CN108727434A - 11- trifluoro methyl benzimidazoles -1,8- naphthalimides-platinum complex and its preparation method and application - Google Patents
11- trifluoro methyl benzimidazoles -1,8- naphthalimides-platinum complex and its preparation method and application Download PDFInfo
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- CN108727434A CN108727434A CN201810729763.8A CN201810729763A CN108727434A CN 108727434 A CN108727434 A CN 108727434A CN 201810729763 A CN201810729763 A CN 201810729763A CN 108727434 A CN108727434 A CN 108727434A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a kind of 11- trifluoro methyl benzimidazoles -1,8- naphthalimides-platinum complexes and its preparation method and application.The preparation method of the complex mainly includes the following steps that：It takes compound shown in compound and formula (III) shown in following formula (II) to be placed in organic solvent, complexation reaction is carried out under the conditions of being heated or not heated to get target product.Complex of the present invention is significantly higher than common antitumor drug cis-platinum to the inhibitory activity of certain cancer cells, and lower to people's normal cell lines of human liver HL-7702 toxicity.Shown in the structure of complex of the present invention such as following formula (I), the structure for preparing compound shown in compound and formula (III) shown in the raw material formula (II) involved in the complex is as follows：
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of 11- trifluoro methyl benzimidazoles -1,8- naphthalimide -
Platinum complex and its preparation method and application.
Background technology
Platinum antineoplastic complex is a kind of important antitumor drug, and the platinum complexes such as cis-platinum, carboplatin illustrate good
Good antitumor activity, is important clinical anti-cancer drug.Therefore, design and the new and effective less toxic platinum metals base of screening are anti-swollen
Tumor complex becomes current research hotspot.
Naphthoyl imide compounds are a kind of classical small molecule DNA intercalator, representation compound Amonafide
(amonafide) and mitonafide (mitonafide) has very high active anticancer to more plants of cancer cells.But it has not yet to see
There is the preparation method of 11- trifluoro methyl benzimidazoles -1,8- naphthalimides-platinum complex and its correlation of cytotoxicity is reported
Road.
Invention content
The technical problem to be solved in the present invention is to provide a kind of structure novel and the 11- fluoroform high to cytotoxicity
Base benzimidazole -1,8- naphthalimide-platinum complex and its preparation method and application.
The present invention relates to compound shown in following formula (I)s or its pharmaceutically acceptable salts：
The present invention also provides the preparation methods of above compound, mainly include the following steps that：Take following formula (II) shownization
It closes compound shown in object and formula (III) in organic solvent, complexation reaction is carried out under the conditions of being heated or not heated to get target
Product；
Pt(DMSO)2Cl2(III)。
In above-mentioned preparation method, compound shown in the formula (II) is that 11- trifluoro methyl benzimidazoles -1,8- naphthoyl is sub-
Amine, the compound can refer to existing literature (Banerji K D, Sen K K, Mazumdar A K D, Synthesis of
some naphthoylenebenzimidazole,Journal of the Indian Chemical Society,197653
(11), 1159-61) synthesized, also can designed, designed synthetic route synthesized.It is preferred that being synthesized using following methods：.
1,8- naphthalene anhydrides and 4- trifluoromethyl o-phenylenediamines is stoichiometrically taken to be placed in polar solvent (selected from acetic acid, diformazan
The combination of one or more of benzene, toluene, DMF, DMSO and ethylene glycol monomethyl ether) in back flow reaction (about 4-8h), reaction
After, it is cooling, there is solid precipitation, collects solid, it is dry to get to compound 11- trifluoromethyls shown in the formula (II)
Benzimidazole -1,8- naphthalimide (yellow crystals or powder), specific synthetic route is as follows：
In above-mentioned preparation method, compound shown in the formula (III) is that cis- dichloro two (dimethyl sulfoxide (DMSO)) closes platinum
(II), existing literature (Al-Allaf T A K, et al.Transit.Met.Chem., 1998) is can refer to be prepared.
In above-mentioned preparation method, the molar ratio of compound shown in compound and formula (III) shown in the formula (II) is chemistry
Ratio is measured, in actual operation, compound shown in compound or formula (III) shown in formula (II) also can be relatively excessive, but excessive
Products therefrom can be caused impure.
In above-mentioned preparation method, the organic solvent can be selected from methanol, ethyl alcohol, chloroform, dichloromethane, dimethyl
The combination of one or more of sulfoxide (DMSO) and n,N-Dimethylformamide (DMF).When being selected as organic solvent
In above-mentioned selection when two or more mixtures, the proportioning between them can be arbitrary proportioning.The dosage of the organic solvent can
It determines as needed.In specific dissolving step, compound shown in compound shown in formula (II) and formula (III) can be used respectively
Organic solvent dissolves, and remixes and reacts together；Also after compound shown in compound shown in formula (II) and formula (III) being mixed
It is dissolved again with organic solvent.
11- trifluoro methyl benzimidazoles -1,8- naphthalimide-platinum complex of the present invention, can in specific prepare
It is prepared using solwution method or solvent-thermal method.
When being prepared using solwution method, include mainly：Compound shown in compound and formula (III) shown in formula (II) is taken to dissolve
In organic solvent, complexation reaction being carried out under the conditions of being heated or not heated, is filtered while hot after reaction, filtrate cooling has
Solid is precipitated, and collects solid, as target product.
In above-mentioned solwution method, it whether complete can react by thin-layer chromatography tracing detection.In order to improve the yield of reaction,
Reaction is preferably performed under heating conditions, and is further preferably carried out under conditions of >=40 DEG C, more preferably in 60-80 DEG C of condition
Lower progress, when reaction carries out in this preferred range, the time of reaction is usually 24-48h.In this method, 1mmol's
Compound is usually dissolved with the organic solvent of 6-25mL shown in the formula (III) of compound and 1mmol shown in formula (II).
When being prepared using solvent-thermal method, include mainly：Take compound shown in compound and formula (III) shown in formula (II) molten
Solution is subsequently placed in container (being usually the heavy-walled glass pipe or pressure bottle of one end open), in organic solvent through liquid nitrogen frozen
After be evacuated to vacuum, sealing after complexation reaction is carried out under heating condition, it is cooling, have crystal precipitation, collect solid, as target is produced
Object.In this method, reaction preferably carries out under conditions of >=40 DEG C, is more preferably carried out under the conditions of 60-80 DEG C, when reaction exists
When being carried out in this preferred range, the time of reaction is usually 24-48h.When using the method, shown in the formula (II) of 1mmol
Compound is usually dissolved with the organic solvent of 5-20mL shown in compound and the formula (III) of 1mmol.
The target product that above-mentioned solvent-thermal method is precipitated is crystal, and the product that solwution method is precipitated is usually powdered, gained
Powdered target product further can obtain crystal using the method for solvent crystallization, specially：Powdered target product is set
The in the mixed solvent of a kind of composition in a kind of and chloroform and dichloromethane in methanol and ethyl alcohol, under the conditions of 60-80 DEG C
24-48h is reacted, the target product of lenticular is can be obtained after cooling.
The invention also includes above-mentioned 11- trifluoro methyl benzimidazoles -1,8- naphthalimides-platinum complex or its pharmaceutically may be used
The salt application in preparation of anti-tumor drugs of receiving.
The present invention further comprises a kind of pharmaceutical composition, it contains the above-mentioned 11- trifluoromethyls of the upper effective dose for the treatment of
Benzimidazole -1,8- naphthalimides-platinum complex or its pharmaceutically acceptable salt.
Compared with prior art, the present invention provides a kind of 11- trifluoro methyl benzimidazole -1,8- naphthoyls of structure novel
Imines-platinum complex, short preparation period, yield is high, stable quality；Our experimental result show that the complex is to certain
The inhibitory activity of a little cell strains is significantly higher than its parent nucleus and cis-platinum (such as human liver cancer cells Hep G2, human glioma cell
Strain U251), while its to the toxicity of normal cell well below tumor Drugs (such as cis-platinum and 5 FU 5 fluorouracil), be expected to use
In the preparation of antitumor drug.
Description of the drawings
Fig. 1 is the crystal structure figure of final product made from the embodiment of the present invention 1；
Fig. 2 is that compound I and the Topo I of various concentration act on agarose gel electrophoresis figure.
Specific implementation mode
With reference to specific embodiment, the present invention is described in further detail, to more fully understand present disclosure, but
The present invention is not limited to following embodiments.
(i.e. 11- trifluoro methyl benzimidazoles -1,8- naphthoyls are sub- for compound shown in formula (II) involved in following embodiment
Amine) it is prepared as follows to obtain：
Take 1,8- naphthalene anhydrides (5g, 25.2mmol, 1.0equiv), 4- trifluoromethyls o-phenylenediamine (4.29g, 25.2mmol,
It 1.0equiv) is placed in 100ml round-bottomed flasks, after 50mL acetic acid is added, reaction is heated to 118 DEG C and is stirred at reflux 7h.Stop anti-
It answers, cooled to room temperature, there is yellow solid precipitation, filter, obtain compound (yellow powdery solid) shown in formula (II)
7.16g, 1H NMR (400MHz, DMSO) δ 8.79 (d, J=7.2Hz, 1H), 8.74 (d, J=7.2Hz, 1H), 8.60 (dd, J=
13.8,8.3Hz, 2H), 8.45 (d, J=8.2Hz, 1H), 8.24 (s, 1H), 8.02-7.91 (m, 2H), 7.84 (d, J=
8.4Hz,1H).13C NMR(101MHz,DMSO)δ160.87,151.72,143.73,136.48,133.42,132.43,
132.16,130.12,128.12,127.88,127.17,123.06,122.18,122.14,120.23,117.37,117.33,
116.60,63.02.MS m/z:339.06[M+H]+.
Embodiment 1
Measure 11- trifluoro methyl benzimidazoles -1,8- naphthalimide (100.06mg, 0.2958mmol), two (diformazan of dichloro
Sulfoxide) close platinum (II) (Pt (DMSO)2Cl2) (124.53mg, 0.2958mmol), 6ml methanol and 6ml chloroforms, it is placed in round-bottomed flask
In, at being 60 DEG C in temperature, it is stirred to react 48h, is filtered to remove unreacting material while hot after reaction, filtrate is cooled to room
Temperature has yellow solid precipitation, collects solid, dry, obtains product as yellow powder 107.00mg, yield 53.14%.
The characterizations such as mass spectrum, elemental analysis and the analysis of X- single crystal diffractions are carried out to this implementation products therefrom, it is specific as follows：
(1)MS m/z:690.9979[M–2Cl+DMSO]+.
(2)Anal.Calc.(f for C21H15Cl2F3N2O2PtS)C 36.96；H 2.22；N 4.11%, Found.C
37.01；H 2.23；N 4.08%.
(3) taking this implementation of 10mg products therefrom and 5ml methanol/chloroform mixed solution, (volume ratio of methanol and chloroform is 1:
1) it is placed in tube sealing, is warming up to 90 DEG C, react 12h, it is cooling, there is crystal precipitation, collects crystal, it is dry, obtain yellow crystals.It will
Gained yellow crystals are parsed through X-Ray single crystal diffractions, and crystallographic data is as described in Table 1, and part bond distance and bond angle are as follows
It states shown in table 2, the crystal structure of products therefrom is as shown in Figure 1.
Table 1：The crystallography and structural modifications data of product
Table 2：The strong length in the part of productWith bond angle [°]
Accordingly, it can be determined that product as yellow powder obtained by the present embodiment is trifluoro methyl benzimidazole -1 target product 11-,
8- naphthalimides-platinum complex, shown in structural formula such as following formula (I)：
Embodiment 2
Take 11- trifluoro methyl benzimidazoles -1,8- naphthalimide (338.28mg, 1mmol), Pt (DMSO)2Cl2
(422.9mg, 1mmol) and 12ml methanol, is placed in heavy wall pressure bottle, at being 70 DEG C in temperature after dissolving, is stirred to react 36h,
Cooled to room temperature has yellow solid precipitation, detaches, dry, obtains yellow powder 403.43mg, yield 53.00%.
Mass spectrum, elemental analysis and the analysis of X- single crystal diffractions are carried out to this implementation products therefrom, determine production obtained by the present embodiment
Object is target compound.
Embodiment 3
Take 11- trifluoro methyl benzimidazoles -1,8- naphthalimide (250.46mg, 0.7404mmol), Pt (DMSO)2Cl2
(311.64mg, 0.7404mmol) and 8ml DMSO, are placed in round-bottomed flask, at being 80 DEG C in temperature after dissolving, are stirred to react
For 24 hours, cooled to room temperature has yellow solid precipitation, detaches, dry, obtains yellow powder 320.96mg, yield 57.10%.
Mass spectrum, elemental analysis and the analysis of X- single crystal diffractions are carried out to this implementation products therefrom, determine production obtained by the present embodiment
Object is target compound.
Embodiment 4
Take 11- trifluoro methyl benzimidazoles -1,8- naphthalimide (125.23mg, 0.3702mmol), Pt (DMSO)2Cl2
(155.82mg, 0.3702mmol) and 10ml chloroforms, are placed in round-bottomed flask, at being 80 DEG C in temperature after dissolving, are stirred to react,
40h to be reacted, is filtered to remove unreacting material while hot after reaction, cooled to room temperature has yellow solid precipitation, separation,
It is dry, obtain yellow powder 129.28mg, yield 46.00%.
Mass spectrum, elemental analysis and the analysis of X- single crystal diffractions are carried out to this implementation products therefrom, determine production obtained by the present embodiment
Object is target compound.
Embodiment 5
Take 11- trifluoro methyl benzimidazoles -1,8- naphthalimide (125.23mg, 0.3702mmol), Pt (DMSO)2Cl2
(155.82mg, 0.3702mmol), 6ml ethyl alcohol and 7ml dichloromethane, are placed in round-bottomed flask, at being 40 DEG C in temperature, stir
48h to be reacted, is filtered to remove unreacting material while hot after reaction, cooled to room temperature has yellow solid precipitation, separation,
It is dry, obtain yellow powder 25.36mg, yield 20.00%.
Mass spectrum, elemental analysis and the analysis of X- single crystal diffractions are carried out to this implementation products therefrom, determine production obtained by the present embodiment
Object is target compound.
Embodiment 6
Embodiment 5 is repeated, unlike, reaction temperature is room temperature.
Finally obtain yellow powder 10.12mg, yield 7.90%.
Mass spectrum, elemental analysis and the analysis of X- single crystal diffractions are carried out to this implementation products therefrom, determine production obtained by the present embodiment
Object is target compound.
Experimental example 1：Target compound of the present invention tests the anti tumor activity in vitro of a variety of human tumor cell lines：
The antitumor work of the 11- trifluoro methyl benzimidazoles -1,8- naphthalimides-platinum complex to illustrate the invention
Complex has been carried out with, applicant antitumor activity experiment (with common antitumor drug 5 FU 5 fluorouracil (5-FU) and
Cis-platinum (Cis-platin) is reference), and to carrying out to normal cell by compound made from 1 the method for above-described embodiment
Toxicity test.
1. the inoculation and culture of cell
Selected cell strain is placed in 37 DEG C, 5%CO2In incubator under the conditions of abundant humidifying, it is inoculated in containing 10% inactivation
It is cultivated in the PPMI1640 culture solutions of newborn bovine serum.Cell growth status is observed with inverted microscope, replaces 2-3 training weekly
Base is supported, passage in 6-7 days is primary, and when inoculation is passed on 0.25% trypsin digestion, is usually taken passage 3-4 time, is in logarithm life
Long-term cell is for testing.
2. the active primary dcreening operation of Compound cellular level
(complex wherein of the present invention is by 1 the method system of above-described embodiment to compound used in this experiment
), all compounds are configured to 100 μ g/mL by purity >=95%, and cosolvent DMSO final concentrations are no more than 1%, it is dense to test this
For each compound to the inhibiting rate of cancer cell, all inhibiting rates are more than 50% and meet suppressed (or impaired) form of cell under light microscopic under degree
(such as cell shrinkage, the broken, floating) of variation, and be not prodigious compound to normal cell toxicity, then preliminary judgement is
The compound primary dcreening operation is effective, i.e., seeks IC into next step50Stage.
3. cell growth inhibition test (mtt assay)
MTT colorimetric methods are a kind of methods of detection cell growth and survival.Testing principle：It is different from dead cell, it is exogenous
MTT can be reduced to the bluish violet crystallization first a ceremonial jade-ladle, used in libation (Formazan) of water-insoluble simultaneously by the succinate dehydrogenase in living cells mitochondria
It is deposited in cell.Dimethyl sulfoxide (DMSO) (DMSO) can dissolve the first a ceremonial jade-ladle, used in libation in cell, with enzyme-linked immunosorbent assay instrument in 490nm wavelength
Place measures its absorbance value, can reflect living cells quantity indirectly.Within the scope of certain cell number, MTT crystallize the amount to be formed with it is thin
Born of the same parents' number is directly proportional.This method be widely used in the Activity determinations of some bioactie agents, large-scale screening anti-tumor medicine,
Cell toxicity test and tumor radiosensitivity measure etc., have the characteristics that high sensitivity, economic.
The cell in exponential phase is taken, per 180 μ L of hole (about 4500-5000 cell) celliferous culture medium inoculated
In 96 well culture plates, in 37 DEG C, 5%CO2It is cultivated for 24 hours under the conditions of abundant humidifying.After cell is adherent, add by the amount of 20 μ L of every hole
Enter sample, each sample sets 6 multiple holes, concurrently sets corresponding blank control.Continue after cultivating 48h, 10 μ L are added per hole
MTT reagents (a concentration of 5mg/mL) continue after being incubated 4h, and supernatant is abandoned in suction, and 150 μ L DMSO are added per hole, and slight concussion is anti-
5-8min is answered, crystalline particle is made fully to dissolve.Blank control group returns to zero, and removal bias light is measured with 490nm wavelength with microplate reader
After absorption value absorbance value (Value), calculating cell proliferation inhibition rate, the test-compound good to primary dcreening operation antitumous effect, after
The continuous IC for being continued to do corresponding cell strain with 5 concentration gradients50Value, all experiments are averaged after being repeated 3 times.Experimental result is detailed
It see the table below 3.
From the data in table 3, complex of the present invention is thin to human liver cancer cells Hep G2, human glioma
The inhibitory activity of born of the same parents' strain U251 is superior to common antitumor drug cis-platinum, and ligands and complexes are to people's normal cell lines of human liver HL-
7702 toxicity is less than cis-platinum.The above result shows that by the way that 11- trifluoro methyl benzimidazole -1,8- naphthalimide mesh cores are drawn
Entering to prepare novel 11- trifluoro methyl benzimidazoles -1,8- naphthalimides-platinum antineoplastic complex in the structure of platinum metals is
It is feasible, the new antitumoral complex of high-efficiency low-toxicity can be filtered out.But complex of the present invention is to all human cancer cells
Inhibitory activity not all better than its ligand, that is to say, that by 11- trifluoro methyl benzimidazole -1,8- naphthalimide mesh cores
Platinum metals structure is introduced to differ the cytotoxicity surely improved to tumour cell.
Table 3：Semi-inhibit rate concentration (C of the compound to different tumor cell lines50, μM)
ndaExpression is not tested.
Experimental example 2：The Anticancer Effect and Mechanism of complex of the present invention
The antitumor action of the 11- trifluoro methyl benzimidazoles -1,8- naphthalimides-platinum complex to illustrate the invention
Mechanism, applicant study the Anticancer Effect and Mechanism of the complex based on topoisomerase I target spot.
1. with topoisomerase I repercussion study
It is a common target of naphthoyl imide compounds and cis-platinum based on topoisomerase, we are solidifying using agarose
The interaction of gel electrophoresis and Western blotting research complex and topoisomerase.
Fig. 2 is compound I and Topo the I effect agarose gel electrophoresis figures that various concentration is added.Showing of electrophoresis result
Closing object I in vitro has compared with high inhibition effect TopoI, and urging for the TopoI of 0.1U/L can be completely inhibited under 20 μM of concentration
Change function, compound can completely inhibit topoisomerase I activity at 80 μM.Classical Topo I toxic agents camptothecine (T) in vitro for
The 503nhibiting concentration of topoisomerase I is about 17 μM, and compound I is suitable with its to the inhibitory activity of topoisomerase I.
Fig. 2 experiments show that compound I has stronger topoisomerase enzyme inhibition activity, therefore it is presumed that it plays anticancer work
Property may be by inhibiting the activity of intracellular topoisomerase.
Claims (7)
1. compound or its pharmaceutically acceptable salt shown in following formula (I)s：
2. the preparation method of compound described in claim 1, it is characterised in that：It mainly includes the following steps that：Take following formula (II)
Compound is placed in organic solvent shown in shown compound and formula (III), and complexation reaction is carried out under the conditions of being heated or not heated,
Up to target product；
Pt(DMSO)2Cl2(III)。
3. the preparation method of compound according to claim 1, it is characterised in that：The organic solvent be selected from methanol,
The combination of one or more of ethyl alcohol, chloroform, dichloromethane, dimethyl sulfoxide (DMSO) and n,N-Dimethylformamide.
4. the preparation method of compound according to claim 1, it is characterised in that：It is described reaction under conditions of >=40 DEG C into
Row.
5. the preparation method of compound according to claim 1, it is characterised in that：It is described reaction under the conditions of 60-80 DEG C into
Row.
6. compound described in claim 1 or its pharmaceutically acceptable salt application in preparation of anti-tumor drugs.
7. a kind of pharmaceutical composition, it is characterised in that：Compound or its medicine described in claim 1 containing the upper effective dose for the treatment of
Acceptable salt on.
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