CN114940691A - Difunctional cisplatin derivative containing fluorescent group and application thereof in killing bacteria - Google Patents

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

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CN114940691A
CN114940691A CN202210606115.XA CN202210606115A CN114940691A CN 114940691 A CN114940691 A CN 114940691A CN 202210606115 A CN202210606115 A CN 202210606115A CN 114940691 A CN114940691 A CN 114940691A
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崇辉
刘煊崴
房司雨
陈鹏
张瑜
赪胤
王天奕
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Yangzhou University
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Abstract

The invention relates to the field of sterilization materials, in particular to a dual-functional cis-platinum derivative containing a fluorescent group and application thereof in killing bacteria. The dual-functional cis-platinum derivative containing the fluorescent group is cis-bis-boron dipyrrole-methylene pyridine-diamino platinum (II) nitrate (cBBP) prepared from fluorescent molecules, aromatic heterocycles and cis-platinum, and has high-efficiency photodynamic sterilization effect: for multiple antibiotic resistant species (Acinetobacter baumannii), cBBP was used at a light dose of 30J/cm 2 When the action concentration is 400 ng/mL, the bacteriostasis rate can reachMore than 99.99 percent. The effect of the method reaches the similar micromolecule photodynamic sterilization efficiency, and the method has the advantages that the preparation process is simpler, and in the range of the illumination dose and the concentration, the method has no obvious killing effect on normal cells. Therefore, it has potential as a highly effective bactericidal material.

Description

Difunctional cisplatin derivative containing fluorescent group and application thereof in killing bacteria
Technical Field
The invention relates to the field of sterilization materials, in particular to a dual-functional cis-platinum derivative containing a fluorescent group and application thereof in killing bacteria.
Background
Bacterial infections are life-threatening to humans, and the widespread use of traditional drug antibiotics has further led to the emergence of antibiotic-resistant strains, 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, using Photosensitizers (PSs) that produce toxic Reactive Oxygen Species (ROS) for antimicrobial therapy. The sensitivity of PSs in ROS production or their effectiveness is highly dependent on its light absorption and intersystem crossing (ISC) capabilities. ISCs can be tuned by HOMO-LUMO (high Occupied Molecular Orbital-Lowest Occupied Molecular Orbital) engineering to achieve small energy gaps between the triplet (T1) and singlet (S1) states. Due to the non-invasive nature of PDT, drug resistance is negligible, toxicity is low, and side effects are minimal, thus showing great antimicrobial potential.
Cis-diamminedichloroplatinum ((SP-4-2) -diamminedichloroplatinum), also known as cisplatin (DDP). It is a common platinum complex, consisting of platinum, two amino groups and two chloride ions. DDP is a broad-spectrum anti-tumor drug, and the action mechanism of the DDP is to block the DNA replication of tumor cells and ensure that the cells cannot normally divide. DDP can also be applied to sterilization using a similar mechanism of action. DDP is used as a raw material to synthesize the photosensitizer. The bifunctional cisplatin derivative is characterized in that two chlorine atoms in cisplatin are replaced by other groups, and when the substituent groups are lipophilic groups, the bifunctional cisplatin derivative is favorably in full contact with bacteria and wrapped around the surfaces of the bacteria, so that the antibacterial potential is improved.
Multidrug resistant acinetobacter baumannii (A), (B), (CAcinetobacter baumanniiMRAB) is a typical representative of gram-negative bacteria, the highly organized structure of the bacterial membrane of MRAB, which inhibits binding and penetration by foreign invaders, naturally occurring in nature, remaining stable under extreme pH and temperature conditions. In recent decades, acinetobacter baumannii has become the most common pathogenic bacterium of nosocomial infection, and the drug resistance rate thereof has increased year by year, and the antibacterial effectiveness and applicability of newly synthesized drugs can be studied by using the bacterium.
The disadvantages 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 the production of ROS, and because ROS have a short lifespan and a small effective radius, inefficient production of ROS is a problem that limits its widespread use, and needs to be further studied and solved in the future.
Disclosure of Invention
Aiming at the problem of bacterial drug resistance in the process of anti-tumor cell replication in the prior art, the invention provides the bifunctional cisplatin derivative containing the fluorescent group, which has the advantages of simple preparation method, low toxicity, stable structure of the prepared compound and capability of overcoming the drug resistance of cells.
The invention firstly provides a dual-functional cis-platinum derivative containing a fluorescent group, which is characterized by being prepared from a fluorescent molecule, an aromatic heterocycle and cis-platinum, and the structural formula is as follows:
Figure 962181DEST_PATH_IMAGE001
。
formula (1)
1. Further, the bifunctional cisplatin derivative represented by 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:
Figure 201664DEST_PATH_IMAGE002
；
and step 2, adding silver nitrate into a cisplatin DMF (dimethyl formamide) solution, centrifuging after the reaction is finished, taking a 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 cBBP. The reaction formula is as follows:
Figure 610780DEST_PATH_IMAGE003
Figure 55536DEST_PATH_IMAGE004
。
further, in the step 1, 4-dioxane is used as a solvent, potassium carbonate is used as an acid-binding agent, and the molar ratio of the solvent to the acid-binding agent is 1: 2 palladium acetate and triphenylphosphine are used as catalyst systems, and the reaction system comprises 8-methyl BODIPY: 4-bromopyridine: palladium acetate: the molar ratio of triphenylphosphine was 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, and column chromatography [ dichloromethane: the ethyl acetate was 4:1 (v/v) ] isolated and purified to give the product.
Further, in step 2, the concentration of the DMF solution of cisplatin is 0.5M, and the ratio of silver nitrate: cisplatin: the molar ratio of BODIPY containing pyridine substituents is 1: 1: 1.8; the reaction temperature is 20-60 ℃, and the reaction time is 15-20 hours under the condition of keeping out of the sun; the separation and purification steps are as follows: the solvent DMF was distilled off, washed with methanol: the volume ratio of the ethyl ether is 1: 3 recrystallization 3 times to give cBBP.
The prepared difunctional cisplatin derivative containing the fluorescent group comprises a fluorescent active luminophore part, an aromatic amine part and a platinum coordination part, the compound structure is stable, the preparation method steps are simple, and the use of toxic reagents is reduced; meanwhile, the bifunctional cisplatin derivative containing BODIPY has antibacterial activity, and the molecular toxicity does not harm normal cells; the fluorescence active luminophore part has fluorescence 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 resistance without damaging normal cells due to molecular toxicity.
The invention also provides application of the bifunctional cisplatin derivative containing the fluorescent group in killing bacteria.
Drawings
FIG. 1 shows the preparation of an example of a bifunctional cisplatin derivative cBBP containing a fluorescent group 1 H NMR spectrum.
FIG. 2 shows the preparation of a fluorophore-containing bifunctional cisplatin derivative cBBP 13 C NMR spectrum.
FIG. 3 is a high resolution mass spectrum of a bifunctional cisplatin derivative cBBP containing a fluorescent group.
Figure 4 is a graph of the MRAB killing efficiency of the bifunctional cisplatin derivative cBBP under light.
FIG. 5 is a fluorescence image of the binding of the bifunctional cisplatin derivative cBBP to MRAB.
Fig. 6 is the original drawing of fig. 5.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
The synthesis of the bifunctional cisplatin derivative cBBP containing fluorescent group of this example was carried out sequentially by the following procedure.
(1) Weighing 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), placed in a 10 mL single-neck flask; subsequently, 4 mL of 1, 4-dioxane solvent was added to the flask, and the mixture was thoroughly mixed. Nitrogen was introduced into the reaction mixture for 5 minutes (flow rate: 50 mL/min) to completely remove oxygen from the reaction system. Adding catalyst palladium acetate (4.5 mg, 0.02 mmol) into the reaction system in the nitrogen atmosphere, and continuously introducing nitrogen for 5 minutes (the flow rate is kept unchanged); a spherical condenser pipe is arranged on a single-mouth bottle containing a reaction system, and a nitrogen atmosphere device is arranged on the upper part of the condenser pipe so as to keep the reaction system in a nitrogen atmosphere protective environment; heating the reaction system to 100 ℃ and keeping for 15 hours, and then naturally cooling to room temperature; adding 1mL of 1 mol/L aqueous solution of sodium fluoride into the reaction system to quench the reaction; extracting the reaction liquid three times by using ethyl acetate (the volume of each extraction liquid is 20 mL), combining organic phases, removing residual water in the organic phases by using anhydrous magnesium sulfate (5 g), filtering, concentrating on a rotary evaporator to obtain a crude product, separating the crude product by using a thin layer chromatography column (200-mesh 300-mesh silica gel), wherein the column height is 7.5 cm, and the eluent composition is dichloromethane: ethyl acetate = 4:1 (v/v), concentrating the organic solution of the purified product by using a rotary evaporator, and drying the concentrated organic solution by using a vacuum drying oven to obtain an orange solid which is BODIPY containing pyridine substituent. The reaction formula of the above process is as follows:
Figure 157484DEST_PATH_IMAGE005
。
(2) weighing cisplatin (60 mg, 0.2 mmol) and AgNO 3 (34 mg, 0.2 mmol) is placed in a 10 mL single-neck flask, 4 mL of DMF solvent is added into the flask to dissolve the reactants, the upper end of the single-neck flask is sealed, and tinfoil is used for wrapping the reaction system; heating the reaction system to 55 ℃ overnight, stirring and reacting (the time is 12 hours); then, the generated silver chloride precipitate was removed by filtration, the filtrate was transferred to a 10 mL single-neck flask, and BODIPY (122 mg, 0.36 mmol) containing a pyridine substituent as the reactant of the aforementioned step (1) was added thereto, the upper end of the single-neck flask was closed, the reaction system was wrapped with tinfoil, the reaction system was warmed to 55 ℃, and stirred overnight (16 hours); then, the solvent DMF was removed by using a vacuum distillation apparatus, the obtained crude product was dissolved in 10 mL of methanol, unreacted cisplatin was removed by filtration, and 30 mL of diethyl ether was added to the filtrate under stirring to precipitate a crude product. And after the crude product is centrifugally collected, repeating the processes of methanol dissolution, ether precipitation and centrifugal collection for two to three times, and performing vacuum drying to obtain the target product cBBP. The reaction formula is as follows:
Figure 195848DEST_PATH_IMAGE006
。
as shown in the figure1 is the bifunctional cisplatin derivative cBBP containing BODIPY prepared in the example 1 H NMR spectrum, FIG. 2 shows that the bifunctional cisplatin derivative cBBP containing BODIPY 13 C NMR spectrum. As shown in fig. 1, the signals at 2.009 and 2.424ppm represent eight methyl hydrogens in cBBP, with an integrated area of about 12, corresponding to the actual structure. The signals at 4.450 and 4.706ppm represent the methylene hydrogen in the cBBP, and the integrated area is 4, corresponding to the actual structure. The signal at 6.230ppm represents the amino hydrogen in cBBP with an integrated area of about 3, corresponding to the actual structure. The signals at 7.304 and 7.319ppm represent the aromatic hydrogens of the BODIPY ring system in cBBP, and the integrated area is 4, corresponding to the actual structure. The signals at two chemical shifts of 8.653 and 8.657ppm represent the aromatic hydrogen of the pyridine ring system in cBBP, and the integrated areas are about 4 respectively, corresponding to the actual structures. Considering the symmetry of the chemical structure, cBBP should exhibit a nuclear magnetic resonance carbon signal at 11, corresponding to the data in fig. 2. As shown in fig. 3, the high resolution mass spectrum result of cBBP is consistent with its theoretical molecular weight, and in conclusion, the chemical structure of cBBP is fully verified.
Example 2
(1) Bacterial culture
A liquid medium (100 ml LB: NaCl 1g, yeast powder 0.5g, peptone 1 g) for bacterial growth was prepared, and gram-negative bacteria Acinetobacter baumannii (MRAB, multidrug-resistant bacteria) were cultured. Adding MRAB single colonies into 5ml LB, respectively, culturing at 37 deg.C for 2-3 hr, shaking to OD value of about 0.5 (0.495-0.510) determined by nucleic acid protein detector, and estimating bacteria content of 10 per 1ml bacteria liquid 8 CFU/ml。
(2) Sterilizing by illumination
Experiment of cBBP killing MRAB: in a 24-well bacterial culture plate, an amount of cBBP prepared in example 1 was dissolved in a 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 the total amount of the solution of 1ml, adding 20 microliter of the cultured bacterial solution, and fully contacting for 20 minutes under the dark condition, thenThen at 100 mV/cm 2 Sterilizing by irradiating for five minutes under a xenon lamp, and taking a bacterium solution at intervals of one minute to perform plate spotting. The solid medium (100 ml solid medium: 1g sodium chloride, 0.5g yeast powder, 1g peptone and 1.5g agar) after spotting was placed in an incubator at 37 ℃ overnight for the bacteria to grow naturally.
Counting the number of the counting plates: 18 0.2 mL EP tubes were removed and placed on an EP tube holder and 90. mu.L of PBS buffer was added. Firstly, 10 microliter of bacterial liquid is transferred from stock solution in an experimental orifice plate by using a liquid transfer gun, and the bacterial liquid is diluted to 10 of the concentration of the stock solution in a gradient manner -1 、10 -2 、10 -3 For dilution to 10 -3 50 microliter of the bacterial liquid is taken for plate spotting.
(3) Calculation of Sterilization efficiency
On the solid culture medium which is overnight, bacteria grow into bacterial colonies which can be seen by naked eyes, the number of the bacterial colonies on the culture plate in different time periods is counted, and the sterilization efficiency of the culture plate is calculated according to the change of the number of the bacterial colonies within five minutes. And 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 well plate solution before sterilization was 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 during five minutes of light exposure, C 0 The number of colonies in the solution in the well plate before sterilization.
(4) Repeat the experiment
And (3) repeating the operation of the step (2), sterilizing the MRAB by using cBBP with different concentrations respectively, and repeating the experiment of each group for three times. FIG. 4 is a graph of the efficiency of cBBP in killing MRAB under light. As shown in the following table and FIG. 4, the sterilizing efficiency of 400 ng/mL cBBP after 5 min of illumination can reach more than 99.99%.
cBBP sterilization experimental results
Efficiency of sterilization cBBP 50 ng/mL cBBP 100 ng/mL cBBP 200 ng/mL cBBP 400 ng/mL
Irradiating for 1 min 30.50% 63.44% 92.91% 99.58%
Irradiating for 2 min 46.54% 92.29% 97.09% 99.94%
Illuminating for 3 min 44.34% 94.50% 98.36% 99.98%
Irradiating for 4 min 59.79% 96.35% 99.40% 99.99%
Illuminating for 5 min 58.01% 97.79% 99.63% 99.99%
Example 3
This example investigates the fluorometric patterns of the binding of the bifunctional cisplatin derivative cBBP containing BODIPY to Acinetobacter baumannii
To a 1.5mL EP tube, 100. mu.L of MRAB was added, 100. mu.L of DAPI staining solution (i.e., 2- (4-Amidinophenyl) -6-indelcarbamidine dihydrate, also known as DAPI dihydrate, of formula C16H15N5 & 2 HCl) was added, 100. mu.L of a suspension of the bifunctional cisplatin derivative cBBP containing BODIPY was added to the experimental group, and 100. mu.L of ultrapure water was added to the experimental control group. The experimental group and the experimental control group are respectively and independently mixed uniformly and incubated for 15-20 min in the dark. Then, the mixture was centrifuged at 8000 rpm for 5 min, and the precipitate was dissolved in 100. mu.l of PBS buffer solution and photographed by a two-photon laser confocal microscope, and FIG. 5 is a fluorescence image of the combination of cBBP and MRAB. Fig. 5 shows that cBBP molecules are wrapped around the outer surface of the bacterial nucleoplasm, and active oxygen sterilizing substances generated by cBBP illumination can effectively act on acinetobacter baumannii in a positioning manner, so that higher sterilizing efficiency is achieved.
Example 4
In this example, a toxicity test of bifunctional cisplatin derivative cBBP containing BODIPY on Hela cells was studied using Hela cells as target cells.
Hela cell suspension was prepared, inoculated into 96-well plates at 100 uL/well in liquid medium, and inoculated at about 1 x 10 4 Individual cells, blank group were media only. Culturing at 37 deg.C for 24 hr to make the cells adhere to the wall. A dimethyl sulfoxide (DMSO) solution with a concentration of 1 mM/L cBBP is prepared and diluted into solutions with different concentrations such as 2, 4, 6, 8, 10 (uM/L) and the like. And adding 10uL of cBBP solution with different concentrations into each hole of the hole plate, not adding cBBP samples into the blank group and the control group, preparing 5 parallel groups, culturing in an incubator at 37 ℃ for 8 hours, illuminating for 30 min, and then returning to the incubator to continue culturing for 16 hours. After the culture, the culture medium containing cBBP is aspirated, 100uL of the culture medium is added into each well, 10uL of CCK-8 solution is added, and the culture is incubated in an incubator 1h. The absorbance at 450nm was measured using a microplate reader, according to the calculation formula: inhibition (%) = [ (Ac-As)/(Ac-Ab)]And x 100%, wherein As is the absorbance of the experimental wells, Ab is the absorbance of the blank wells, and Ac is the absorbance of the control wells, and the inhibition rates of cBBP on Hela cells at different concentrations are obtained.
As shown in the table, when the concentration of cBBP molecules is 6 uM/L, no obvious inhibition rate is generated on Hela cells, the relative molecular mass of cBBP is M =1030, and the concentration for effectively killing the multi-drug-resistant Acinetobacter baumannii is 400 ng/mL and is far less than 6 uM/L.
Results of cBBP cytotoxicity test
cBBP 2 uM/L 4 uM/L 6 uM/L 8 uM/L 10 uM/L Control group Blank group
Absorbance of the solution 0.5342 0.4822 0.4592 0.1949 0.1808 0.5402 0.1481
Inhibition rate 1.52 % 14.80 % 20.66 % 88.06 % 91.66 %
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention. Although the present invention has been described with reference to the specific embodiments, it should be understood that the scope of the present invention is not limited thereto, and those skilled in the art will appreciate that various modifications and variations can be made without inventive changes by those skilled in the art based on the technical solutions of the present invention.

Claims (5)

1. A dual-functional cis-platinum derivative containing a fluorescent group is characterized by being prepared from a fluorescent molecule, an aromatic heterocycle and cis-platinum, and the structural formula is as follows:
Figure DEST_PATH_IMAGE002
cis-bis-BODIPY-METHYLPYRIDINE-DIAMINOPLATINUM (II) NITRATE (cBBP) OF THE FORMULA (1)
The bifunctional cisplatin derivative containing a fluorescent group as described in claim 1, wherein the bifunctional cisplatin derivative represented by 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:
Figure DEST_PATH_IMAGE004
；
and 2, adding silver nitrate into a DMF (dimethyl formamide) solution of cisplatin, centrifuging after the reaction is finished, taking supernate, adding the reaction product purified in the step 1 into the supernate, and separating and purifying after the reaction is finished under the protection of inert gas to obtain cBBP.
2. The reaction formula is as follows:
Figure DEST_PATH_IMAGE006
Figure DEST_PATH_IMAGE007
。
3. the bifunctional cisplatin derivative as claimed in claim 2, wherein in step 1, 4-dioxane is used as solvent, potassium carbonate is used as acid-binding agent, and the molar ratio of the bifunctional cisplatin derivative as claimed in claim 1: 2 palladium acetate and triphenylphosphine are used as catalyst systems, and the reaction system comprises 8-methyl BODIPY: 4-bromopyridine: palladium acetate: the molar ratio of triphenylphosphine was 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, and column chromatography [ dichloromethane: the ethyl acetate was 4:1 (v/v) ] isolated and purified to give the product.
4. The bifunctional cisplatin derivative as claimed in claim 2, wherein in step 2, the concentration of the DMF solution of cisplatin is 0.5M, and the ratio of silver nitrate: cisplatin: the molar ratio of BODIPY containing pyridine substituents is 1: 1: 1.8; the reaction temperature is 20-60 ℃; under the condition of keeping out of the sun, the reaction time is 15-20 hours; the separation and purification steps are as follows: the solvent DMF was distilled off, washed with methanol: the volume ratio of the ethyl ether is 1: 3 recrystallization 3 times to give cBBP.
5. Use of a bifunctional cisplatin derivative containing a fluorescent group as described in any one of claims 1-4 as a microbicidal agent.
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