CN113683644A

CN113683644A - Bis-quinoline iridium complex for treating cisplatin-resistant cancer cells and preparation method and application thereof

Info

Publication number: CN113683644A
Application number: CN202110988709.7A
Authority: CN
Inventors: 杨燕; 覃其品; 谢秋季; 潘凤华; 甘雨; 覃芳香; 梁晓敏; 冯清丽; 龙鸿敏; 李威; 陈志林
Original assignee: Yulin Normal University
Current assignee: Yulin Normal University
Priority date: 2021-08-26
Filing date: 2021-08-26
Publication date: 2021-11-23
Anticipated expiration: 2041-08-26
Also published as: CN113683644B

Abstract

The invention discloses a biquinoline iridium complex for treating cisplatin-resistant cancer cells, a preparation method and application thereof, belongs to the field of medicines, and aims to solve the technical problem of drug resistance of cisplatin-type medicines of lung cancer in the prior art, wherein the method specifically comprises the following steps: (1) mixing the iridium dimer [ Ir (2pq)₂Cl]₂Adding the ligand 8-hydroxyquinoline derivative and a polar solvent to obtain a mixed solution; (2) reacting the obtained mixed solution at 90 ℃ under a sealed condition to obtain a precipitate; (3) and filtering and drying the precipitate to obtain the target complex. Researches find that the complex 2a-2f has good inhibition effect on A549/DDP and SK-OV-3/DDP, and IC thereof₅₀The value is 0.11-1.83 mu M, the in vitro anti-tumor activity of the compound is far greater than that of a 1a-1f ligand and a clinical anti-cancer drug cisplatin, and the compound is normalThe toxicity of HL-7702 cells is very low, which indicates that the cells target tumors and overcome the drug resistance of cisplatin. The research on in vivo anticancer shows that the in vivo anticancer inhibition effect reaches 64.1 percent, and the compound has potential medicinal value and is expected to be used for preparing various antitumor medicaments.

Description

Bis-quinoline iridium complex for treating cisplatin-resistant cancer cells and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a biquinoline iridium complex for treating cisplatin-resistant cancer cells and a preparation method and application thereof.

Background

Cisplatin drugs are one of the most common chemotherapy drugs in clinical treatment, have obvious curative effect on the treatment of various cancers, and the drug resistance limits the further clinical use of the cisplatin drugs; in addition, the metal iridium complex has long phosphorescence life and large stokes shift, is widely applied to the fields of fluorescent probes, biological imaging, anticancer and the like, and has great prospect as a metal antitumor drug in view of the characteristics of the iridium complex. Therefore, the design of the anticancer iridium complex which targets tumors and overcomes the drug resistance of cisplatin drugs is urgently needed.

Currently, 8-hydroxyquinolinesAnd the 1-phenylpyrazole derivative iridium complex is reported to have better inhibiting effect on cervical cancer HeLa and ovarian cancer cis-platinum drug-resistant cell SK-OV-3/DDP, and is targeted to a mitochondrial membrane of the cervical cancer HeLa (Q. -P. Qin, et al. European Journal of Medicinal Chemistry,2020,192,112192.), but no relevant report is made on synthesizing the metal iridium complex by using 8-hydroxyquinoline derivative and 2-phenylquinoline as a mixed ligand. This study was initiated with the active 8-hydroxyquinoline derivative (1 a-1 f) dimer with 2-phenylquinoline [ Ir (2pq)₂Cl]₂2pq ═ 2-phenylquinoline), and an iridium complex [ Ir (1a) (2pq) thereof was synthesized₂](2a)、[Ir(1b)(2pq)₂](2b)、[Ir(1c)(2pq)₂](2c)、[Ir(1d)(2pq)₂](2d)、[Ir(1e)(2pq)₂](2e) And [ Ir (1f) (2pq)₂](2f) The 8-hydroxyquinoline metal iridium complex for inhibiting the cisplatin resistant cell A549/DDP of the human non-small cell lung cancer cell is researched 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 biquinoline iridium complex for treating cisplatin-resistant cancer cells.

The invention also aims to provide a preparation method of the biquinoline iridium complex for treating the cisplatin-resistant cancer cells.

The invention also aims to provide application of the biquinoline iridium complex for treating the cisplatin-resistant cancer cells in preparation of antitumor drugs.

The first purpose of the invention is realized by the following technical scheme: a bisquinoline iridium complex for treating cisplatin-resistant cancer cells has a chemical structural formula shown as the following formula 1-6:

the second purpose of the invention is realized by the following technical scheme: a preparation method of a biquinoline iridium complex for treating cisplatin-resistant cancer cells comprises the following steps:

(1) mixing the iridium dimer [ Ir (2pq)₂Cl]₂And ligand 8-hydroxyquinoline derivative (1 a-1 f), adding into a polar solvent to obtain a mixed solution;

(2) reacting the obtained mixed solution at 90 ℃ under a sealed condition to obtain a precipitate;

(3) and filtering and drying the precipitate to obtain the target complex.

As a further improvement, in the step (1), the iridium dimer [ Ir (2pq) ]₂Cl]₂And 8-hydroxyquinoline derivative (1 a-1 f) ligand at a ratio of 1: 2.

Further, the ligands of the 8-hydroxyquinoline derivative (1 a-1 f) include 5, 7-diiodo-8-hydroxyquinoline (1a), 5, 7-dichloro-8-hydroxyquinoline (1b), 5-chloro-7-iodo-8-hydroxyquinoline (1c), 5, 7-dibromo-8-hydroxyquinoline (1d), 5, 7-dichloro-2-methyl-8-hydroxyquinoline (1e) and 5, 7-dibromo-2-methyl-8-hydroxyquinoline (1 f).

Further, in the step (2), the polar solvent is any one of dichloromethane and methanol or ethanol or a methanol-ethanol mixed solution (in any volume ratio).

Further, the dichloromethane is 0.1-1.5mL, the methanol is 3.5mL, the ethanol is 5.5mL, and the methanol-ethanol mixed solution is 2.5 mL.

Further, in the step (2), the reaction time is 48h, and neither the excessive temperature nor the insufficient temperature has a product or is not a main product.

Further, in the step (3), the drying time is 55 ℃.

The third purpose of the invention is realized by the application of the biquinoline iridium complex in preparing antitumor drugs.

The chemical formula of the bisquinoline iridium complex (2a-2f) is [ Ir (1a) (2pq)2] (2a), [ Ir (1b) (2pq)2] (2b), [ Ir (1c) (2pq)2] (2c), [ Ir (1d) (2pq)2] (2d), [ Ir (1e) (2pq)2] (2e) and [ Ir (1f) (2pq)2] (2f), and the chemical structural formula is shown in FIG. 14.

Dimer of 2-phenylquinoline ([ Ir (2pq) ]according to the present invention₂Cl]₂2pq ═ 2-phenylquinoline) reference synthesis (r.j.watts, et al.j.am. chem.soc.,1984,106,6647-6653.) having the structural formula shown in figure 15.

Advantageous effects

Compared with the prior art, the invention has the advantages that: the invention provides 6 novel bisquinoline iridium complexes [ Ir (1a) (2pq)₂](2a)、[Ir(1b)(2pq)₂](2b)、[Ir(1c)(2pq)₂](2c)、[Ir(1d)(2pq)₂](2d)、[Ir(1e)(2pq)₂](2e) And [ Ir (1f) (2pq)₂](2f) As well as a process for its preparation and use; and the activity and toxicity experiments of the compounds on non-small cell lung cancer cis-platinum resistant strain A549/DDP, human ovarian cancer cis-platinum resistant strain SK-OV-3/DDP and human normal liver HL-7702 cells are considered. Experimental results show that the complex 2a-2f has good inhibition effect on A549/DDP and SK-OV-3/DDP, and IC thereof₅₀0.11-1.83 μ M, overcomes the resistance of cisplatin, especially 2e has the best activity to A549/DDP, and IC thereof₅₀The value is 0.11 +/-0.04 mu M, is the anticancer drug of the first 8-hydroxyquinoline iridium complex reaching the nM level, and the in vitro antitumor activity of the anticancer drug is far greater than that of the ligand (1 a-1 f)>50 mu M) and the clinical anticancer drug cisplatin (>50 μ M) and they have little toxicity (IC) to normal cells HL-7702₅₀> 50 μ M), suggesting that they target tumors and overcome cisplatin resistance. The research on in vivo anticancer for the first time shows that the in vivo anticancer inhibition effect reaches 64.1 percent, has potential medicinal value and is expected to be used for preparing various antitumor medicaments.

Drawings

FIG. 1 is an electrospray mass spectrum of a complex 2a prepared in example 1 of the present invention;

FIG. 2 is an electrospray mass spectrum of a complex 2b prepared in example 1 of the present invention;

FIG. 3 is an electrospray mass spectrum of complex 2c prepared in example 1 of the present invention;

FIG. 4 is an electrospray mass spectrum of complex 2d prepared in example 1 of the present invention;

FIG. 5 is an electrospray mass spectrum of a complex 2f prepared in example 1 of the present invention;

FIG. 6 is a single crystal structural view of a complex 2c obtained in example 1 of the present invention;

FIG. 7 is a single crystal structural view of a complex 2d obtained in example 1 of the present invention;

FIG. 8 is a NMR chart of complex 2a obtained in example 1 of the present invention;

FIG. 9 is a NMR chart of complex 2b obtained in example 1 of the present invention;

FIG. 10 is a NMR chart of complex 2d obtained in example 1 of the present invention;

FIG. 11 is a NMR chart of complex 2e obtained in example 1 of the present invention;

FIG. 12 is a NMR chart of a complex 2e obtained in example 1 of the present invention;

FIG. 13 is a NMR chart of complex 2f obtained in example 1 of the present invention;

FIG. 14 is a chemical structural formula of bis-quinoline iridium complex (2a-2f) of the present invention;

FIG. 15 is a chemical structural formula of an iridium dimer of the present invention;

FIG. 16 is a scheme showing the synthesis of a complex of the present invention.

Detailed Description

The invention will be further described with reference to specific embodiments shown in the drawings.

Example 1

The preparation method of the biquinoline iridium complex for treating the cisplatin-resistant cancer cells comprises the following steps:

(2) reacting the obtained mixed solution for 48 hours at 90 ℃ under a sealed condition to obtain a precipitate;

(3) and filtering and drying the precipitate to obtain the target complex 2a-2f with the yield of 78.2-91.6%.

In the step (1), the iridium dimer [ Ir (2pq) ]₂Cl]₂And 8-hydroxyquinoline derivative (1 a-1 f) ligand at a ratio of 1: 2.

The 8-hydroxyquinoline derivative (1 a-1 f) ligands include 5, 7-diiodo-8-hydroxyquinoline (1a), 5, 7-dichloro-8-hydroxyquinoline (1b), 5-chloro-7-iodo-8-hydroxyquinoline (1c), 5, 7-dibromo-8-hydroxyquinoline (1d), 5, 7-dichloro-2-methyl-8-hydroxyquinoline (1e) and 5, 7-dibromo-2-methyl-8-hydroxyquinoline (1 f).

In the step (2), the polar solvent is any one of dichloromethane and methanol or ethanol or a methanol-ethanol mixed solution (in any volume ratio).

0.1-1.5mL of dichloromethane, 3.5mL of methanol, 5.5mL of ethanol and 2.5mL of methanol-ethanol mixed solution.

In the step (3), the drying time was 55 ℃.

The resulting complexes 2a-2f were identified:

(1) the electrospray mass spectrum of complexes 2a-2f is shown in FIGS. 1-5, wherein M is the molecular weight of each complex.

2a

2b

2c

2d

2f

m/z

998.0

814.05

906.00

903.95

917.70

Fragments

[M+H]⁺

(2) The single crystal structures of complexes 2c and 2d are shown in FIGS. 6 and 7.

(3) The nuclear magnetic resonance hydrogen and carbon spectra of the complexes 2a-2f are shown in figures 8-13.

Data for compound 2 a: the yield was 78.2%;¹H NMR(500MHz,DMSO-d6)δ8.97(d,J＝8.9Hz,1H),8.51(d,J＝8.7Hz,1H),8.46(d,J＝8.5Hz,2H),8.41(d,J＝9.2Hz,1H),8.21(d,J＝7.9Hz,1H),8.08(d,J＝7.9Hz,1H),7.92(dd,J＝16.2,8.9Hz,3H),7.85(d,J＝8.2Hz,1H),7.76(d,J＝4.9Hz,1H),7.51(dd,J＝8.7,5.0Hz,1H),7.46–7.42(m,1H),7.39(d,J＝8.9Hz,1H),7.34(dt,J＝14.8,7.9Hz,2H),7.07(t,J＝7.4Hz,1H),6.99–6.92(m,2H),6.76–6.72(m,1H),6.63(t,J＝7.8Hz,2H),6.13(d,J＝7.6Hz,1H)。

data for compound 2 b: the yield was 91.6%;¹H NMR(500MHz,DMSO-d6)δ9.01(d,J＝3.7Hz,1H),8.53(d,J＝8.4Hz,2H),8.47(d,J＝8.5Hz,1H),8.41(d,J＝8.6Hz,1H),8.22(s,1H),8.15(d,J＝8.4Hz,1H),8.10(d,J＝8.5Hz,1H),7.93(d,J＝7.7Hz,1H),7.86(d,J＝9.6Hz,2H),7.77(dd,J＝8.5,4.1Hz,2H),7.54(dd,J＝8.1,4.8Hz,1H),7.43(t,J＝7.4Hz,2H),7.34(d,J＝7.6Hz,1H),7.09–7.05(m,1H),7.00–6.94(m,2H),6.73(d,J＝7.4Hz,1H),6.63(dd,J＝13.8,7.0Hz,2H),6.15(d,J＝7.0Hz,1H)。

data for compound 2 c: the yield was 85.4%.

Data for compound 2 d: the yield was 79.9%;¹H NMR(500MHz,DMSO-d6)δ8.98(d,J＝8.5Hz,1H),8.55(d,J＝8.7Hz,1H),8.52(d,J＝9.5Hz,1H),8.47(d,J＝9.3Hz,2H),8.41(d,J＝8.2Hz,1H),8.37(d,J＝9.3Hz,1H),8.21(d,J＝7.9Hz,1H),8.10–8.08(m,1H),7.93(d,J＝7.8Hz,1H),7.84(d,J＝5.6Hz,1H),7.65(s,1H),7.55(dd,J＝7.9,5.6Hz,1H),7.45–7.41(m,2H),7.37–7.32(m,2H),7.08(d,J＝6.0Hz,1H),6.98(d,J＝5.7Hz,1H),6.84–6.81(m,1H),6.76–6.72(m,1H),6.63(d,J＝6.7Hz,1H),6.51–6.47(m,1H),6.15(d,J＝8.1Hz,1H)。

data for compound 2 e: the yield is 90.0%;¹H NMR(500MHz,DMSO-d6)δ9.11(d,J＝8.9Hz,1H),8.52–8.46(m,3H),8.40(d,J＝8.9Hz,1H),8.12(d,J＝7.8Hz,1H),8.08(d,J＝8.7Hz,1H),7.99(d,J＝7.6Hz,1H),7.90(d,J＝8.1Hz,2H),7.58(d,J＝9.0Hz,1H),7.41(t,J＝7.4Hz,1H),7.33(q,J＝8.9,8.1Hz,3H),7.27–7.23(m,1H),7.05–7.01(m,1H),6.94(q,J＝7.8Hz,2H),6.64(dt,J＝21.5,7.4Hz,2H),6.57(d,J＝7.6Hz,1H),5.96(d,J＝7.8Hz,1H),2.10(s,3H).¹³C NMR(126MHz,DMSO)δ171.65,170.31,164.41,160.64,153.30,149.73,147.79,147.56,147.15,146.91,140.13,139.73,138.65,134.80,134.44,132.29,131.11,130.51,130.20,129.62,129.34,128.70,128.09,128.00,127.84,127.62,126.68,126.64,126.55,126.40,125.39,125.26,124.40,122.17,120.87,119.57,117.97,117.60,110.20,40.50,40.33,40.25,40.16,40.00,39.83,39.66,39.50,25.37。

data for compound 2 f: the yield was 78.6%;¹H NMR(500MHz,DMSO-d6)δ9.10(d,J＝8.9Hz,1H),8.53–8.46(m,3H),8.40(d,J＝9.0Hz,1H),8.13(d,J＝7.8Hz,1H),8.02(d,J＝8.5Hz,1H),7.99(d,J＝7.8Hz,1H),7.91(d,J＝7.6Hz,2H),7.55(d,J＝7.6Hz,2H),7.43–7.39(m,1H),7.33(t,J＝8.0Hz,2H),7.28–7.24(m,1H),7.04–7.00(m,1H),6.97–6.91(m,2H),6.68–6.65(m,1H),6.62(t,J＝7.6Hz,1H),6.58(d,J＝7.8Hz,1H),5.95(d,J＝7.6Hz,1H),2.10(s,3H)。

(4) the results of elemental analysis are shown in Table 1.

Table 1 results of elemental analysis of complexes 2a to 2f in examples

Therefore, the target product of the obtained red-brown bulk crystal or red-brown powder can be determined to be the complex 2a-2f, and the structural formula of the complex is shown in figure 14.

Example 2

Different from example 1, in the step (2), the solvent is 0.5mL of dichloromethane and 5.5mL of ethanol which are added dropwise, and the yield is 79.9-90.0%.

Example 3

Different from example 1 in that the solvent added dropwise in the step (2) was a mixed solution of 1.5mL of dichloromethane and 2.5mL of methanol-ethanol, and the yield was 81.2-91.1%.

In order to fully illustrate the application of the biquinoline iridium complex for treating the cisplatin-resistant cancer cells in pharmacy, the applicant performs in-vitro and in-vivo anti-tumor activity experiments on the complex.

Experiment on proliferation inhibition activity of iridium anti-cancer complex on various human tumor cell strains

1. Cell lines and cell cultures

The experiment selects 3 cell strains such as a non-small cell lung cancer cisplatin-resistant strain A549/DDP, a human ovarian cancer cisplatin-resistant strain SK-OV-3/DDP, a human normal liver HL-7702 cell 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, and cultured in an incubator containing 5% CO2 at 37 ℃.

2. Preparation of test Compounds

The purity of the ligand and the complex used needs to be more than or equal to 95 percent, the DMSO stock solution of the ligand and the complex is 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 degree of inhibition of the growth of normal cells or selected tumor cells by each compound under the concentration is tested.

3. Cell growth inhibition assay (MTT method)

(1) Taking normal cells or tumor cells in a logarithmic growth phase, digesting the cells or tumor cells by 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, and enabling the density of cells to be detected to reach 1000-10000 holes (the edge holes are filled with sterile PBS);

(2)5％CO₂incubating for 24h at 37 ℃ until a cell monolayer is paved on the bottom of each well, adding 10 mu L of medicine with a certain concentration gradient into each well, and arranging 4 compound wells in each concentration gradient;

(3)5％CO₂incubating for 48h at 37 ℃, and observing under an inverted microscope;

(4) add 10. mu.L of MTT solution (5mg/mL PBS, i.e., 0.5% MTT) to each well and continue culturing 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 each compound 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 Compounds on various cell lines₅₀Value (μ M)

Slave IC₅₀The activity screening result shows that the complex 2a-2f has good inhibition effect on A549/DDP and SK-OV-3/DDPIC thereof₅₀0.11-1.83 μ M, overcomes the resistance of cisplatin, especially 2e has the best activity to A549/DDP, and IC thereof₅₀The value is 0.11 +/-0.04 mu M, is the anticancer drug of the first 8-hydroxyquinoline iridium complex reaching the nM level, and the in vitro antitumor activity of the anticancer drug is far greater than that of the ligand (1 a-1 f)>50 mu M) and the clinical anticancer drug cisplatin (>50 μ M) and they have little toxicity (IC) to normal cells HL-7702₅₀> 50 μ M), suggesting that they target tumors and overcome cisplatin resistance. It is worth emphasizing that the complex 2a-2f is the first proven 8-hydroxyquinoline iridium complex which has obvious inhibition effect on the cisplatin-resistant strain lung cancer A549/DDP, has potential medicinal value and is expected to be used for preparing various antitumor medicaments.

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 ═ V_t/V₀In which V is_tVolume at each measurement, V₀Volume when grouped;

relative tumor increment rate T/C ═ T_RTV/C_RTV)×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 experiment shown in the above Table 3, after 15 days of administration, the complex 2e has a better inhibitory effect on tumor nude mice, and the tumor suppression rate is as high as 64.1%, which far exceeds the tumor suppression rate (33.1%) of clinical drug cisplatin (the cisplatin data is from M. -X. tan, et al. Dalton trans.,2020,49, 1613-one 1619.). In conclusion, the iridium complex 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-tumor medicaments.

TABLE 3 in vivo anti-tumor results of Complex 2e on A549/DDP-bearing nude mice

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

1. A biquinoline iridium complex for treating cisplatin-resistant cancer cells is characterized in that the chemical structural formula is as follows:

2. the preparation method of the biquinoline iridium complex for treating cisplatin-resistant cancer cells as claimed in claim 1, comprising the following steps:

(1) mixing the iridium dimer [ Ir (2pq)₂Cl]₂And ligand 8-hydroxyquinoline derivative (1 a-1 f) into a polar solvent to obtain a mixed solution;

(3) and filtering and drying the precipitate to obtain the target complex.

3. The bisquine for treating cisplatin-resistant cancer cell as claimed in claim 2A process for producing an iridium complex, characterized in that in the step (1), the iridium dimer [ Ir (2pq) ]₂Cl]₂And ligand 8-hydroxyquinoline derivative (1 a-1 f) in a mass ratio of 1: 2.

4. The method for preparing a bis-quinoline iridium complex for treating cisplatin-resistant cancer cells as claimed in any of claims 2 or 3, wherein the ligand 8-hydroxyquinoline derivative (1 a-1 f) is 5, 7-diiodo-8-hydroxyquinoline (1a), 5, 7-dichloro-8-hydroxyquinoline (1b), 5-chloro-7-iodo-8-hydroxyquinoline (1c), 5, 7-dibromo-8-hydroxyquinoline (1d), 5, 7-dichloro-2-methyl-8-hydroxyquinoline (1e) or 5, 7-dibromo-2-methyl-8-hydroxyquinoline (1 f).

5. The preparation method of the bis-quinoline iridium complex for treating cisplatin-resistant cancer cells as claimed in claim 2, wherein the polar solvent is a mixed solution of dichloromethane and methanol or a mixed solution of dichloromethane and ethanol or a mixed solution of dichloromethane and methanol-ethanol.

6. The preparation method of the bisquinoline iridium complex for treating cisplatin-resistant cancer cell as claimed in claim 5, wherein the dichloromethane is 0.1-1.5mL, the methanol is 3.5mL, the ethanol is 5.5mL, and the methanol-ethanol mixed solution is 2.5 mL.

7. The preparation method of the bis-quinoline iridium complex for treating cisplatin-resistant cancer cells as claimed in claim 2, wherein in the step (2), the reaction time is 48 h.

8. The preparation method of the bis-quinoline iridium complex for treating cisplatin-resistant cancer cells as claimed in claim 2, wherein in the step (3), the drying time is 55 ℃.

9. The use of the biquinoline iridium complex for treating cisplatin-resistant cancer cells as claimed in claim 1 in the preparation of an antitumor medicament.

10. The use of the biquinoline iridium complex for the treatment of cisplatin-resistant cancer cells as claimed in claim 1 in the preparation of an antitumor medicament, wherein said tumors comprise lung cancer and liver cancer.