CN109021020B - 11, 12-dimethyl benzimidazole-1, 8-naphthalimide-platinum complex and preparation method and application thereof - Google Patents
11, 12-dimethyl benzimidazole-1, 8-naphthalimide-platinum complex and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an 11, 12-dimethylbenzimidazole-1, 8-naphthalimide-platinum complex and a preparation method and application thereof. The preparation method of the complex mainly comprises the following steps: putting a compound shown in a formula (II) and a compound shown in a formula (III) into an organic solvent, and carrying out a coordination reaction under the heating condition or the non-heating condition to obtain a target product. The complex has obviously higher inhibitory activity on certain cancer cells than that of a common antitumor drug cisplatin, and has lower toxicity on normal human liver cells HL-7702. The complex of the invention has a structure shown in the following formula (I), and the structures of the compound shown in the formula (II) and the compound shown in the formula (III) which are used as raw materials for preparing the complex are as follows:
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to an 11, 12-dimethylbenzimidazole-1, 8-naphthalimide-platinum complex as well as a preparation method and application thereof.
Background
Since the discovery of platinum metal-based antitumor complexes such as cisplatin and carboplatin, the development of novel high-efficiency low-toxicity platinum metal-based antitumor complexes becomes a current research hotspot.
Naphthalimide compounds are a class of classical small molecule DNA intercalators, and represent compounds amonafide (amonafide) and mitonafide (mitonafide) which have high anticancer activity on multiple cancer cells. However, no 11, 12-dimethylbenzimidazole-1, 8-naphthalimide-platinum complex preparation method and relevant reports on cytotoxicity are found at present.
Disclosure of Invention
The invention aims to provide an 11, 12-dimethylbenzimidazole-1, 8-naphthalimide-platinum complex which has a novel structure, high toxicity to some tumor cells and low toxicity to normal liver cells, and a preparation method and application thereof.
The invention relates to a compound shown as the following formula (I) or a pharmaceutically acceptable salt thereof:
the invention also provides a preparation method of the compound, which mainly comprises the following steps: taking a compound shown in a formula (II) and a compound shown in a formula (III) to perform a coordination reaction in an organic solvent under the heating condition or the non-heating condition to obtain a target product;
in the preparation method, the compound shown in the formula (II) is 11, 12-dimethylbenzimidazole-1, 8-naphthalimide, and a synthetic route is designed by self for synthesis.
Taking 1, 8-naphthalic anhydride and 3, 4-dimethyl o-phenylenediamine according to a stoichiometric ratio, placing the 1, 8-naphthalic anhydride and the 3, 4-dimethyl o-phenylenediamine in a polar solvent (one or a combination of more than two of acetic acid, dimethylbenzene, methylbenzene, DMF, DMSO and ethylene glycol monomethyl ether) for reflux reaction (about 4-8h), cooling after the reaction is finished, separating out solids, collecting the solids, and drying to obtain the compound 11, 12-dimethyl benzimidazole-1, 8-naphthalimide (yellow crystal or powder) shown in the formula (II), wherein the specific synthetic route is shown as follows:
in the above production method, the compound represented by the formula (III) is cis-bis (dimethyl sulfoxide) platinum (II) dichloride, and can be produced by referring to the existing literature (Al-Allaf T AK, et Al. Transit. Met. chem., 1998).
In the above-mentioned preparation method, the molar ratio of the compound represented by the formula (II) to the compound represented by the formula (III) is stoichiometric, and in actual operation, the compound represented by the formula (II) or the compound represented by the formula (III) may be relatively excessive, but the excessive amount may cause the obtained product to be impure.
In the above preparation method, the organic solvent may be one or a combination of two or more selected from methanol, ethanol, chloroform, dichloromethane, dimethyl sulfoxide (DMSO) and N, N-Dimethylformamide (DMF). When the organic solvent is selected from a mixture of two or more of the above-mentioned solvents, the ratio of the organic solvent to the organic solvent may be any ratio. The amount of the organic solvent may be determined as required. In a specific dissolving step, the compound shown in the formula (II) and the compound shown in the formula (III) can be respectively dissolved by organic solvents and then mixed together for reaction; the compound represented by the formula (II) and the compound represented by the formula (III) may be mixed and then dissolved in an organic solvent.
The 11, 12-dimethylbenzimidazole-1, 8-naphthalimide-platinum complex can be prepared by a solution method or a solvothermal method during specific preparation.
When the preparation method adopts a solution method, the method mainly comprises the following steps: dissolving the compound shown in the formula (II) and the compound shown in the formula (III) in an organic solvent, carrying out coordination reaction under the condition of heating or not, filtering while the solution is hot after the reaction is finished, cooling the filtrate, separating out solids, and collecting the solids, thus obtaining the target product.
In the solution method, whether the reaction is complete or not can be followed by thin layer chromatography. In order to improve the yield of the reaction, the reaction is preferably carried out under heating, more preferably at not less than 40 ℃, still more preferably at 60 to 80 ℃, and when the reaction is carried out within this preferred temperature range, the reaction time is usually 24 to 48 hours. In this method, 1mmol of the compound represented by the formula (II) and 1mmol of the compound represented by the formula (III) are usually dissolved in 6 to 25mL of an organic solvent.
When the preparation is carried out by a solvothermal method, the preparation mainly comprises the following steps: dissolving the compound shown in the formula (II) and the compound shown in the formula (III) in an organic solvent, then placing the solution in a container (usually a thick-wall glass tube or a pressure-resistant bottle with an opening at one end), freezing the solution by using liquid nitrogen, vacuumizing, sealing the solution by melting, carrying out coordination reaction under a heating condition, cooling, separating out crystals, and collecting the solid, namely the target product. In this process, the reaction is preferably carried out at 40 ℃ or higher, more preferably 60 to 80 ℃ or lower, and when the reaction is carried out in this preferred temperature range, the reaction time is usually 24 to 48 hours. In this method, 1mmol of the compound of the formula (II) and 1mmol of the compound of the formula (III) are usually dissolved in 5 to 20mL of an organic solvent.
The target product precipitated by the solvothermal method is crystals, while the product precipitated by the solution method is usually powder, and the obtained powder target product can be further crystallized by a solvent method to obtain the crystals, specifically: putting the powdery target product into a mixed solvent consisting of one of methanol and ethanol and one of chloroform and dichloromethane, reacting for 24-48h at the temperature of 60-80 ℃, and cooling to obtain the crystalline target product.
The invention also comprises the application of the 11, 12-dimethylbenzimidazole-1, 8-naphthalimide-platinum complex or the pharmaceutically acceptable salt thereof in preparing anti-tumor drugs.
The present invention further includes a pharmaceutical composition comprising a therapeutically effective amount of the above 11, 12-dimethylbenzimidazole-1, 8-naphthalimide-platinum complex or a pharmaceutically acceptable salt thereof.
Compared with the prior art, the invention provides the 11, 12-dimethylbenzimidazole-1, 8-naphthalimide-platinum complex with a novel structure, and the complex has the advantages of short preparation period, high yield and stable quality; the test results of the applicant show that the inhibitory activity of the complex on certain cell strains is remarkably higher than that of the nucleus pulposus and cisplatin (such as human liver cancer cell SMMC-7721 and human glioma cell strain U251), and meanwhile, the toxicity of the complex on normal cells is far lower than that of common anticancer drugs (such as cisplatin and 5-fluorouracil), so that the complex is expected to be used for preparing the antitumor drugs.
Drawings
FIG. 1 is a crystal structure diagram of a final product obtained in example 1 of the present invention;
FIG. 2 is a graph of agarose gel electrophoresis of different concentrations of Compound I and Topo I.
Detailed Description
The present invention will be better understood from the following detailed description of specific examples, which should not be construed as limiting the scope of the present invention.
The compound represented by the formula (II) (i.e., 11, 12-dimethylbenzimidazole-1, 8-naphthalimide) referred to in the following examples was prepared as follows:
1, 8-naphthalic anhydride (5g, 25.2mmol, 1.0equiv) and 3, 4-dimethyl o-phenylenediamine (3.47g, 25.2mmol, 1.0equiv) were placed in a 100mL round bottom flask, after addition of 50mL of acetic acid, the reaction was heated to 118 ℃ and stirred at reflux for 7 h. The reaction was stopped, and the reaction mixture was naturally cooled to room temperature, whereby a yellow solid precipitated and was filtered to obtain 6.31g of the compound represented by the formula (II) (yellow powdery solid) in 83.93% yield,1H NMR(400MHz,DMSO)1H NMR(400MHz,DMSO)8.71(t,J＝7.6Hz,2H),8.53(d,J＝8.2Hz,1H),8.37(d,J＝8.2Hz,1H),8.22(s,1H),7.93(dt,J＝17.1,7.8Hz,2H),7.64(s,1H).13C NMR(101MHz,DMSO)160.63,142.45,141.50,136.03,134.69,134.50,132.47,132.36,131.64,130.37,128.05,127.72,126.90,126.88,123.35,120.89,120.38,115.93,40.61,40.40,40.19,39.98,39.77,39.56,39.36,20.72,20.51.MS m/z:299.11[M+H]+
example 1
11, 12-Dimethylbenzimidazole-1, 8-naphthalimide (100mg, 0.3354mmol), bis (dimethyl sulfoxide) dichloroplatinum (II) (Pt (DMSO))2Cl2) (141.20mg, 0.3354mmol), 5ml methanol and 5ml chloroform, placing in a round bottom flask, stirring and reacting at 60 ℃ for 48h, filtering to remove unreacted raw materials while the reaction is still hot, cooling the filtrate to room temperature to precipitate yellow solid, collecting the solid, and drying to obtain 130mg of yellow powder product with yield of 60.46%.
The product obtained by the implementation is characterized by mass spectrum, element analysis, X-single crystal diffraction and the like, and the method comprises the following specific steps:
(1)MS m/z:685.0704[M-Cl+DMSO]+.
(2)Anal.Calc.(for C22H20Cl2N2O2PtS)C 41.13；H 3.14；N 4.36％,Found.C41.33；H 3.17；N 4.35％。
(3) 12mg of the product obtained in the implementation example and 5ml of methanol/chloroform mixed solution (the volume ratio of methanol to chloroform is 1:1) are placed in a sealed tube, the temperature is raised to 90 ℃, the reaction is carried out for 10 hours, the reaction is carried out, the crystal is separated out, the crystal is collected and dried, and the yellow crystal is obtained. The obtained yellow crystal was analyzed by X-Ray single crystal diffraction, and its crystallographic data are shown in Table 1 below, and its partial bond lengths and bond angles are shown in Table 2 below, and the crystal structure of the obtained product is shown in FIG. 1.
Table 1: crystallographic and structural correction data of the product
Table 2: partial growth of the product
Angle of harmony key [ ° ]]
Therefore, the yellow powder product obtained in this example can be determined to be the target product 11, 12-dimethylbenzimidazole-1, 8-naphthalimide-platinum complex, and the structural formula of the complex is shown as the following formula (I):
example 2
Taking 11, 12-dimethylbenzimidazole-1, 8-naphthalimide (298.3mg, 1mmol), Pt (DMSO)2Cl2(422.9mg, 1mmol) and 9ml methanol in a thick-walled pressure-resistant bottle, dissolving, reacting at 70 deg.C under stirring for 36h, naturally cooling to room temperature to precipitate yellow solid, separating, and drying to obtain yellow powder 434.45mg with yield of 60.30%.
The product obtained in this example was subjected to mass spectrometry, elemental analysis, and further X-ray single crystal diffraction analysis, and it was confirmed that the product obtained in this example was the target compound.
Example 3
Taking 11, 12-dimethylbenzimidazole-1, 8-naphthalimide (220.8mg, 0.7404mmol), Pt (DMSO)2Cl2(311.64mg, 0.7404mmol) and 5ml DMSO were placed in a round-bottomed flask, and after dissolution, the reaction was stirred at 80 ℃ for 24 hours, and cooled to room temperature naturally, a yellow solid precipitated, isolated, and dried to give 294.22mg as a yellow powder with a yield of 55.26%.
The product obtained in this example was subjected to mass spectrometry, elemental analysis, and further X-ray single crystal diffraction analysis, and it was confirmed that the product obtained in this example was the target compound.
Example 4
Taking 11, 12-dimethylbenzimidazole-1, 8-naphthalimide (110.40mg, 0.3702mmol), Pt (DMSO)2Cl2(155.82mg, 0.3702mmol) and 5ml of chloroform were placed in a round-bottomed flask, and after dissolution, the reaction was stirred at 80 ℃ for 42 hours, and after the reaction was completed, unreacted raw materials were removed by filtration while the reaction was still hot, and the reaction was naturally cooled to room temperature, whereby a yellow solid was precipitated, separated and dried to obtain 120mg of a yellow powder, and the yield was 45.10%.
The product obtained in this example was subjected to mass spectrometry, elemental analysis, and further X-ray single crystal diffraction analysis, and it was confirmed that the product obtained in this example was the target compound.
Example 5
Taking 11, 12-dimethylbenzimidazole-1, 8-naphthalimide (110.40mg, 0.3702mmol), Pt (DMSO)2Cl2(155.82mg, 0.3702mmol), 5ml ethanol and 5ml dichloromethane are put into a round-bottom flask and stirred to react for 48 hours at the temperature of 40 ℃, unreacted raw materials are removed by filtration while the reaction is hot, the mixture is naturally cooled to room temperature, yellow solid is precipitated, separated and dried, 53.24mg of yellow powder is obtained, and the yield is 20.00%.
The product obtained in this example was subjected to mass spectrometry, elemental analysis, and further X-ray single crystal diffraction analysis, and it was confirmed that the product obtained in this example was the target compound.
Example 6
Example 5 was repeated, except that the reaction temperature was normal temperature.
13.3mg of yellow powder was obtained in 5.00% yield.
The product obtained in this example was subjected to mass spectrometry, elemental analysis, and further X-ray single crystal diffraction analysis, and it was confirmed that the product obtained in this example was the target compound.
Experimental example 1: the target compound of the invention is used for in vitro anti-tumor activity experiments on various human tumor cell strains:
to illustrate the antitumor activity of the 11, 12-dimethylbenzimidazole-1, 8-naphthalimide-platinum complex of the present invention, the applicant performed antitumor activity tests on both complexes (using common antitumor drugs 5-fluorouracil (5-FU) and cisplatin (Cis-platinum) as references), and performed toxicity tests on normal cells on the compounds prepared as described in example 1 above.
1. Inoculation and culture of cells
The selected cell lines were all incubated at 37 ℃ with 5% CO2The culture medium is inoculated into PPMI1640 culture solution containing 10% inactivated newborn calf serum to be cultured in an incubator under the condition of sufficient humidification. Observing cell growth by an inverted microscope, replacing the culture medium for 2-3 times every week, carrying out passage once every 6-7 days, digesting and carrying out passage by 0.25% trypsin during inoculation, generally taking out and carrying out passage for 3-4 times, and using the cells in logarithmic growth phase for experiment.
2. Primary screening of cellular levels of Compounds
The compound used in the experiment (wherein the complex is prepared by the method described in the above example 1), the purity is more than or equal to 95%, all the compounds are prepared into 100 mu g/mL, the final concentration of the cosolvent DMSO is not more than 1%, the inhibition rate of each compound on cancer cells under the concentration is tested, and the compound is preliminarily judged to be effective in primary screening when the inhibition rate is more than 50%, the compound accords with the inhibited (or damaged) morphological change of cells under a light microscope (such as cell shrinkage, breakage, floating and the like) and has no great toxicity on normal cells, namely the next step is carried out to obtain IC50And (5) stage.
3. Cell growth inhibition assay (MTT method)
MTT colorimetric method is a method for detecting cell growth and survival. The detection principle is as follows: unlike dead cells, exogenous MTT can be reduced to water-insoluble blue-violet crystalline Formazan (Formazan) by succinate dehydrogenase in mitochondria of living cells and deposited in cells. Methanezan in cells can be solubilized by dimethyl sulfoxide (DMSO), and the number of viable cells can be indirectly reflected by measuring the light absorption at 490nm using an enzyme linked immunosorbent assay. Within a certain range of cell number, MTT crystals are formed in an amount proportional to the cell number. The method is widely used for activity detection of some bioactive factors, large-scale antitumor drug screening, cytotoxicity test, tumor radiosensitivity determination and the like, and has the characteristics of high sensitivity, economy and the like.
Cells in logarithmic growth phase were seeded in 96-well plates at 37 ℃ with 5% CO in 180. mu.L (about 4500-2Culturing for 24h under fully humidified conditions. After the cells adhere to the wall, samples are added according to the amount of 20 mu L per well, each sample is provided with 6 multiple wells, and corresponding blank control is set at the same time. After further culturing for 48h, adding 10 mu of LMTT reagent (the concentration is 5mg/mL) into each hole, further incubating for 4h, removing the supernatant by suction, adding 150 mu of DMSO into each hole, and slightly shaking for reaction for 5-8min to fully dissolve the crystal particles. Zeroing blank control group, and measuring absorbance value after removing background light absorption value with enzyme-labeling instrument at 490nm wavelength
Value), calculating cell proliferation inhibition rate, and continuously using 5 concentration gradients to continuously make IC of corresponding cell strain for preliminarily screening test compounds with good anti-tumor effect50Values, averaged after 3 replicates for all experiments. The results are detailed in table 3 below.
Table 3: half inhibition rate concentration (C) of compound on different tumor cell lines50，μM).
Nd means no test
As can be seen from the data in the table 3, the inhibitory activity of the complex of the invention on human hepatoma cells SMMC-7721, human glioma cell strains U251, human cervical carcinoma cells Hela, human ovarian carcinoma cells SKOV-3 and human large-cell lung carcinoma cells NCI-H460 is superior to that of the common antitumor drug cisplatin, and the toxicity of the ligand and the complex on human hepatoma normal cells HL-7702 is obviously lower than that of the cisplatin. The results show that the novel 11, 12-dimethyl benzimidazole-1, 8-naphthalimide-platinum anti-tumor complex prepared by introducing the 11, 12-dimethyl benzimidazole-1, 8-naphthalimide nucleus into a platinum metal structure is feasible, and the novel anti-tumor complex with high efficiency and low toxicity can be screened out. The complex of the invention has better inhibitory activity to all human cancer cells than the ligand thereof, that is, the cytotoxicity to tumor cells can be improved by introducing 11, 12-dimethylbenzimidazole-1, 8-naphthalimide nucleus into a platinum metal structure.
Experimental example 2: the anti-tumor action mechanism of the complex of the invention
In order to illustrate the anti-tumor action mechanism of the 11, 12-dimethylbenzimidazole-1, 8-naphthalimide-platinum complex, the applicant researches the anti-tumor action mechanism of the complex based on a topoisomerase I target.
1. Interaction study with topoisomerase I
Based on that topoisomerase is a common target of naphthalimide compounds and cisplatin, agarose gel electrophoresis and a western blot method are used for researching the interaction of the complex and the topoisomerase.
FIG. 2 is a graph of agarose gel electrophoresis of compounds I added at various concentrations with Topo I. Electrophoresis results show that the compound I has a strong inhibition effect on TopoI in vitro, the compound I can completely inhibit the catalytic function of 0.1U/L TopoI under the concentration of 20 mu M, and the compound can completely inhibit the activity of topoisomerase I under the concentration of 80 mu M. The semi-inhibitory concentration of classical Topo I toxin camptothecin in vitro on topoisomerase I was approximately 17 μ M, which is comparable to the inhibitory activity of compound I on topoisomerase I.
FIG. 2 shows that compound I has strong topoisomerase inhibitory activity, so I speculate that it exerts anticancer activity probably by inhibiting the activity of topoisomerase in cells.
Claims (7)
1. A compound of the following formula (I) or a pharmaceutically acceptable salt thereof:
2. a process for the preparation of a compound according to claim 1, characterized in that: the method mainly comprises the following steps: putting a compound shown in a formula (II) and a compound shown in a formula (III) into an organic solvent, and carrying out a coordination reaction under the heating condition or the non-heating condition to obtain a target product;
3. a process for the preparation of a compound according to claim 2, characterized in that: the organic solvent is one or the combination of more than two of methanol, ethanol, chloroform, dichloromethane, dimethyl sulfoxide and N, N-dimethylformamide.
4. A process for the preparation of a compound according to claim 2, characterized in that: the reaction is carried out at a temperature of more than or equal to 40 ℃.
5. A process for the preparation of a compound according to claim 2, characterized in that: the reaction is carried out at 60-80 ℃.
6. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-neoplastic drug.
7. A pharmaceutical composition characterized by: comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
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