CN105399740A - Acridine derivative, preparation method thereof and application of same serving as anti-tumor drug - Google Patents
Acridine derivative, preparation method thereof and application of same serving as anti-tumor drug Download PDFInfo
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- CN105399740A CN105399740A CN201510870147.0A CN201510870147A CN105399740A CN 105399740 A CN105399740 A CN 105399740A CN 201510870147 A CN201510870147 A CN 201510870147A CN 105399740 A CN105399740 A CN 105399740A
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses an acridine derivative and a preparation method and application of the same serving as an anti-tumor drug. The chemical name of the acridine derivative is 7-benzo [b]-[1, 10] phenanthroline p-chlorobenzamide thiourea. The structural formula of the acridine derivative is shown in the description, has the effect of the antitumor activity and has the good application prospect on development of drugs for treating tumors.
Description
Technical field
The invention belongs to pharmaceutical field.More particularly, the present invention relates to a kind of acridine derivatives and preparation method thereof and as the purposes in antitumor drug.
Background technology
Acridine is the nitrogenous organic heterocyclic molecule that a class is subject to extensive concern, because its structure is large ring conjugated system, tool rigid planar structure, can be used as the macromolecular embedded bodies such as DNA, in antitumor, antiviral, anti-malarial, antibacterial, biological fluorescent labeling and treatment acquired immune deficiency syndrome (AIDS) etc., all show very strong physiologically active people extracted from natural product or adopted the method for chemosynthesis to obtain a large amount of acridine compounds, have studied their pharmacologically active and the mechanism of action.In order to improve it to the affine performance of DNA, the rejection of multiple enzyme and cytotoxicity etc., continuous exploration and improvement have been carried out to its structure of modification, innovation of the present invention is by benzo [b]-[1, the 7-position of 10] o-phenanthroline ring connects active group amide group thiocarbamide structure, synthesizing new acridine derivatives, this derivative not yet has report at present.
Summary of the invention
An object of the present invention is to solve at least the problems referred to above, and the advantage will illustrated at least is below provided.
A further object of the invention is to provide a kind of acridine derivatives 7-benzo [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide, and this compound has the effect of anti-tumor activity, has the applications well prospect developing into treatment tumour.
In order to realize, according to these objects of the present invention and other advantage, providing a kind of acridine derivatives, it is characterized in that,
1) chemical name of this compound is that 7-benzo [b]-[1,10] o-phenanthroline is to chloro-benzoyl amino thiocarbamide;
2) structural formula is:
A kind of acridine derivatives 7-benzo [b]-[1,10] o-phenanthroline, to the preparation method of chloro-benzoyl amino thiocarbamide, comprising:
Step one, with o-bromobenzoic acid and 8-quinolylamine for raw material, salt of wormwood and copper powder are catalyzer, add Pentyl alcohol as solvent, under 140 DEG C of reflux conditionss, obtain compound N-quinolyl anthranilic acid through ullmann reaction;
Step 2, N-quinolyl anthranilic acid close ring with phosphorus oxychloride, obtained compound 7-chlorobenzene also [b]-[1,10] o-phenanthroline;
Under the effect of phase-transfer catalyst Tetrabutyl amonium bromide, there is nucleophilic substitution reaction with NaSCN and obtain compound 7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates in step 3,7-chlorobenzene also [b]-[1,10] o-phenanthroline;
Step 4,7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates is added p-chloro benzoyl hydrazine after being dissolved in acetonitrile, back flow reaction, after filtering and washing, obtain 7-benzo [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide.
Preferably, described acridine derivatives 7-benzo [b]-[1,10] o-phenanthroline comprises the following steps the concrete preparation method of chloro-benzoyl amino thiocarbamide:
Steps A, by the o-bromobenzoic acid of 5.2 weight parts, the 8-quinolylamine of 4.9 weight parts, the salt of wormwood of 7.5 weight parts and the copper powder mixing of 0.3 weight part, add the Pentyl alcohol of 24.3 weight parts again as solvent, return stirring 2h at 140 DEG C, after reaction terminates, remove solvent under reduced pressure, gained residue adds 600 weight parts waters, 20min is reacted at 80 DEG C, filtered while hot, washing leaching cake, combining water layer, water layer concentrated hydrochloric acid is acidified to pH and equals 2, now separate out a large amount of black powder, suction filtration, gained solid acetone recrystallization, obtain compound N-quinolyl anthranilic acid,
Step B, the N-quinolyl anthranilic acid of 1.971 weight parts is mixed with the phosphorus oxychloride of 11.84 weight parts, in 15min, oil bath is heated to 85 ~ 90 DEG C, when there is vigorous reaction, remove heating bath immediately, if react too fierce, flask is cooled with cold water, treat that boiling eases up, oil bath temperature is increased to 135 ~ 140 DEG C, reaction 2h, after reaction terminates, residuum is the slow well-beaten strong aqua of impouring after the cooling period, in the mixture of trash ice and chloroform, with chloroform and ammonia water mixture washing flask, undissolved solids is no longer included after 30min, isolate chloroform layer, water layer continuation chloroform extraction, combined chloroform layer, Calcium Chloride Powder Anhydrous dried overnight, filter, steaming desolventizes, obtain compound 7-chlorobenzene also [b]-[1, 10] o-phenanthroline,
Step C, by the 7-chlorobenzene of 0.3 weight part also [b]-[1,10] the acetone mixing of o-phenanthroline and 23.64 weight parts, backflow adds the NaSCN of 0.275 weight part and the Tetrabutyl amonium bromide of 0.075 weight part after dissolving, after back flow reaction 3h, yellow solid powder is had to separate out, suction filtration, obtains 7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates after water washing;
Step D, by the 7-benzo [b]-[1 of 0.24 weight part, 10] the acetonitrile mixing of o-phenanthroline lsothiocyanates and 27.65 weight parts, after add the p-chloro benzoyl hydrazine of 0.17 weight part, back flow reaction 2h, a large amount of solid is had to separate out in reaction process, cooling suction filtration obtains bright yellow solid and is 7-benzo [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide.
The present invention discloses simultaneously and protects this acridine derivatives and preparing the purposes in antitumor drug.
The present invention at least comprises following beneficial effect: experiment proves, novel acridine derivatives disclosed in this invention has very strong restraining effect to MGC-803, BEL-7404, NCI-H460 cell strain, show significant anti-tumor activity, can be used for preparation and there is selectivity antitumor drug.
Part is embodied by explanation below by other advantage of the present invention, target and feature, part also will by research and practice of the present invention by those skilled in the art is understood.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, can implement according to this with reference to specification sheets word to make those skilled in the art.
It should be noted that experimental technique described in following embodiment if no special instructions, is ordinary method, described reagent and material, if no special instructions, all can obtain from commercial channels.
The invention provides a kind of acridine derivatives, it is characterized in that,
1) chemical name of this compound is that 7-benzo [b]-[1,10] o-phenanthroline is to chloro-benzoyl amino thiocarbamide;
2) structural formula is:
Molecular formula: C24H16ClN6OS
Relative molecular weight: 457.93;
3) physico-chemical property: yellow powder, m.p.188-195 DEG C, 1HNMR (DMSO-d6, 400MHz), δ: 11.79 (br, s, 1H,-NH), 11.22 (br, s, 1H,-NH), 10.77 (br, s, 1H,-NH), 9.78 (s, 1H, ArH), 9.54 (d, 1H, J=9.0, ArH), 8.99 (d, 1H, J=8.5, ArH), 8.67 (s, 1H, ArH), 8.42 (d, 2H, J=7.2, ArH), 8.21 (d, 1H, J=7.2, ArH), 8.11-8.28 (m, 2H, ArH), 7.74-7.88 (m, 2H, ArH), 7.69 (d, 1H, J=7.2, ArH), 7.45 (d, 1H, J=7.2, ArH), 7.38-7.42 (m, 2H, ArH), 13CNMR (DMSO-d6,100MHz), δ 182.69,169.77,150.21,148.49,144.67,132.19,131.72,131.84,130.51,130.17,129.95,129.78,129.56,129.11,128.33,127.41,126.28,124.22,123.55.
The synthetic route of this compound is as follows:
This acridine derivatives 7-benzo [b]-[1,10] o-phenanthroline, to the preparation method of chloro-benzoyl amino thiocarbamide, comprising:
Step one, with o-bromobenzoic acid and 8-quinolylamine for raw material, salt of wormwood and copper powder are catalyzer, add Pentyl alcohol as solvent, under 140 DEG C of reflux conditionss, obtain compound N-quinolyl anthranilic acid through ullmann reaction;
Step 2, N-quinolyl anthranilic acid close ring with phosphorus oxychloride, obtained compound 7-chlorobenzene also [b]-[1,10] o-phenanthroline;
Under the effect of phase-transfer catalyst Tetrabutyl amonium bromide, there is nucleophilic substitution reaction with NaSCN and obtain compound 7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates in step 3,7-chlorobenzene also [b]-[1,10] o-phenanthroline;
Step 4,7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates is added p-chloro benzoyl hydrazine after being dissolved in acetonitrile, back flow reaction, after filtering and washing, obtain 7-benzo [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide.
Embodiment 1
Described acridine derivatives 7-benzo [b]-[1,10] o-phenanthroline comprises the following steps the concrete preparation method of chloro-benzoyl amino thiocarbamide:
Steps A, by the o-bromobenzoic acid of 5.2 weight parts, the 8-quinolylamine of 4.9 weight parts, the salt of wormwood of 7.5 weight parts and the copper powder mixing of 0.3 weight part, add the Pentyl alcohol of 24.3 weight parts again as solvent, return stirring 2h at 140 DEG C, after reaction terminates, remove solvent under reduced pressure, gained residue adds 600 weight parts waters, 20min is reacted at 80 DEG C, filtered while hot, washing leaching cake, combining water layer, water layer concentrated hydrochloric acid is acidified to pH and equals 2, now separate out a large amount of black powder, suction filtration, gained solid acetone recrystallization, obtain compound N-quinolyl anthranilic acid, productive rate 36%,
Step B, the N-quinolyl anthranilic acid of 1.971 weight parts is mixed with the phosphorus oxychloride of 11.84 weight parts, in 15min, oil bath is heated to 85 ~ 90 DEG C, when there is vigorous reaction, remove heating bath immediately, if react too fierce, flask is cooled with cold water, treat that boiling eases up, oil bath temperature is increased to 135 ~ 140 DEG C, reaction 2h, after reaction terminates, residuum is the slow well-beaten strong aqua of impouring after the cooling period, in the mixture of trash ice and chloroform, with chloroform and ammonia water mixture washing flask, undissolved solids is no longer included after 30min, isolate chloroform layer, water layer continuation chloroform extraction, combined chloroform layer, Calcium Chloride Powder Anhydrous dried overnight, filter, steaming desolventizes, obtain compound 7-chlorobenzene also [b]-[1, 10] o-phenanthroline, productive rate 18%,
Step C, by the 7-chlorobenzene of 0.3 weight part also [b]-[1,10] the acetone mixing of o-phenanthroline and 23.64 weight parts, backflow adds the NaSCN of 0.275 weight part and the Tetrabutyl amonium bromide of 0.075 weight part after dissolving, after back flow reaction 3h, there is yellow solid powder to separate out, suction filtration, after water washing, obtain 7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates, productive rate 94%;
Step D, by the 7-benzo [b]-[1 of 0.24 weight part, 10] the acetonitrile mixing of o-phenanthroline lsothiocyanates and 27.65 weight parts, after add the p-chloro benzoyl hydrazine of 0.17 weight part, back flow reaction 2h, a large amount of solid is had to separate out in reaction process, cooling suction filtration obtains bright yellow solid and is 7-benzo [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide.
Embodiment 2
Anti tumor activity in vitro is tested
Experiment reagent
The phosphate buffer solution (PBS) that buffered soln (pH=7.43) is 0.05moLL-1; Dimethyl sulfoxide (DMSO) (DMSO) is domestic analytical pure, PPMI1640 nutrient solution, high sugared DEME nutrient solution, DMEM nutrient solution is a kind of substratum containing each seed amino acid and glucose, develop on the basis of MEM substratum, tire bovine whey (FBS), 0.05% trypsin trypsin) equal purchased from American GIBCO company such as-0.02%, EDTA.Cell proliferation and citotoxicity detection kit (MTT) are purchased from Sigma company.
Laboratory apparatus
BCN-1360 Bechtop (east, Harbin connection), Forma3110CO
2incubator (USA), TECANInfiniteM200 microplate reader (Mannedorf, Switzerland), inverted microscope (Nikon), 7 degree of thermostat containers (Beijing Fu Yilian), automatic plate washer (the upper farsighted biology of Nereid), 96 porocyte culture plates (Costar, USA).
Experimental technique
The cultivation of cell and going down to posterity
Selected cell strain is all placed in 37 DEG C, incubator under the abundant humidifying condition of 5%CO2, is inoculated in the PPMI1640 nutrient solution containing 10% deactivation new-born calf serum and cultivates.With inverted microscope observation of cell growing state, change weekly 2 ~ 3 subcultures, within 6 ~ 7 days, go down to posterity once, go down to posterity with 0.25% tryptic digestion during inoculation, usually get and go down to posterity 3 ~ 4 times, be in logarithmic phase cell for experiment.
The preparation of liquid
Accurately take sample, be added in the 1.5mL centrifuge tube of sterilizing, add DMSO and be made into 2mM compound stock solution ,-20 DEG C of freezen protective.Respective concentration application is diluted to appropriate D-hanks after melting before use.The compound concentration that measuring is selected is respectively 20 μMs.
MTT experiment method
Get the cell being in logarithmic phase, every hole 180 μ L (an about 4500-5000 cell) celliferous culture medium inoculated in 96 well culture plates, in 37 DEG C, 5%CO
224h is cultivated under abundant humidifying condition.After cell attachment, add sample by the amount of every hole 20 μ L, 6 multiple holes established by each sample, set corresponding blank simultaneously.After continuing to cultivate 48h, every hole adds 10 μ LMTT reagent (concentration is 2mg/mL), and after continuing to hatch 4h, inhale and abandon supernatant liquor, every hole adds 150 μ LDMSO again, and slight concussion reaction 5-8min, makes crystalline particle fully dissolve.Blank group returns to zero, with microplate reader with 490nm wavelength measure the absorbance after removing bias light absorption value (
value), the IC of corresponding cell strain is by 5 concentration gradients
50value, all experiments are averaged after all repeating 3 times.
The 7-benzo [b] embodiment 1 obtained-[1,10] o-phenanthroline is to chloro-benzoyl amino thiocarbamide and 72 hours action time of MGC-803, BEL-7404, NCI-H460 cell strain, and result is as shown in table 1:
Table 17-benzo [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide and positive controls 5-FU to the medium effective concentration (IC of tumor cell line
50) table
From the results shown in Table 1,7-benzo [b]-[1 of the present invention, 10] o-phenanthroline shows through anticancer experiment in vitro chloro-benzoyl amino thiocarbamide, and this compound has strong anti-tumor activity, and its anti-tumor activity is all strong than positive control 5-FU.The present invention is that the new acridine type antitumor drug of research and development provides new thinking.
Although embodiment of the present invention are open as above, but it is not restricted to listed in specification sheets and embodiment utilization, it can be applied to various applicable the field of the invention completely, for those skilled in the art, can easily realize other amendment, therefore do not deviating under the universal that claim and equivalency range limit, the present invention is not limited to specific details and illustrates here and the embodiment described.
Claims (4)
1. an acridine derivatives, is characterized in that,
1) chemical name of this compound is that 7-benzo [b]-[1,10] o-phenanthroline is to chloro-benzoyl amino thiocarbamide;
2) structural formula is:
2. a preparation method for acridine derivatives as claimed in claim 1, is characterized in that, comprising:
Step one, with o-bromobenzoic acid and 8-quinolylamine for raw material, salt of wormwood and copper powder are catalyzer, add Pentyl alcohol as solvent, under 140 DEG C of reflux conditionss, obtain compound N-quinolyl anthranilic acid through ullmann reaction;
Step 2, N-quinolyl anthranilic acid close ring with phosphorus oxychloride, obtained compound 7-chlorobenzene also [b]-[1,10] o-phenanthroline;
Under the effect of phase-transfer catalyst Tetrabutyl amonium bromide, there is nucleophilic substitution reaction with NaSCN and obtain compound 7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates in step 3,7-chlorobenzene also [b]-[1,10] o-phenanthroline;
Step 4,7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates is added p-chloro benzoyl hydrazine after being dissolved in acetonitrile, back flow reaction, after filtering and washing, obtain 7-benzo [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide.
3. the preparation method of acridine derivatives as claimed in claim 2, is characterized in that, specifically comprise the following steps:
Steps A, by the o-bromobenzoic acid of 5.2 weight parts, the 8-quinolylamine of 4.9 weight parts, the salt of wormwood of 7.5 weight parts and the copper powder mixing of 0.3 weight part, add the Pentyl alcohol of 24.3 weight parts again as solvent, return stirring 2h at 140 DEG C, after reaction terminates, remove solvent under reduced pressure, gained residue adds 600 weight parts waters, 20min is reacted at 80 DEG C, filtered while hot, washing leaching cake, combining water layer, water layer concentrated hydrochloric acid is acidified to pH and equals 2, now separate out a large amount of black powder, suction filtration, gained solid acetone recrystallization, obtain compound N-quinolyl anthranilic acid,
Step B, the N-quinolyl anthranilic acid of 1.971 weight parts is mixed with the phosphorus oxychloride of 11.84 weight parts, in 15min, oil bath is heated to 85 ~ 90 DEG C, when there is vigorous reaction, remove heating bath immediately, if react too fierce, flask is cooled with cold water, treat that boiling eases up, oil bath temperature is increased to 135 ~ 140 DEG C, reaction 2h, after reaction terminates, residuum is the slow well-beaten strong aqua of impouring after the cooling period, in the mixture of trash ice and chloroform, with chloroform and ammonia water mixture washing flask, undissolved solids is no longer included after 30min, isolate chloroform layer, water layer continuation chloroform extraction, combined chloroform layer, Calcium Chloride Powder Anhydrous dried overnight, filter, steaming desolventizes, obtain compound 7-chlorobenzene also [b]-[1, 10] o-phenanthroline,
Step C, by the 7-chlorobenzene of 0.3 weight part also [b]-[1,10] the acetone mixing of o-phenanthroline and 23.64 weight parts, backflow adds the NaSCN of 0.275 weight part and the Tetrabutyl amonium bromide of 0.075 weight part after dissolving, after back flow reaction 3h, yellow solid powder is had to separate out, suction filtration, obtains 7-benzo [b]-[1,10] o-phenanthroline lsothiocyanates after water washing;
Step D, by the 7-benzo [b]-[1 of 0.24 weight part, 10] the acetonitrile mixing of o-phenanthroline lsothiocyanates and 27.65 weight parts, after add the p-chloro benzoyl hydrazine of 0.17 weight part, back flow reaction 2h, a large amount of solid is had to separate out in reaction process, cooling suction filtration obtains bright yellow solid and is 7-benzo [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide.
4. a purposes for acridine derivatives as claimed in claim 1, it is characterized in that, described acridine derivatives is preparing the purposes in antitumor drug.
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| CN104327050A (en) * | 2014-09-30 | 2015-02-04 | 广西中医药大学 | Acridine amide thiourea derivative, preparation method and uses thereof |
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| WO2015142684A1 (en) * | 2014-03-15 | 2015-09-24 | Wake Forest University | Design, synthesis, and biological activity of platinum-benz[c]acridine hybrid agents and methods associated therewith |
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- 2015-12-02 CN CN201510870147.0A patent/CN105399740B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2015142684A1 (en) * | 2014-03-15 | 2015-09-24 | Wake Forest University | Design, synthesis, and biological activity of platinum-benz[c]acridine hybrid agents and methods associated therewith |
| CN104327050A (en) * | 2014-09-30 | 2015-02-04 | 广西中医药大学 | Acridine amide thiourea derivative, preparation method and uses thereof |
| CN104326979A (en) * | 2014-09-30 | 2015-02-04 | 广西中医药大学 | 2-methyl-9-acridine(p-methoxy benzamido)thiourea, preparation method and uses thereof |
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