CN114940691B - Difunctional cisplatin derivative containing fluorescent groups and application thereof in killing bacteria - Google Patents

Difunctional cisplatin derivative containing fluorescent groups and application thereof in killing bacteria Download PDF

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CN114940691B
CN114940691B CN202210606115.XA CN202210606115A CN114940691B CN 114940691 B CN114940691 B CN 114940691B CN 202210606115 A CN202210606115 A CN 202210606115A CN 114940691 B CN114940691 B CN 114940691B
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崇辉
刘煊崴
房司雨
陈鹏
张瑜
王赪胤
王天奕
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Yangzhou University
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Abstract

The invention relates to the field of bactericidal materials, in particular to a difunctional cisplatin derivative containing a fluorescent group and application thereof in killing bacteria. The difunctional cisplatin derivative containing the fluorescent group is cis-difluoro boron dipyrrole-methylene pyridine-diamine platinum (II) nitrate (cBP) prepared from fluorescent molecules, aromatic heterocycle and cisplatin, and has high-efficiency photodynamic sterilization effect: for multiple antibiotic resistant strains (Acinetobacter baumannii), the light dose of cBP is 30J/cm 2 When the action concentration is 400ng/mL, the bacteriostasis rate can reach more than 99.99 percent. The effect of the method reaches the same kind of small molecular photodynamic sterilization efficiency, and has the advantages that the preparation process is simpler, and the method has no obvious killing effect on normal cells in the illumination dosage and concentration range. Therefore, it has potential as a highly efficient bactericidal material.

Description

Difunctional cisplatin derivative containing fluorescent groups and application thereof in killing bacteria
Technical Field
The invention relates to the field of bactericidal materials, in particular to a difunctional cisplatin derivative containing a fluorescent group and application thereof in killing bacteria.
Background
The widespread use of traditional pharmaceutical antibiotics has further led to the emergence of antibiotic-resistant strains of bacteria, and there is a need to develop effective therapeutic agents against multidrug-resistant bacteria (MDR), where the effects of photodynamic therapy (PDT) are highly desirable, and which utilize Photosensitizers (PSs) to generate toxic Reactive Oxygen Species (ROS) for antimicrobial treatment. The sensitivity of PSs, or their effectiveness, in ROS production is highly dependent on its light absorption and intersystem crossing (ISC) capability. ISC can be tuned by HOMO-LUMO (Highest Occupied Molecular Orbital-Lowest Occupied Molecular Orbital) engineering to achieve a small energy gap between triplet (T1) and singlet (S1). Because of the non-invasive nature of PDT, resistance is negligible, toxicity is low, and side effects are minimal, thus showing great antimicrobial potential.
Cisplatin (SP-4-2) -diamminediamminediammonium, also known as cisplatin (DDP). It is a common platinum complex consisting of platinum with two amino groups and two chloride ions. DDP is a broad-spectrum antineoplastic medicine, and its action mechanism is to block DNA replication of tumor cells, so that the cells can not divide normally. DDP can also be used for sterilization with a similar mechanism of action. DDP is used as raw material to synthesize a photosensitizer. The difunctional cisplatin derivative refers to that two chlorine atoms in cisplatin are replaced by other groups, and when the substituent groups are lipophilic groups, the difunctional cisplatin derivative is beneficial to fully contacting bacteria, wrapping the surfaces of the bacteria, and improving antibacterial potential.
Multidrug resistant acinetobacter baumannii (Acinetobacter baumannii, MRAB) is a typical representation of gram-negative bacteria, and the highly organized structure of the bacterial membrane of MRAB can inhibit the binding and penetration of foreign invaders, which naturally occur in nature and remain stable under extreme pH and temperature conditions. In recent decades, acinetobacter baumannii has become the most common pathogen for nosocomial infections, and its drug resistance has increased year by year, with which the antibacterial effectiveness and applicability of newly synthesized drugs can be studied.
The defects are that: many PDT-based treatment systems suffer from poor biocompatibility due to poor selectivity. In addition, since the formation of aggregates in physiological environments inhibits ROS production, and since ROS have a short lifetime and a small effective radius, the inefficient production of ROS is a problem that limits its wide application, and still needs to be continuously studied and solved at a later date.
Disclosure of Invention
Aiming at the problem of bacterial drug resistance in the anti-tumor cell replication process in the prior art, the invention provides the difunctional cisplatin derivative containing the fluorescent groups, which has the advantages of simple preparation method, low toxicity, stable structure of the prepared compound and capability of overcoming the cell drug resistance.
The invention firstly provides a difunctional cisplatin derivative containing a fluorescent group, which is characterized by being prepared from fluorescent molecules, aromatic heterocycle and cisplatin, and having the structural formula:
(1)
1. Further, the difunctional cisplatin derivative of the structural formula (1) is prepared by the following steps:
step 1, adding 8-methyl BODIPY into a 1, 4-dioxane solution containing 4-bromopyridine, heating and refluxing to obtain BODIPY containing pyridine substituent, and purifying a reaction product, wherein the reaction formula is as follows:
and 2, adding silver nitrate into DMF solution of cisplatin, centrifuging after the reaction is finished, taking supernatant, adding the reaction product purified in the step 1 into the supernatant, and separating and purifying after the reaction is finished under the protection of inert gas to obtain cBP. The reaction formula is as follows:
further, in the step 1, 4-dioxane is taken as a solvent, potassium carbonate is taken as an acid binding agent, and the molar ratio is 1:2, palladium acetate and triphenylphosphine are used as a catalyst system, and 8-methyl BODIPY is used in a reaction system: 4-bromopyridine: palladium acetate: the molar ratio of triphenylphosphine is 10:12:1:2, wherein the concentration of 8-methyl BODIPY relative to 1, 4-dioxane is 0.M, the reaction temperature is the reflux temperature of 1, 4-dioxane, and the reaction time is 12-18 hours under the atmosphere of inert gas or nitrogen; and (3) separating and purifying: the solvent was evaporated to dryness on a rotary evaporator, column chromatography [ dichloromethane: ethyl acetate 4:1 (v/v) ] to yield the product.
Further, in step 2, the DMF solution of cisplatin is 0.5M, and the silver nitrate: cisplatin: the molar ratio of BODIPY containing pyridine substituent is 1:1:1.8; the reaction temperature is 55 ℃, and the reaction time is 16 hours under the light-proof condition; the separation and purification steps are as follows: the solvent DMF was distilled off and methanol was used: the volume ratio of the diethyl ether is 1:3 recrystallises 3 times to obtain cBBP.
The prepared double-functional cisplatin derivative containing the fluorescent group comprises a fluorescent active luminous group part, an aromatic amine part and a platinum coordination part, the structure of the compound is stable, the preparation method has simple steps, and the use of toxic reagents is reduced; meanwhile, the difunctional cisplatin derivative containing BODIPY has antibacterial activity, and the molecular toxicity does not harm normal cells; the fluorescent active luminous group part has fluorescent property, and the distribution position of molecules relative to bacteria can be observed through a fluorescence microscope; it also has the ability to overcome bacterial drug resistance without damaging normal cells by molecular toxicity.
The invention also provides application of the difunctional cisplatin derivative containing the fluorescent groups to bacterial killing.
Drawings
FIG. 1 shows a bifunctional cisplatin derivative cBP containing a fluorescent group prepared in the example 1 H NMR spectrum.
FIG. 2 is a diagram of a bifunctional cisplatin derivative cBP containing a fluorescent group 13 C NMR spectrum.
FIG. 3 is a graph of the effectiveness of the difunctional cisplatin derivative cBBP in killing MRAB under light.
FIG. 4 is a fluorescence plot of the binding of the difunctional cisplatin derivative cBP to MRAB.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
The synthesis of the difunctional cisplatin derivative cBP containing the fluorescent group in the embodiment is realized through the following processes in sequence.
(1) Weighing the reaction raw materials: 8-methyl BODIPY (52.4 mg,0.2 mmol), 4-bromopyridine (37.9 mg,0.24 mmol), acid-binding agent potassium carbonate (33 mg,0.24 mmol), catalyst ligand triphenylphosphine (10.5 mg,0.04 mmol), were placed in a 10mL single-neck flask; subsequently, 4mL of 1, 4-dioxane as a solvent was added to the flask, and the above materials were thoroughly mixed. Nitrogen was introduced into the reaction mixture for 5 minutes (flow: 50 mL/min) to completely discharge oxygen from the reaction system. Palladium acetate (4.5 mg,0.02 mmol) as a catalyst was added to the nitrogen atmosphere reaction system and the nitrogen was continuously fed for 5 minutes (the flow rate was kept constant); a spherical condensing pipe is arranged on a single-port bottle containing a reaction system, and a nitrogen atmosphere device is arranged at the upper part of the condensing pipe so as to keep the reaction system in a nitrogen atmosphere protection environment; heating the reaction system to 100 ℃ and keeping the temperature for 15 hours, and then naturally cooling to room temperature; adding 1mol/L sodium fluoride aqueous solution into the reaction system to perform 1mL quenching reaction; the reaction was extracted three times with ethyl acetate (20 mL each time), the organic phases were combined, the residual water in the organic phase was removed with anhydrous magnesium sulfate (5 g), filtered and concentrated on a rotary evaporator to give a crude product, which was then separated using a thin layer chromatography column (200-300 mesh silica gel) with a column height of 7.5cm, and the eluent composition was dichloromethane: ethyl acetate = 4:1 (v/v), the organic solution of the purified product was concentrated using a rotary evaporator and dried in a vacuum oven to give an orange solid as BODIPY containing pyridine substituents. The reaction formula of the above process is as follows:
(2) Cisplatin (60 mg,0.2 mmol), agNO was weighed out 3 (34 mg,0.2 mmol) was placed in a 10mL single-necked flask, 4mL DMF was added to the flask to dissolve the reactants, the upper end of the single-necked flask was closed, and the reaction system was wrapped with tinfoil; the reaction system was heated to 55 ℃ overnight and stirred for reaction (time 12 hours); subsequently, the generated silver chloride precipitate was removed by filtration, the filtrate was transferred to a 10mL single-necked flask, and BODIPY (122 mg,0.36 mmol) containing pyridine substituent as the reactant in the above step (1) was added thereto, the upper end of the single-necked flask was closed, the reaction system was wrapped with tin foil, the reaction system was warmed to 55℃and stirred overnight (16 hours); the solvent DMF was then removed using a reduced pressure distillation apparatus, the resulting crude product was dissolved in 10mL of methanol, unreacted cisplatin was removed by filtration, and the filtrate was added with 30mL of diethyl ether under stirring to precipitate the crude product. And (3) after centrifugally collecting the crude product, repeating the processes of dissolving methanol, precipitating diethyl ether and centrifugally collecting for two to three times, and drying in vacuum to obtain the target product cBBP. The aforementioned reaction formula is as follows:
as shown in FIG. 1, the bifunctional cisplatin derivative cBP containing BODIPY prepared in this example 1 HNMR spectra, FIG. 2 shows the difunctional cisplatin derivative cBP containing BODIPY 13 C NMR spectrum. As shown in FIG. 1, the two signals with chemical shifts 2.009 and 2.424ppm represent eight methyl hydrogens in cBBP, and the integrated area is about 12, corresponding to the actual structure. Two signals with chemical shifts of 4.450 and 4.706ppm represent methylene hydrogen in cBBP, and the integral area is 4, corresponding to the actual structure. The signal at a chemical shift of 6.230ppm represents the amino hydrogen in cBP and its integrated area is about 3, corresponding to the actual structure. Two signals with chemical shifts of 7.304 and 7.319ppm represent BODIPY ring system aromatic hydrogen in cBBP, and the integral area of the two signals is 4, which corresponds to the actual structure. Two signals with chemical shifts of 8.653 and 8.657ppm represent pyridine ring aromatic hydrogen in cBBP, and the integral area is about 4, respectively, corresponding to the actual structure. Considering symmetry of chemical structure, cBBP should beNuclear magnetic resonance carbon signals appear at 11, corresponding to the data in fig. 2. Analysis according to the high-resolution mass spectrum result of the cBP is consistent with the theoretical molecular weight of the cBP, so that the chemical structure of the cBP is fully verified.
Example 2
(1) Bacterial culture
A liquid medium (100 ml of LB: naCl 1g, yeast powder 0.5g, peptone 1 g) for bacterial growth was prepared, and Acinetobacter baumannii (MRAB, multidrug-resistant bacteria), a gram-negative bacterium, was cultured. Adding single colony of MRAB into 5ml LB, culturing at 37deg.C for 2-3 hr, shaking to OD value of about 0.5 (0.495-0.510) by nucleic acid protein detector, and estimating the number of bacteria in each 1ml bacterial liquid to be 10 8 CFU/ml。
(2) Illumination sterilization
Experiment of cBBP killing MRAB: in a 24-well bacterial culture plate, a certain amount of cBP prepared in example 1 was dissolved in PBS buffer solution (1 liter of PBS: naCl 8g, na) 2 HPO 4 ·12H 2 O 2.9g、KCl 0.2g、KH 2 PO 4 0.24g、H 2 O1L) to a total of 1ml, adding 20. Mu.l of the cultured bacterial liquid, allowing the bacterial liquid to fully contact for 20 minutes under dark conditions, and then performing 100mV/cm 2 The bacteria are sterilized by illumination under a xenon lamp for five minutes, and bacterial liquid is taken once every one minute for spot plating. The solid medium (100 ml of solid medium: 1g of sodium chloride, 0.5g of yeast powder, 1g of peptone, 1.5g of agar) after spotting was placed in an incubator at 37℃overnight for natural growth of bacteria.
Dot plate count: 18 EP tubes, 0.2mL, were removed and placed in an EP tube rack, and 90. Mu.L of PBS buffer solution was added, respectively. Firstly, 10 microliters of bacterial liquid is removed from stock solution in an experimental hole plate by a liquid-transferring gun, and the bacterial liquid is subjected to gradient dilution to 10 percent of the concentration of the stock solution -1 、10 -2 、10 -3 For dilution to 10 -3 50 microliters of the bacterial liquid was sampled and spotted.
(3) Calculation of sterilizing efficiency
On the solid medium overnight, bacteria grew into macroscopic bacterial colonies, and the number of colonies on the plates was counted for different time periods, according to five minutesThe bacterial colony number within the clock is changed, and the sterilization efficiency is calculated. And (3) measuring different sterilization efficiencies according to different CBBP concentrations, and observing the change of the sterilization effect along with the concentration. The number of colonies in the pore plate solution before sterilization is about 2-8 x 10 6 CFU/ml, sterilization efficiency= (C 0 -C)/C 0 *100%, where C is the number of colonies present in the well plate solution per minute in five minutes of illumination, C 0 Is the number of colonies in solution in the well plate before sterilization.
(4) Repeated experiments
Repeating the operation of the step (2), and respectively sterilizing the MRAB by using cBBP with different concentrations, wherein each group of experiments is repeated three times. FIG. 3 is a graph showing the efficiency of cBP killing MRAB under light. As shown in the following table and FIG. 3, the sterilization efficiency of 400ng/mL cBP after 5min of illumination can reach more than 99.99%.
cBP sterilization experimental result
Example 3
In this example, a fluorescence image of the binding of the BODIPY-containing bifunctional cisplatin derivative cBB to Acinetobacter baumannii was studied by adding 100. Mu.l of MRAB to a 1.5mL EP tube, adding 100. Mu.l of DAPI staining solution (i.e., 2- (4-Amidinophelyl) -6-indolecarbamidine dihydrochloride, also called DAPI dihydrochloride, molecular formula C16H15N 5. 2 HCl), adding 100. Mu.l of the BODIPY-containing suspension of the bifunctional cisplatin derivative cBBP to the experimental group, and adding 100. Mu.l of ultrapure water to the experimental control group. The experimental group and the experimental control group are respectively and evenly mixed and incubated for 15-20min in a dark place. Then, the precipitate was centrifuged at 8000rpm for 5min, and 100. Mu.l of PBS buffer solution was added for dissolution, and the solution was photographed by a two-photon laser confocal microscope, and FIG. 4 is a fluorescence chart of the binding of cBP and MRAB.
Fig. 4 shows that cBBP molecules wrap around the outer surface of bacterial nucleoplasm, and active oxygen bactericidal substances generated by cBBP illumination can be effectively positioned to act on acinetobacter baumannii, so that higher bactericidal efficiency is achieved.
Example 4
In this embodiment, hela cells were used as target cells, and a toxicity test of the cBBP, a bifunctional cisplatin derivative containing BODIPY, on Hela cells was studied.
Preparing a Hela cell suspension, inoculating into a 96-well plate, and inoculating about 1×10 per well of 100uL of liquid medium 4 The cells, blank, were fed with medium only. Culturing in a 37 ℃ incubator for 24 hours to adhere cells. A Dimethylsulfoxide (DMSO) solution was prepared at a concentration of 1 mM/LcBP, and diluted to solutions of different concentrations of 2, 4, 6, 8, 10 (uM/L), etc. 10uL of cBP solution with different concentrations is respectively added into each hole of the pore plate, the cBP sample is not added into the blank group and the control group, 5 parallel groups are manufactured by the same sample, and after the culture in a 37 ℃ incubator for 8 hours, the culture is continued for 16 hours after illumination for 30 minutes. After the culture, the cBP-containing medium was aspirated, 100uL of medium was added again to each well, and 10uL of CCK-8 solution was added thereto, and incubated in an incubator for 1 hour. Absorbance at 450nm was measured using a microplate reader, according to the calculation formula: inhibition ratio (%) = [ (Ac-As)/(Ac-Ab)]And x 100%, wherein As is experimental hole absorbance, ab is blank hole absorbance, ac is control hole absorbance, and inhibition ratios of cBP with different concentrations on Hela cells are obtained.
As shown in the table, the cBP has no obvious inhibition rate to Hela cells when the concentration of the cBP molecules is 6uM/L, and the concentration of the cBP relative molecular mass M=1030, which is used for effectively killing the multi-drug resistant Acinetobacter baumannii, is 400ng/mL and is far less than 6uM/L.
Results of cBP cytotoxicity experiments
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the invention, but it is to be understood that modifications may be made to the technical solution described in the foregoing embodiment or equivalents may be substituted for elements thereof by those skilled in the art, although the invention has been described in detail with reference to the foregoing embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention. While the foregoing describes the embodiments of the present invention, it should be understood that the present invention is not limited to the embodiments, and that various modifications and changes can be made by those skilled in the art without any inventive effort.

Claims (4)

1. The difunctional cisplatin derivative containing the fluorescent group is characterized by being prepared from fluorescent molecules, aromatic heterocycle and cisplatin, and has the structural formula:
2. the method for preparing a bifunctional cisplatin derivative having a fluorescent group as claimed in claim 1, wherein the bifunctional cisplatin derivative having a structural formula of formula (1) is prepared by:
step 1, adding 8-methyl BODIPY into a 1, 4-dioxane solution containing 4-bromopyridine, heating and refluxing to obtain BODIPY containing pyridine substituent, and purifying a reaction product, wherein the reaction formula is as follows:
step 2, adding silver nitrate into DMF solution of cisplatin, centrifuging after the reaction is finished, taking supernatant, adding the reaction product purified in the step 1 into the supernatant, and separating and purifying after the reaction is finished under the protection of inert gas to obtain cBP; the reaction formula is as follows:
3. the method for preparing the difunctional cisplatin derivative containing the fluorescent group according to claim 2, wherein in step 1, 4-dioxane is used as a solvent, potassium carbonate is used as an acid binding agent, and the molar ratio is 1:2, palladium acetate and triphenylphosphine are used as a catalyst system, and 8-methyl BODIPY is used in a reaction system: 4-bromopyridine: palladium acetate: the molar ratio of triphenylphosphine is 10:12:1:2, wherein the concentration of 8-methyl BODIPY relative to 1, 4-dioxane is 0.05M, the reaction temperature is the reflux temperature of 1, 4-dioxane, and the reaction time is 12-18 hours under the atmosphere of inert gas or nitrogen; and (3) separating and purifying: evaporating the solvent on a rotary evaporator, and separating and purifying by column chromatography to obtain the product, wherein the eluent used by the column chromatography is dichloromethane: the volume ratio of the ethyl acetate is 4:1 mixed solution.
4. The method for preparing a bifunctional cisplatin derivative having a fluorescent group as claimed in claim 2, wherein in step 2, the DMF solution of cisplatin is 0.5M in concentration, and the silver nitrate: cisplatin: the molar ratio of BODIPY containing pyridine substituent is 1:1:1.8; the reaction is carried out under the light-shielding condition, and the reaction temperature is 55 ℃; the reaction time was 16 hours; the separation and purification steps are as follows: the solvent DMF was distilled off and methanol was used: the volume ratio of the diethyl ether is 1:3 recrystallises 3 times to obtain cBBP.
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