CN105399740B - Acridine derivatives and preparation method thereof and it is used as the purposes in antineoplastic - Google Patents
Acridine derivatives and preparation method thereof and it is used as the purposes in antineoplastic Download PDFInfo
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- CN105399740B CN105399740B CN201510870147.0A CN201510870147A CN105399740B CN 105399740 B CN105399740 B CN 105399740B CN 201510870147 A CN201510870147 A CN 201510870147A CN 105399740 B CN105399740 B CN 105399740B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- 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
- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses acridine derivatives and preparation method thereof and as the purposes in antineoplastic, the chemical names of the acridine derivatives is 7 benzos [b] [1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide；Structural formula is：
Description
Technical field
The invention belongs to drug field.It is more particularly related to a kind of acridine derivatives and preparation method thereof and
It is used as the purposes in antineoplastic.
Background technology
Acridine is the nitrogenous organic heterocyclic molecule that a class is received significant attention, because its structure is big ring conjugated system, tool
Rigid planar structure, can as the macromoleculars such as DNA insert, antitumor, antiviral, anti-malarial, antibacterial, bioluminescence visit
Very strong physiologically active people are shown in terms of pin and treatment AIDS to extract or using chemistry conjunction from natural products
Into method obtain substantial amounts of acridine compound, have studied their pharmacological activity and the mechanism of action.It is right in order to improve it
DNA affine performance, the rejection of a variety of enzymes and cytotoxicity etc., continuous exploration has been carried out to its structure of modification with changing
Enter, innovation of the invention is by connecting active group acid amides on the 7- positions of benzo [b]-[1,10] o-phenanthroline ring
Base thiocarbamide structure, synthesizing new acridine derivatives, derivative not yet has been reported that at present.
The content of the invention
It is an object of the invention to solve at least the above, and provide the advantage that at least will be described later.
It is a still further object of the present invention to provide a kind of acridine derivatives 7- benzos [b]-[1,10] o-phenanthroline to chlorobenzene
Formamido thiocarbamide, the compound has the effect of antitumor activity, with the applications well prospect for developing into treatment tumour.
In order to realize according to object of the present invention and further advantage there is provided a kind of acridine derivatives, its feature exists
In,
1) chemical name of the compound is 7- benzos [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide；
2) structural formula is：
A kind of acridine derivatives 7- benzos [b]-[1,10] o-phenanthroline is to the preparation method of chloro-benzoyl amino thiocarbamide, bag
Include：
Step 1: using o-bromobenzoic acid and 8- aminoquinolines as raw material, potassium carbonate and copper powder are catalyst, add n-amyl alcohol
As solvent, under 140 DEG C of counterflow conditions, compound N-quinolyl ortho-aminobenzoic acid is obtained through ullmann reaction；
Step 2: N- quinolyls ortho-aminobenzoic acid is with POCl3 cyclization, be made compound 7- chlorobenzenes simultaneously [b]-[1,
10] o-phenanthroline；
Step 3: 7- chlorobenzenes simultaneously [b]-[1,10] o-phenanthroline phase transfer catalyst TBAB effect under, with
NaSCN occurs nucleophilic substitution and compound 7- benzos [b]-[1,10] o-phenanthroline isothiocyanates is made；
Step 4: 7- benzos [b]-[1,10] o-phenanthroline isothiocyanates to be dissolved in after acetonitrile and add to chlorobenzoyl
After hydrazine, back flow reaction, filtering and washing, 7- benzos [b]-[1,10] o-phenanthroline is obtained to chloro-benzoyl amino thiocarbamide.
Preferably, described acridine derivatives 7- benzos [b]-[1,10] o-phenanthroline is specific to chloro-benzoyl amino thiocarbamide
Preparation method comprises the following steps：
Step A, by the o-bromobenzoic acid of 5.2 parts by weight, the 8- aminoquinolines of 4.9 parts by weight, 7.5 parts by weight potassium carbonate
Mixed with the copper powder of 0.3 parts by weight, add the n-amyl alcohol of 24.3 parts by weight as solvent, the return stirring 2h at 140 DEG C, instead
After should terminating, solvent is removed under reduced pressure, gained residue adds 600 parts by weight water, 20min is reacted at 80 DEG C, is filtered while hot, wash
Filter cake, combining water layer, water layer is acidified to pH with concentrated hydrochloric acid equal to 2, now separates out a large amount of black powders, and suction filtration, gained solid is used
Acetone recrystallization, obtains compound N-quinolyl ortho-aminobenzoic acid；
Step B, the N- quinolyls ortho-aminobenzoic acid of 1.971 parts by weight mixed with the POCl3 of 11.84 parts by weight,
In being heated to 85~90 DEG C in 15min in oil bath, when occurring vigorous reaction, heating bath is removed immediately, if reaction is excessively fierce, is used
Cold water cools down flask, treats that boiling eases up, and oil bath temperature is increased to 135~140 DEG C, reacts 2h, after reaction terminates, residue is cold
But in the mixture that the concentrated ammonia liquor being sufficiently stirred for, trash ice and chloroform are slowly poured into after, flask is washed with chloroform and ammonia water mixture,
There is no undissolved solids after 30min, chloroform layer is isolated, water layer continuation is extracted with chloroform, merge chloroform layer, anhydrous chlorine
Change calcium to be dried overnight, filter, solvent is evaporated off, compound 7- chlorobenzenes simultaneously [b]-[1,10] o-phenanthroline is obtained；
Step C, by the 7- chlorobenzenes of 0.3 parts by weight, simultaneously [b]-[1,10] o-phenanthroline and the acetone of 23.64 parts by weight are mixed,
Added after backflow dissolving after the NaSCN of 0.275 parts by weight and the TBAB of 0.075 parts by weight, back flow reaction 3h, there is Huang
Color solid powder is separated out, suction filtration, and 7- benzos [b]-[1,10] o-phenanthroline isothiocyanates is obtained after water washing；
Step D, by the 7- benzos [b] of 0.24 parts by weight-[1,10] o-phenanthroline isothiocyanates and 27.65 parts by weight
Acetonitrile is mixed, the rear p-chloro benzoyl hydrazine for adding 0.17 parts by weight, back flow reaction 2h, has a large amount of solids to separate out in course of reaction,
It is 7- benzos [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide that cooling suction filtration, which obtains bright yellow solid,.
Present invention simultaneously discloses with protect purposes of the acridine derivatives in antineoplastic is prepared.
The present invention at least includes following beneficial effect：It is demonstrated experimentally that new acridine derivatives pair disclosed in this invention
MGC-803, BEL-7404, NCI-H460 cell line have very strong inhibitory action, show significant antitumor activity, can use
There is selective antineoplastic in preparing.
Further advantage, target and the feature of the present invention embodies part by following explanation, and part will also be by this
The research and practice of invention and be understood by the person skilled in the art.
Embodiment
With reference to embodiment, the present invention is described in further detail, to make those skilled in the art with reference to specification
Word can be implemented according to this.
It should be noted that experimental method described in following embodiments, is conventional method unless otherwise specified, institute
Reagent and material are stated, unless otherwise specified, is commercially obtained.
The present invention provides a kind of acridine derivatives, it is characterised in that
1) chemical name of the compound is 7- benzos [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide；
2) structural formula is：
Molecular formula：C24H16ClN6OS
Relative molecular weight：457.93；
3) physicochemical property：Yellow powder, m.p.188-195 DEG C；1H NMR(DMSO-d6,400M Hz),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)；13C NMR (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 the compound is as follows：
Acridine derivatives 7- benzos [b]-[1,10] o-phenanthroline is to the preparation method of chloro-benzoyl amino thiocarbamide, bag
Include：
Step 1: using o-bromobenzoic acid and 8- aminoquinolines as raw material, potassium carbonate and copper powder are catalyst, add n-amyl alcohol
As solvent, under 140 DEG C of counterflow conditions, compound N-quinolyl ortho-aminobenzoic acid is obtained through ullmann reaction；
Step 2: N- quinolyls ortho-aminobenzoic acid is with POCl3 cyclization, be made compound 7- chlorobenzenes simultaneously [b]-[1,
10] o-phenanthroline；
Step 3: 7- chlorobenzenes simultaneously [b]-[1,10] o-phenanthroline phase transfer catalyst TBAB effect under, with
NaSCN occurs nucleophilic substitution and compound 7- benzos [b]-[1,10] o-phenanthroline isothiocyanates is made；
Step 4: 7- benzos [b]-[1,10] o-phenanthroline isothiocyanates to be dissolved in after acetonitrile and add to chlorobenzoyl
After hydrazine, back flow reaction, filtering and washing, 7- benzos [b]-[1,10] o-phenanthroline is obtained to chloro-benzoyl amino thiocarbamide.
Embodiment 1
Described acridine derivatives 7- benzos [b]-[1,10] o-phenanthroline is to the specific side of preparation of chloro-benzoyl amino thiocarbamide
Method comprises the following steps：
Step A, by the o-bromobenzoic acid of 5.2 parts by weight, the 8- aminoquinolines of 4.9 parts by weight, 7.5 parts by weight potassium carbonate
Mixed with the copper powder of 0.3 parts by weight, add the n-amyl alcohol of 24.3 parts by weight as solvent, the return stirring 2h at 140 DEG C, instead
After should terminating, solvent is removed under reduced pressure, gained residue adds 600 parts by weight water, 20min is reacted at 80 DEG C, is filtered while hot, wash
Filter cake, combining water layer, water layer is acidified to pH with concentrated hydrochloric acid equal to 2, now separates out a large amount of black powders, and suction filtration, gained solid is used
Acetone recrystallization, obtains compound N-quinolyl ortho-aminobenzoic acid, yield 36%；
Step B, the N- quinolyls ortho-aminobenzoic acid of 1.971 parts by weight mixed with the POCl3 of 11.84 parts by weight,
In being heated to 85~90 DEG C in 15min in oil bath, when occurring vigorous reaction, heating bath is removed immediately, if reaction is excessively fierce, is used
Cold water cools down flask, treats that boiling eases up, and oil bath temperature is increased to 135~140 DEG C, reacts 2h, after reaction terminates, residue is cold
But in the mixture that the concentrated ammonia liquor being sufficiently stirred for, trash ice and chloroform are slowly poured into after, flask is washed with chloroform and ammonia water mixture,
There is no undissolved solids after 30min, chloroform layer is isolated, water layer continuation is extracted with chloroform, merge chloroform layer, anhydrous chlorine
Change calcium to be dried overnight, filter, solvent is evaporated off, compound 7- chlorobenzenes simultaneously [b]-[1,10] o-phenanthroline, yield 18% is obtained；
Step C, by the 7- chlorobenzenes of 0.3 parts by weight, simultaneously [b]-[1,10] o-phenanthroline and the acetone of 23.64 parts by weight are mixed,
Added after backflow dissolving after the NaSCN of 0.275 parts by weight and the TBAB of 0.075 parts by weight, back flow reaction 3h, there is Huang
Color solid powder is separated out, suction filtration, and 7- benzos [b]-[1,10] o-phenanthroline isothiocyanates, yield 94% is obtained after water washing；
Step D, by the 7- benzos [b] of 0.24 parts by weight-[1,10] o-phenanthroline isothiocyanates and 27.65 parts by weight
Acetonitrile is mixed, the rear p-chloro benzoyl hydrazine for adding 0.17 parts by weight, back flow reaction 2h, has a large amount of solids to separate out in course of reaction,
It is 7- benzos [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide that cooling suction filtration, which obtains bright yellow solid,.
Embodiment 2
Anti tumor activity in vitro is tested
Experiment reagent
Cushioning liquid (pH=7.43) is 0.05moLL-1 phosphate buffer solution (PBS)；Dimethyl sulfoxide (DMSO) (DMSO)
It is pure for domestic analysis, PPMI1640 nutrient solutions, high sugar DEME nutrient solutions, DMEM nutrient solutions are a kind of containing various amino acid and grape
The culture medium of sugar, is developed, tire bovine whey (FBS) on the basis of MEM culture mediums, and 0.05% trypsase (trypsin)-
0.02%, EDTA etc. are purchased from GIBCO companies of the U.S..Cell is bred and citotoxicity detection kit (MTT) is purchased from Sigma public affairs
Department.
Laboratory apparatus
BCN-1360 superclean benches (Harbin east connection), Forma 3110CO2Incubator (USA), TECAN
Infinite M200 ELIASAs (Mannedorf, Switzerland), inverted microscope (Nikon), 7 degree of insulating box (Beijing good fortune
Meaning connection), automatic plate washer (the farsighted biology of upper Nereid), 96 porocyte culture plates (Costar, USA).
Experimental method
The culture and passage of cell
Selected cell line is placed in 37 DEG C, in the incubator under the conditions of the abundant humidifyings of 5%CO2, is inoculated in containing 10% inactivation
Cultivated in the PPMI1640 nutrient solutions of NBCS.Cell growth status is observed with inverted microscope, is changed 2~3 times weekly
Culture medium, 6~7 days passage once, during inoculation with 0.25% Trypsin Induced pass on, generally take passage 3~4 times, in pair
Number growth period cell is used to test.
The preparation of decoction
Sample accurately is weighed, is added in the 1.5mL centrifuge tubes of sterilizing, DMSO is added and is made into 2mM compound deposits
Liquid, -20 DEG C of freezen protectives.After melting before use respective concentration application is diluted to appropriate D-hanks.The change that measuring is selected
Compound concentration is respectively 20 μM.
MTT experiment method
The cell in exponential phase is taken, per the μ L of hole 180 (about 4500-5000 cell) celliferous culture medium inoculated
In 96 well culture plates, in 37 DEG C, 5%CO224h is cultivated under the conditions of abundant humidifying.After after cell attachment, add by every μ L of hole 20 amount
Enter sample, each sample sets 6 multiple holes, concurrently sets corresponding blank control.Continue to cultivate after 48h, 10 μ L are added per hole
MTT reagents (concentration is 2mg/mL), continue to be incubated after 4h, supernatant is abandoned in suction, 150 μ L DMSO are added per hole, and slight concussion is anti-
5-8min is answered, crystalline particle is fully dissolved.Blank control group returns to zero, and is determined with ELIASA with 490nm wavelength and removes bias light
After absorption value absorbance (Value), the IC of corresponding cell line is of 5 concentration gradients50Value, after all experiments are repeated 3 times
Average.
7- benzos [b]-[1,10] o-phenanthroline that embodiment 1 is obtained to chloro-benzoyl amino thiocarbamide and MGC-803,
BEL-7404, NCI-H460 cell line action time 72 hours, as a result as shown in table 1：
The 7- benzos [b] of table 1-[1,10] o-phenanthroline is to chloro-benzoyl amino thiocarbamide and positive controls 5-FU pair
Medium effective concentration (the IC of tumor cell line50) table
From the results shown in Table 1,7- benzos [b]-[1,10] o-phenanthroline of the invention is to chloro-benzoyl amino sulphur
Urea shows that the compound has strong antitumor activity through anticancer experiment in vitro, and its antitumor activity is than positive control 5-
Fluoropyrimidine is strong.The present invention provides new thinking to research and develop new acridine type antineoplastic.
Although embodiment of the present invention is disclosed as above, it is not restricted in specification and embodiment listed
With it can be applied to various suitable the field of the invention completely, can be easily for those skilled in the art
Other modification is realized, therefore under the universal limited without departing substantially from claim and equivalency range, the present invention is not limited
In specific details and shown here as the embodiment with description.
Claims (4)
1. a kind of acridine derivatives, it is characterised in that
1) chemical name of the compound is 7- benzos [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide；
2) structural formula is：
2. a kind of preparation method of acridine derivatives as claimed in claim 1, it is characterised in that including：
Step 1: using o-bromobenzoic acid and 8- aminoquinolines as raw material, potassium carbonate and copper powder are catalyst, add n-amyl alcohol conduct
Solvent, under 140 DEG C of counterflow conditions, compound N-quinolyl ortho-aminobenzoic acid is obtained through ullmann reaction；
Step 2: N- quinolyls ortho-aminobenzoic acid is with POCl3 cyclization, compound 7- chlorobenzenes are made, and simultaneously [b]-[1,10] is adjacent
Phenanthroline；
Step 3: simultaneously [b]-[1,10] o-phenanthroline is under the effect of phase transfer catalyst TBAB for 7- chlorobenzenes, with NaSCN
Compound 7- benzos [b]-[1,10] o-phenanthroline isothiocyanates is made in generation nucleophilic substitution；
Step 4: 7- benzos [b]-[1,10] o-phenanthroline isothiocyanates to be dissolved in after acetonitrile and add p-chloro benzoyl hydrazine, return
After stream reaction, filtering and washing, 7- benzos [b]-[1,10] o-phenanthroline is obtained to chloro-benzoyl amino thiocarbamide.
3. the preparation method of acridine derivatives as claimed in claim 2, it is characterised in that specifically include following steps：
Step A, by the o-bromobenzoic acid of 5.2 parts by weight, the 8- aminoquinolines of 4.9 parts by weight, the potassium carbonate of 7.5 parts by weight and
The copper powder mixing of 0.3 parts by weight, adds the n-amyl alcohol of 24.3 parts by weight as solvent, the return stirring 2h at 140 DEG C, reaction
After end, solvent is removed under reduced pressure, gained residue adds 600 parts by weight water, 20min is reacted at 80 DEG C, is filtered while hot, washing filter
Cake, combining water layer, water layer is acidified to pH with concentrated hydrochloric acid equal to 2, now separates out a large amount of black powders, suction filtration, gained solid uses third
Ketone is recrystallized, and obtains compound N-quinolyl ortho-aminobenzoic acid；
Step B, the N- quinolyls ortho-aminobenzoic acid of 1.971 parts by weight mixed with the POCl3 of 11.84 parts by weight, in
85~90 DEG C are heated in 15min in oil bath, when occurring vigorous reaction, heating bath is removed immediately, if reaction is excessively fierce, with cold
Water cooling flask, treats that boiling eases up, and oil bath temperature is increased to 135~140 DEG C, reacts 2h, and after reaction terminates, residue is in cooling
In the mixture for being slowly poured into the concentrated ammonia liquor being sufficiently stirred for, trash ice and chloroform afterwards, flask is washed with chloroform and ammonia water mixture,
There is no undissolved solids after 30min, chloroform layer is isolated, water layer continuation is extracted with chloroform, merge chloroform layer, anhydrous chlorine
Change calcium to be dried overnight, filter, solvent is evaporated off, compound 7- chlorobenzenes simultaneously [b]-[1,10] o-phenanthroline is obtained；
Step C, by the 7- chlorobenzenes of 0.3 parts by weight, simultaneously [b]-[1,10] o-phenanthroline and the acetone of 23.64 parts by weight are mixed, backflow
Added after dissolving after the NaSCN of 0.275 parts by weight and the TBAB of 0.075 parts by weight, back flow reaction 3h, there is yellow to consolidate
Body powder is separated out, suction filtration, and 7- benzos [b]-[1,10] o-phenanthroline isothiocyanates is obtained after water washing；
Step D, the acetonitrile by the 7- benzos [b] of 0.24 parts by weight-[1,10] o-phenanthroline isothiocyanates and 27.65 parts by weight
There are a large amount of solids to separate out in mixing, the rear p-chloro benzoyl hydrazine for adding 0.17 parts by weight, back flow reaction 2h, course of reaction, cooling
It is 7- benzos [b]-[1,10] o-phenanthroline to chloro-benzoyl amino thiocarbamide that suction filtration, which obtains bright yellow solid,.
4. a kind of purposes of acridine derivatives as claimed in claim 1, it is characterised in that the acridine derivatives are preparing anti-swell
Purposes in tumor medicine.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| CA2942891C (en) * | 2014-03-15 | 2018-10-30 | Wake Forest University | Design, synthesis, and biological activity of platinum-benz[c]acridine hybrid agents and methods associated therewith |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (1)
| Title |
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| 吖啶类化合物在抗肿瘤方面的研究进展;郎许亮等;《化学进展》;20120831;第24卷(第8期);第1497-1503页 * |
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