles (CDI), stirs one hour.Add again the compound 4e of 0.5 mmol, splash into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After completion of the reaction, reaction solution adds 30 mL methylene dichloride again, uses saturated common salt water washing, and organic layer anhydrous sodium sulfate drying filters, and column chromatography for separation (chloroform: ethanol volume ratio is 8:1), obtains faint yellow solid, is compound 5j.
Embodiment 12: prepare compound 5k
0.5 mmol cholic acid is dissolved in 20 mL anhydrous methylene chlorides, then adds 0.162 g(1 mmol) N, N-carbonyl dimidazoles (CDI), stirs one hour.Add again the compound 4f of 0.5 mmol, splash into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After completion of the reaction, reaction solution adds 30 mL methylene dichloride again, uses saturated common salt water washing, and organic layer anhydrous sodium sulfate drying filters, and column chromatography for separation (chloroform: ethanol volume ratio is 8:1), obtains faint yellow solid, is compound 5k.
Embodiment 13: prepare compound 5l
0.5 mmol Septochol is dissolved in 20 mL anhydrous methylene chlorides, then adds 0.162 g(1 mmol) N, N-carbonyl dimidazoles (CDI), stirs one hour.Add again the compound 4f of 0.5 mmol, splash into the triethylamine of 1mmol, normal-temperature reaction.TLC detection reaction process.After completion of the reaction, reaction solution adds 30 mL methylene dichloride again, uses saturated common salt water washing, and organic layer anhydrous sodium sulfate drying filters, and column chromatography for separation (chloroform: ethanol volume ratio is 8:1), obtains faint yellow solid, is compound 5l.
The mass spectrum of above synthetic compound, infrared and nuclear magnetic data are in Table.
Embodiment 14:
Intermediate and target compound that the present invention is synthetic have antitumor action, optimize 12 compounds, and pharmacological evaluation is as follows:
(1) experimental technique:
In order to investigate this series compound anti-tumor activity, adopt MTT method to carry out preliminary screening, reference substance is Amonafide.
1. cell culture condition: get cell nursery stage, add containing 10% calf serum, 2 mM Pidolidones, 100U/mL penicillin, in 50 μ g/mL Streptomycin sulphates, 2 mM aminoguanidine nutrient solutions, in 37 ° of C, 5% CO
2in environment, cultivate.
2. cytotoxicity test: the HepG2(liver cancer cell in the vegetative period of taking the logarithm) tumour cell, adjusting cell count is 5 × 10
3individual/mL, is added in 96 well culture plates and makes its adherent spending the night, and adds the sample liquid of concentration known after 24 hours, adds 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 a point sample sets, control group (not adding sample) and blank group (only having substratum, acellular), in microplate reader, measure wavelength 570 nm places optical density value.After recording optical density(OD), calculate the inhibiting rate under different sample concentrations by formula below.
Growth of tumour cell inhibiting rate (%)=(OD contrast-OD experiment)/(OD contrast-OD blank) × 100%
(2) experimental data and result
The anti-tumor activity following table 2 of above-mentioned 12 the synthetic preferred compounds of the present invention:
Table 2 The data of Inhibitory rate activity
Above-mentioned experimental result shows that compound of the present invention has good anti tumor activity in vitro, and multiple compounds are pacified luxuriant and rich with fragrance Nat to being much better than control compound for the external activity of examination cancer cells, for the preparation of new antitumor drug, there is potential using value using the compounds of this invention as active ingredient.
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. cholic acid-the naphthoyl imide compounds as described in claim 1 or 2 suppresses to apply in human liver cancer cell HepG2 growth medicine in preparation as active ingredient.
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| Title |
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| 以胆酸为载体的肝靶向抗肿瘤药物的研究;王文等;《中国新药杂志》;20060208;第15卷(第3期);第175页左栏第3段至第175页右栏第3段 * |
| 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》.2009,第44卷(第7期),第754页左栏第1段至第755页左栏第2段、图1及表4. |
| 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》.2006,第15卷(第3期),第175页左栏第3段至第175页右栏第3段. |
| 萘酰亚胺-多胺缀合物的合成及体外抗癌活性;梅子厚等;《药学学报》;20090712;第44卷(第7期);第754页左栏第1段至第755页左栏第2段、图1及表4 * |
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