CN113527370A - Quinoline iridium complex targeting lung cancer cisplatin drug-resistant cells and synthesis method and application thereof - Google Patents
Quinoline iridium complex targeting lung cancer cisplatin drug-resistant cells and synthesis method and application thereof Download PDFInfo
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- 229960004316 cisplatin Drugs 0.000 title claims abstract description 33
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- KHDNHIVJLRCSIR-UHFFFAOYSA-N iridium;quinolin-8-ol Chemical compound [Ir].C1=CN=C2C(O)=CC=CC2=C1 KHDNHIVJLRCSIR-UHFFFAOYSA-N 0.000 description 1
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0046—Ruthenium compounds
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Abstract
The invention discloses a quinoline iridium complex targeting lung cancer cisplatin drug-resistant cells, a synthesis method and application thereof, belongs to the field of medicines, and mainly solves the technical problem of drug resistance of lung cancer cisplatin drugs in the prior art, wherein the method specifically comprises the following steps: (1) an iridium dimer [ I r (2pq)2Cl]2And 4-bromo-8-hydroxyquinoline or 5-bromo-8-hydroxyquinoline into a polar solvent to obtain a mixed solution; (2) reacting the obtained mixed solution at 100 ℃ under a sealed condition to obtain a precipitate; (3) and filtering and drying the precipitate to obtain the target complex. The research finds that the complexes 4BrIr and 5BrIr target to inhibit the growth of A549/DDP and the IC thereof50The values are 0.53 +/-0.11 mu M and 0.09 +/-0.03 mu M respectively, and the in-vitro anti-lung cancer activity of the compounds is far greater than that of 4Br and 5Br ligands, so that the compounds target lung cancer and overcome the drug resistance of cisplatin. The research on in vivo anticancer finds that the in vivo anticancer drug inhibitsThe preparation effect reaches 43.5 percent, is higher than that of cisplatin drugs, has potential medicinal value and is expected to be used for preparing various anti-lung cancer drugs.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a quinoline iridium complex targeting lung cancer cisplatin drug-resistant cells and a synthesis method thereof. The invention also relates to an application of the quinoline iridium complex targeting the lung cancer cisplatin resistant cells in preparation of anti-lung cancer drugs.
Background
Lung cancer is one of the most common malignant tumors worldwide, and is classified as the first cancer due to its high mortality rate and clinically incurable nature. Currently, the number of drug resistant cases in cisplatin treatment of lung cancer is increasing worldwide, seriously threatening the life health of patients. The iridium complex not only has excellent photophysical properties, but also is very sensitive to the response of a tumor microenvironment, and is suitable for constructing a tumor response targeting material or an anticancer drug.
In addition, a number of metal complexes of 8-hydroxyquinoline have been reported (Q. -P. Qin, et al. Eur. J. Med. chem.,2020,192,112192.), but with 4/5-bromo-8-hydroxyquinoline and 2-No related report is available for synthesizing the metal iridium complex by taking phenylquinoline as a mixed ligand. In the research, active ligands of 4-bromo-8-hydroxyquinoline (4Br) and 5-bromo-8-hydroxyquinoline (5Br) are respectively used as dimers ([ Ir (phq))2Cl]2Phq ═ 2-phenylquinoline), and an iridium complex [ Ir ] was synthesizedIII(phq)2(4Br)]CH3OH (4BrIr) and [ IrIII(phq)2(5Br)](5BrIr) and the 8-hydroxyquinoline iridium complex which targets the cisplatin drug-resistant cells of the human lung cancer is screened for the first time, and the in vivo and in vitro anti-tumor activity and the application thereof are researched.
Disclosure of Invention
One of the purposes of the invention is to provide a quinoline iridium complex targeting lung cancer cisplatin resistant cells.
The invention also aims to provide a synthesis method of the quinoline iridium complex targeting the lung cancer cis-platinum drug-resistant cell.
The invention also aims to provide application of the quinoline iridium complex targeting cis-platinum drug-resistant cells in preparation of anti-lung cancer drugs.
The first purpose of the invention is realized by the following technical scheme: a quinoline iridium complex targeting lung cancer cisplatin resistant cells has a chemical structural formula shown in formula 1-2:
the second purpose of the invention is realized by the following technical scheme: a method for synthesizing quinoline iridium targeted to lung cancer cisplatin-resistant cells comprises the following steps:
(1) adding an iridium dimer and 4-bromo-8-hydroxyquinoline (4Br) or 5-bromo-8-hydroxyquinoline (5Br) into a polar solvent to obtain a mixed solution;
(2) reacting the obtained mixed solution at 100 ℃ under a sealed condition to obtain a precipitate;
(3) and filtering and drying the precipitate to obtain the target complex.
As a further improvement, the stepsIn step (1), an iridium dimer [ Ir (2pq) ]2Cl]2And 4-bromo-8-hydroxyquinoline (4Br) or 5-bromo-8-hydroxyquinoline (5Br) in a ratio of 1: 2.
Further, the polar solvent is dichloromethane and methanol, the volume ratio of the dichloromethane to the methanol is any ratio, and if the other solvents are almost free of products.
Further, the dichloromethane is 0.2-5.5 mL; the methanol is 1-3 mL.
Further, in the step (2), the reaction time is 48h, and neither the product nor the main product is generated when the temperature is too high or too low.
Further, in the step (3), the drying temperature is 55 ℃.
The third purpose of the invention is realized by the application of the quinoline iridium complex in preparing the anti-lung cancer medicament.
The invention relates to a synthesis method and application of quinoline iridium complex targeting lung cancer cisplatin drug-resistant cells, in particular to a 2-phenylquinoline dimer ([ Ir (phq))2Cl]2Phq ═ 2-phenylquinoline) according to the literature (R.J. Watts, et al.J.Am.chem.Soc.,1984,106, 6647-.
Advantageous effects
Compared with the prior art, the invention has the advantages that: the invention provides 2 novel 4-/5-bromo-8-hydroxyquinoline iridium complexes, 4BrIr and 5BrIr, and a synthetic method and application thereof; and the activity and toxicity experiments of the compounds on non-small cell lung cancer A549 and cisplatin resistant strain A549/DDP and human normal liver HL-7702 cells are examined. Experimental results show that the complexes 4BrIr and 5BrIr target and inhibit the growth of A549/DDP, the IC50 values of the complexes are 0.53 +/-0.11 mu M and 0.09 +/-0.03 mu M respectively, the in vitro anti-lung cancer activity of the complexes is far greater than that of 4Br and 5Br ligands, particularly 4BrIr, the anti-cancer activity of the complexes is 473.9 times (66.34 +/-1.21 mu M) of clinical anti-cancer drug cisplatin, and the toxicity of the complexes to normal cells HL-7702 is very low (IC50 is greater than 80 mu M), which indicates that the complexes target lung cancer and overcome the drug resistance of the cisplatin. In vivo anticancer research finds that the in vivo anticancer inhibition effect reaches 45.3 percent, is higher than that of cisplatin drugs, has potential medicinal value and is expected to be used for preparing various anti-lung cancer drugs.
Drawings
FIG. 1 shows a dimer of 2-phenylquinoline [ Ir (phq) ]2Cl]2The structural formula (1);
FIG. 2 is an electrospray mass spectrum of complex 4BrIr prepared in example 1 of the present invention;
FIG. 3 is an electrospray mass spectrum of complex 5BrIr prepared in example 1 of the present invention;
FIG. 4 is a single crystal structure diagram of complex 4BrIr prepared in example 1 of the present invention;
FIG. 5 is a NMR chart of complex 4BrIr prepared in example 1 of the present invention;
FIG. 6 is a NMR chart of complex 5BrIr prepared in example 1 of the present invention;
FIG. 7 shows the structural formula of complex 4BrIr prepared in example 1 of the present invention;
FIG. 8 is the structural formula of complex 5BrIr prepared in example 1 of the present invention.
FIG. 9 is a synthetic route diagram of the present invention.
Detailed Description
The following claims are hereby incorporated into the detailed description of the invention, with the understanding that the present disclosure is to be considered as a full and non-limiting example, and any limited number of modifications that fall within the scope of the claims are intended to be included therein.
Example 1
0.1mmol of iridium dimer [ Ir (2pq) ] is added to a high-temperature pressure-resistant tube having a volume of 25.0mL2Cl]2And 0.2mmol of 4-bromo-8-hydroxyquinoline (4Br) or 5-bromo-8-hydroxyquinoline (5Br), uniformly mixing, dropwise adding 3.0mL of methanol and 0.2mL of dichloromethane, heating to 100 ℃ under a sealed condition, reacting for 48.0h, separating out a reddish brown blocky crystal or reddish brown powder, filtering, and drying in a vacuum drying oven at 55 ℃ to obtain the target complexes 4BrIr and 5BrIr, wherein the yield is 73.5% and 82.3%.
And identifying the obtained complex 4BrIr and 5 BrIr:
(1) electrospray mass spectra of complexes 4BrIr and 5BrIr are shown in FIGS. 2 and 3, wherein M is the molecular weight of each complex.
The complex is 4 BrIr: ESI-MS M/z 776.05[ M- (phq) +2(DMSO)]+；
The complex is 5 BrIr: ESI-MS M/z 776.05[ M + H ]]+。
(2) The structure diagram of the single crystal of the complex is shown in FIG. 4.
(3) The nuclear magnetic resonance hydrogen spectra of the complex 4BrIr and the complex 5BrIr are shown in figures 5 and 6.
Data for compound 4 BrIr:1H NMR(500MHz,DMSO-d6)δ9.10(d,J＝8.9Hz,1H),8.48(d,J＝8.7Hz,2H),8.42(t,J＝8.3Hz,2H),8.22(d,J＝7.9Hz,1H),8.06(d,J＝7.8Hz,1H),7.86(dd,J＝18.7,8.0Hz,2H),7.73(d,J＝5.2Hz,1H),7.52(dd,J＝13.4,7.1Hz,2H),7.40(t,J＝7.3Hz,1H),7.33(dt,J＝14.6,8.0Hz,2H),7.17(t,J＝8.0Hz,1H),7.06(t,J＝7.3Hz,1H),6.97(dt,J＝21.7,7.9Hz,2H),6.72(t,J＝7.2Hz,1H),6.66(d,J＝7.6Hz,1H),6.61(t,J＝7.3Hz,1H),6.54(d,J＝8.1Hz,2H),6.12(d,J＝7.6Hz,1H)。
data for compound 5 BrIr:1H NMR(500MHz,DMSO-d6)δ9.07(d,J＝8.7Hz,1H),8.49(dd,J＝8.8,3.9Hz,2H),8.43(t,J＝9.1Hz,2H),8.22(d,J＝7.9Hz,1H),8.05(dd,J＝13.6,8.2Hz,2H),7.87(dd,J＝20.1,7.9Hz,2H),7.79(d,J＝4.7Hz,1H),7.48(dd,J＝8.7,4.9Hz,1H),7.43(dd,J＝15.7,8.4Hz,2H),7.36(d,J＝8.1Hz,1H),7.34–7.29(m,2H),7.07(t,J＝7.5Hz,1H),6.94(q,J＝8.1Hz,2H),6.73(t,J＝7.4Hz,1H),6.65(d,J＝7.6Hz,1H),6.61(t,J＝7.4Hz,1H),6.40(d,J＝8.7Hz,1H),6.13(d,J＝7.6Hz,1H)。
(4) the results of elemental analysis are shown in Table 1.
Table 1 elemental analysis results of complexes 4BrIr and 5BrIr in examples
Therefore, the target product of the obtained red-brown bulk crystal or red-brown powder can be determined to be a complex, 4BrIr and 5BrIr, and the structural formula of the complex is shown in figures 7 and 8.
Example 2
0.1mmol of iridium dimer [ Ir (2pq) ] is added to a high-temperature pressure-resistant tube having a volume of 25.0mL2Cl]2And 0.2mmol of 4-bromo-8-hydroxyquinoline (4Br) or 5-bromo-8-hydroxyquinoline (5Br), uniformly mixing, dropwise adding 1.0mL of methanol and 5.5mL of dichloromethane, heating to 100 ℃ under a sealed condition, reacting for 48.0h, separating out a reddish brown blocky crystal or reddish brown powder, filtering, and drying in a vacuum drying oven at 55 ℃ to obtain the target complexes 4BrIr and 5BrIr, wherein the yield is 76.2% and 80.9%.
Example 3
0.1mmol of iridium dimer [ Ir (2pq) ] is added to a high-temperature pressure-resistant tube having a volume of 25.0mL2Cl]2And 0.2mmol of 4-bromo-8-hydroxyquinoline (4Br) or 5-bromo-8-hydroxyquinoline (5Br), uniformly mixing, dropwise adding 1.0mL of methanol and 1.0mL of dichloromethane, heating to 100 ℃ under a sealed condition, reacting for 48.0h, separating out a reddish brown blocky crystal or reddish brown powder, filtering, and drying in a vacuum drying oven at 55 ℃ to obtain the target complexes 4BrIr and 5BrIr, wherein the yield is 74.9% and 80.1%.
In order to fully illustrate the use of 1-2 of the present invention in the preparation of drugs, in vivo and in vitro anti-lung cancer activity experiments were performed on the complex 1-2.
Experiment on proliferation inhibition activity of iridium anticancer on various human tumor cell strains
1. Cell lines and cell cultures
The experiment selects 3 cell strains such as non-small cell lung cancer A549, cisplatin-resistant strain A549/DDP, human normal liver HL-7702 cells and the like.
All human cell lines were cultured in RPMI-1640 medium containing 100U/mL penicillin, 10 wt% calf blood, and 100U/mL streptomycin in a volume concentration of 5% CO2The temperature is 37 ℃ in an incubator.
2. Preparation of test Compounds
The purities of the used ligands 4Br, 5Br and the complexes 1-2 are more than or equal to 95 percent, the DMSO stock solutions of the ligands and the 5Br and the complexes are diluted into a final solution of 20 mu mol/L (the final concentration of DMSO is less than or equal to 1 percent) by using a physiological buffer solution, and the inhibition degree of the ligands and the complexes 1-2 on the growth of normal cells or selected tumor cells under the concentration is tested.
3. MTT method for detecting cell growth inhibition experiment
(1) Taking normal cells or lung cancer cells in logarithmic growth phase, digesting with trypsin, preparing a cell suspension with the concentration of 5000/mL by using a culture solution containing 10% calf serum, inoculating 190 mu L of the cell suspension into a 96-hole culture plate, enabling the density of the cells to be detected to reach 1000-10000 holes, and filling the marginal holes with sterile PBS.
(2)5％CO2And incubating for 24h at 37 ℃ until cell monolayers are paved on the bottom of the wells, adding 10 mu L of the medicine with a certain concentration gradient into each well, and arranging 4 multiple wells for each concentration gradient.
(3)5％CO2Incubated at 37 ℃ for 48 hours and observed under an inverted microscope.
(4) mu.L of 5mg/mL MTT solution was added to each well and incubation was continued for 4 h.
(5) Terminating the culture, carefully removing the culture solution in the wells, adding 150 μ L of DMSO into each well to sufficiently dissolve formazan precipitate, mixing uniformly with an oscillator, and measuring the optical density of each well with a microplate reader at a wavelength of 570nm and a reference wavelength of 450 nm;
(6) simultaneously, a zero setting hole (culture medium, MTT, DMSO) and a control hole (cells, culture solution, MTT, a drug dissolving medium with the same concentration, DMSO) are arranged.
(7) The number of living cells was judged from the measured optical density values (OD values), and the larger the OD value, the stronger the cell activity. Using the formula:
calculating the inhibition rate of ligands 4Br, 5Br and complexes 1-2 on the growth of the selected cells, and calculating the IC of each tested compound on each selected cell strain by a Bliss method50The value is obtained. The results are shown in table 2 below.
TABLE 2 IC of each ligand and Complex 1-2 for various cell lines50Value (μ M)
From the screening result of IC50 activity, the complexes 4BrIr and 5BrIr target to inhibit the growth of A549/DDP, and the IC of the complexes50The values are 0.53 +/-0.11 mu M and 0.09 +/-0.03 mu M respectively, the in vitro anti-lung cancer activity of the compound is far greater than that of 4Br and 5Br ligands, especially 4BrIr, the anti-cancer activity of the compound is 473.9 times (66.34 +/-1.21 mu M) of that of a clinical anti-cancer drug cisplatin, and the toxicity of the compound to normal cells HL-7702 is low (IC is)50More than 80 mu M), which shows that the compounds target tumors and overcome the drug resistance of cisplatin, have potential medicinal value and are expected to be used for preparing various anti-lung cancer drugs.
Second, in vivo tumor suppression experiment of tumor-bearing nude mice
(1) Animal requirements:
strain: BALB/c-nu; grade: an SPF level; the week age is as follows: 5-6 w; weight: 18-20 g; sex: male;
(2) animal sources:
supplied by Changzhou Kavens laboratory animals Ltd (laboratory animal production license: SCXK (threo) 2016-.
(3) Site of animal experiment:
license for use of experimental animal: SYXK (threo) 2017-0040.
(4) The requirements of the breeding environment are as follows:
SPF class, IVC independent ventilation system; keeping constant temperature (26 +/-2 ℃) and humidity (40-70%), and turning on and off the lamp for 12h respectively.
(5) Feed:
SPF mouse breeding feed is selected and purchased from Australian cooperative feed Co., Ltd, Beijing.
(6) Main reagents and instruments used for the experiments:
reagent: DMSO, 0.9% of normal saline, 75% of medical alcohol and 4% of paraformaldehyde; the apparatus is as follows: surgical scissors, forceps, a trocar and an electronic vernier caliper.
(7) Basic procedure and operation of the experiment:
(ii) cell culture
For experimental cell lines and cell cultures, please refer to the above section.
② preparation of lotus A549/DDP model
Cancer cells in logarithmic growth phase were collected and prepared into a suspension of 5X 107 viable cells/mL in serum-free medium. 0.2mL of suspension containing about 1X 107 viable cells was extracted with a 1.0mL syringe and then inoculated subcutaneously into the right axilla of nude mice until the subcutaneous tumor grew to about 1cm3In time, the tumor source was generated as a subcutaneous tumor model and passaged on nude mice. Passing tumor on nude mouse for 4 generations until its growth is stable, selecting tumor-bearing mouse with vigorous tumor growth and no rupture, killing cervical vertebra dislocation, sterilizing animal skin with 75% medical alcohol, dissecting tissue block, removing necrotic part, and cutting tumor tissue into 1.5mm3The left and right small blocks are inoculated under the skin of the right axilla of the nude mouse by a trocar. Measuring the tumor diameter of the transplanted tumor by using an electronic vernier caliper until the tumor volume grows to 100-3At time, animals were randomly grouped.
(iii) drug efficacy experiment
Nude tumor mice were randomly divided into vehicle group, drug-added group and cisplatin positive control group, with 7 animals per group. The intraperitoneal injection administration is started on the grouping day, the compound is administered every two days, and the cisplatin is administered every other day. The tumor diameter was measured every three days with an electronic vernier caliper, and the body weight was measured. And (3) killing the cervical vertebra at dislocation on the 15 th day, dissecting tumors, weighing, photographing and calculating the tumor inhibition rate.
Tumor volume calculation formula: v ═ a × b2A is a long diameter, and b is a short diameter;
relative tumor volume RTV ═ Vt/V0，VtVolume at each measurement, V0Volume when grouped;
relative tumor increment rate T/C ═ TRTV/CRTV × 100%;
the tumor growth inhibition ratio (%) (mean tumor weight in vehicle group-mean tumor weight in treatment group)/mean tumor weight in vehicle group × 100%.
As seen from the results of the in vivo tumor suppression experiments shown in Table 3 above, the A549/DDP tumors all had a volume of 571.2 + -42.1 mm after 15 days of administration as 5BrIr (10.0mg/kg/2 days)3Is obviously lower than that of a blank control group 1031.5 +/-123.8 mm3The tumor inhibition rate is as high as 45.3 percent, which far exceeds that of blank groups and clinical drugsThe tumor inhibition rate of the substance cisplatin (33.1%) (cisplatin data is from M. -X. Tan, et al. Dalton trans.,2020,49, 1613-1619.). In conclusion, the 5BrIr shows good in vivo and in vitro anti-tumor activity, has good potential medicinal value, and is expected to be used for preparing various anti-lung cancer medicaments.
TABLE 3 in vivo anti-tumor results of Complex 5BrIr on nude mice with A549/DDP
The above is only a preferred embodiment of the present invention, and it should be noted that it is obvious to those skilled in the art that several variations and modifications can be made without departing from the structure of the present invention, which will not affect the effect and practicality of the present invention.
Claims (9)
1. A quinoline iridium complex targeting lung cancer cisplatin resistant cells is characterized in that the chemical structural formula is shown as the following formula 1:
2. a quinoline iridium complex targeting lung cancer cisplatin resistant cells is characterized in that the chemical structural formula is shown as the following formula 2:
3. the method for synthesizing the quinoline iridium complex targeted to the lung cancer cisplatin-resistant cell as claimed in any one of claims 1-2, comprising the following steps:
(1) adding an iridium dimer and 4-bromo-8-hydroxyquinoline or 5-bromo-8-hydroxyquinoline into a polar solvent to obtain a mixed solution;
(2) reacting the obtained mixed solution at 100 ℃ under a sealed condition to obtain a precipitate;
(3) and filtering and drying the precipitate to obtain the target complex.
4. The method for synthesizing quinoline iridium complex for targeting lung cancer cisplatin-resistant cells as claimed in claim 3, wherein in the step (1), iridium dimer [ Ir (2pq) ]2Cl]2And 4-bromo-8-hydroxyquinoline or 5-bromo-8-hydroxyquinoline in a ratio of 1: 2.
5. The method for synthesizing the quinoline iridium complex targeting lung cancer cisplatin-resistant cells as claimed in claim 3, wherein the polar solvent is dichloromethane and methanol.
6. The method for synthesizing the quinoline iridium complex targeting lung cancer cisplatin-resistant cells as claimed in claim 5, wherein the dichloromethane is 0.2-5.5 mL; the methanol is 1-3 mL.
7. The method for synthesizing the quinolinium iridium complex targeting cells resistant to lung cancer cis-platinum as claimed in claim 3, wherein in the step (2), the reaction time is 48 h.
8. The method for synthesizing the quinoline iridium complex targeted to the lung cancer cisplatin-resistant cell as claimed in claim 3, wherein in the step (3), the drying temperature is 55 ℃.
9. The use of the quinolinium iridium complex targeted to cisplatin-resistant cells as claimed in any of claims 1-2 in the preparation of anti-lung cancer drugs.
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Application publication date: 20211022 Assignee: Guangxi Kangjian AoXin Biomedical Technology Co.,Ltd. Assignor: Yulin Normal University Contract record no.: X2022450000331 Denomination of invention: A quinoline iridium complex targeting cisplatin resistant lung cancer cells and its synthesis and application Granted publication date: 20220715 License type: Common License Record date: 20221217 |