CN113929720B - Complex targeting human lung cancer drug-resistant cells and preparation method thereof - Google Patents
Complex targeting human lung cancer drug-resistant cells and preparation method thereof Download PDFInfo
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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
- C07F15/0073—Rhodium compounds
- C07F15/008—Rhodium compounds without a metal-carbon linkage
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention discloses a target human lung cancer resistantA complex of medicine cells and a preparation method thereof belong to the technical field of medicines. It comprises QB as an active ligand and a certain amount of RhY 3 And carrying out coordination reaction to obtain a reddish brown target product, namely the complex, wherein Y is halogen. The complex of the invention can selectively treat cancer cells such as A549/DDP and the like, and IC thereof 50 The value is 0.08 plus or minus 0.02 mu M, the in vitro anti-tumor activity is far greater than that of ligand and classical metal-based anticancer drug cisplatin, and the toxicity to normal HL-7702 cells is low (IC) 50 >80 mu M), solves the problem that the existing cisplatin-resistant cancer cells are difficult to treat by cisplatin medicaments, hardly causes harm to human bodies, and has great medical application prospect.
Description
Technical Field
The invention belongs to the technical field of medicines, and in particular relates to a complex targeting human lung cancer drug-resistant cells and a preparation method thereof.
Background
The disease burden is an indicator of the health and economic impact of disease, injury and early death on society and countries. At present, the global cancer morbidity and mortality burden is still growing, and cancer has surpassed high mortality chronic diseases such as cardiovascular diseases (such as cerebral apoplexy and coronary heart disease) in many countries in the leading position, which reflects both the acceleration of the aging process of the population and the increase of the exposure of the related risk factors of cancer. Thus, research into cancer treatment problems is necessary.
Currently, there are approved on the market platinum anticancer drugs including cisplatin, carboplatin, oxaliplatin and other platinum drugs. The platinum drugs are clinically used for various solid tumors such as ovarian cancer, prostate cancer, testicular cancer, lung cancer, nasopharyngeal cancer, esophagus cancer, malignant lymphoma, head and neck cancer, thyroid cancer, osteosarcoma and the like. Although cisplatin is one of the best anticancer drugs for chemotherapy effect and is widely used, its toxic side effects such as nephrotoxicity, gastrointestinal toxicity, neurotoxicity, bone marrow toxicity and ototoxicity and drug resistance of tumor cells limit its further application. Therefore, the research and development of the novel high-efficiency, low-toxicity and targeted non-platinum metal anti-tumor chemotherapeutic medicament has great practical significance and theoretical value.
Transition metal complexes, such as rhodium (III) complexes, have attracted attention by researchers due to their unique chemical and biological properties. Rhodium (III) complexes have different modes of action and cellular targets for cancer cells than traditional non-platinum metal anticancer drugs. The rhodium (III) complex has extremely high catalytic activity, can be combined with biological molecules, and can be used as a cell imaging sensor and a small molecule sensor. In addition, the rhodium (III) complex also has higher cytotoxicity, however, the research on the rhodium (III) complex is still in a starting stage, and the research on the rhodium (III) complex has certain limitations on the targeted treatment of human lung cancer drug-resistant cells at present. Quinoline is favored by more and more researchers, mainly because it is a class of pharmaceutical intermediates with multiple excellent biological activities, however, no report is currently available on rhodium (III) complexes with quinolinyl or benzopyran ligands.
Therefore, there is a need to design a rhodium (III) complex that is capable of selectively and effectively treating human lung cancer resistant cells.
Disclosure of Invention
1. Problems to be solved
Aiming at the problems that the platinum drugs in the prior art have strong toxic and side effects on human bodies and tumor cells have drug resistance on the drugs and cannot be reasonably applied, the invention provides the complex targeting drug resistant cells of human lung cancer and a preparation method thereof; by reasonably designing the structure and coordination mode of the rhodium (III) complex, the problem that the platinum drugs in the prior art cannot be reasonably applied in the aspect of targeted treatment of lung cancer is effectively solved.
2. Technical proposal
In order to solve the problems, the technical scheme adopted by the invention is as follows:
the invention relates to a complex targeting human lung cancer drug-resistant cells, which has the following structural formula:
Preferably, the structural formula is:
preferably, said M comprises CH 3 (CH 2 ) n OH or (CH) 3 ) 2 SO, n=0 to 7.
Preferably, it comprises RhN1 or RhQ; rhN1 is
The RhQ is
The preparation method of the complex provided by the invention is that the complex targets human lung cancer drug-resistant cells; ligands QB and RhY 3 Mixing and dissolving in a polar solvent comprising a ligand M to react, wherein the solid obtained by the reaction is the complex; y is halogen; the structural formula of the ligand QB is as follows:
Preferably, the specific operation steps are as follows:
(1) QB and RhCl 3 ·3H 2 Mixing and dissolving O in a polar solvent comprising a ligand M to obtain a mixed solution; the QB comprises QB1 or QB4, wherein QB1 is 3- (2' -pyridyl) -6-chloro-2-imine benzopyran, and the structural formula is as follows
QB4 is 3- (2' -quinolyl) -8-tertiary butyl-2-imine benzopyran, and the structural formula is
M is (CH) 3 ) 2 SO；
(2) The obtained mixed solution reacts at the temperature of 80-100 ℃ to obtain a reaction product after the reaction is completed;
(3) The reaction product is filtered, recrystallized and dried to obtain the complex.
Preferably, in the step (1), QB1 or QB4 is mixed with RhCl 3 ·3H 2 The mol ratio of O is (0.8-1.2): 1, a step of; the polar solvent is one or a combination of more of methanol, acetonitrile, ethanol, dimethyl sulfoxide, acetone and water, and the volume of the polar solvent is 2-20 mL.
Preferably, in the step (2), the reaction time is 12 to 72 hours.
Preferably, in the step (3), the recrystallization is performed using n-hexane and CH 2 Cl 2 Recrystallizing the mixed solution, n-hexane and CH 2 Cl 2 The volume ratio of (20 mL-40 mL): (5 mL-10 mL); the drying temperature is 50-75 ℃.
The other complex targeting human lung cancer drug-resistant cells has the following structural formula:
Preferably, the structural formula is:
preferably, said M comprises CH 3 (CH 2 ) n OH or (CH) 3 ) 2 SO, n=0 to 7.
Preferably, it comprises RhN2 or RhS; the RhN is
The RhS is
The preparation method of the complex provided by the invention is that the complex is another complex targeted to human lung cancer drug-resistant cells; ligands QB and RhY 3 Mixing and dissolving in a polar solvent comprising a ligand M to react, wherein the solid obtained by the reaction is the complex; y is halogen; the structural formula of the ligand QB is as follows:
Preferably, the specific operation steps are as follows:
(1) QB and RhCl 3 ·3H 2 Mixing and dissolving O in a polar solvent comprising a ligand M to obtain a mixed solution; the QB comprisesQB2 or QB3, QB2 is 3- (2' -benzimidazolyl) -6-bromo-2-iminobenzopyran, and has the structural formula of
QB3 is 3- (2' -benzothiazolyl) -8-tert-butyl-2-iminobenzopyran with the structural formula +.>
M is CH 3 OH；
(2) The obtained mixed solution reacts at the temperature of 80-100 ℃ to obtain a reaction product after the reaction is completed;
(3) The reaction product is filtered, recrystallized and dried to obtain the complex.
Preferably, in the step (1), QB2 or QB3 and RhCl 3 ·3H 2 The mol ratio of O is (0.8-1.2): 1, a step of; the polar solvent is one or a combination of more of methanol, acetonitrile, ethanol, dimethyl sulfoxide, acetone and water, and the volume of the polar solvent is 2-20 mL.
Preferably, in the step (2), the reaction time is 12 to 72 hours.
Preferably, in the step (3), the recrystallization is performed using n-hexane and CH 2 Cl 2 Recrystallizing the mixed solution, n-hexane and CH 2 Cl 2 The volume ratio of (20 mL-40 mL): (5 mL-10 mL); the drying temperature is 50-75 ℃.
The preferable complexes RhN, rhN2, rhS and RhQ targeted to the human lung cancer drug-resistant cells can be applied to in-vitro and in-vivo antitumor drugs prepared from the active ingredients, and can also be applied to the preparation of antitumor drugs targeted to the human lung cancer drug-resistant cells.
3. Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
(1) The complex targeted to the human lung cancer drug-resistant cells has excellent inhibition on cancer cells, in particular to human lung adenocarcinoma A549 cells and human lung adenocarcinoma cisplatin drug-resistant cells A549/DDP, wherein the complex has good inhibition effect on human lung adenocarcinoma cisplatin drug resistanceCell A549/DDP has targeted inhibition and IC thereof 50 The value range is 0.08 mu M-2.74 mu M, while the toxicity to human normal liver cell HL-7702 is lower, and the IC thereof is low 50 The value is maintained substantially above 80 μm; in addition, the in-vivo anti-tumor effect of the preferable complex RhQ in the invention is 55.3 percent, which is obviously higher than that of clinical cisplatin (33.1 percent), and the preferable complex RhQ is expected to be used for preparing anti-tumor drugs. Therefore, the complex of the invention can selectively treat cancer cells such as A549/DDP, solves the problem that the existing cisplatin-resistant cancer cells are difficult to treat by cisplatin medicaments, hardly causes harm to human bodies, and has great medical application prospect.
(2) The preparation method of the complex of the invention is that the complex targets human lung cancer drug-resistant cells, and the ligands QB and RhY are 3 Mixing and dissolving in a polar solvent comprising a ligand M to react, wherein the solid obtained by the reaction is the complex, and Y is halogen; by the method, the complex targeted to the human lung cancer drug-resistant cells can be prepared, and particularly the complexes RhN1, rhN2, rhS and RhQ show excellent performance of targeted inhibition of the growth of human lung adenocarcinoma cisplatin drug-resistant cells A549/DDP.
Drawings
FIG. 1 is a schematic structural diagram of the complexes RhN1, rhN2, rhS and RhQ of the present invention;
FIG. 2 is a synthetic reaction equation for the complexes RhN1, rhN2, rhS and RhQ of the present invention;
FIG. 3 is an electrospray mass spectrum of complex RhN1 of the present invention;
FIG. 4 is a diagram of a complex RhN1 of the invention 1 H NMR spectrum;
FIG. 5 is a schematic diagram of the molecular structure of the complex RhN1 of the invention;
FIG. 6 is an electrospray mass spectrum of complex RhN2 of the present invention;
FIG. 7 is a schematic diagram of the molecular structure of the complex RhN2 of the invention;
FIG. 8 is an electrospray mass spectrum of complex RhS of the present invention;
FIG. 9 is a diagram of a complex RhS of the invention 1 H NMR spectrogram;
FIG. 10 is a schematic diagram of the molecular structure of the complex RhS of the invention;
FIG. 11 is an electrospray mass spectrum of complex RhQ of the present invention;
FIG. 12 is a complex RhQ of the invention 1 H NMR spectrum;
FIG. 13 is a schematic diagram of the molecular structure of the complex RhQ of the invention.
Detailed Description
The following detailed description of exemplary embodiments of the invention refers to the accompanying drawings, which form a part hereof, and in which are shown by way of illustration exemplary embodiments in which features of the invention are identified by reference numerals. The following more detailed description of the embodiments of the invention is not intended to limit the scope of the invention, as claimed, but is merely illustrative and not limiting of the invention's features and characteristics in order to set forth the best mode of carrying out the invention and to sufficiently enable those skilled in the art to practice the invention. It will be understood that various modifications and changes may be made without departing from the scope of the invention as defined by the appended claims. The detailed description and drawings are to be regarded in an illustrative rather than a restrictive sense, and if any such modifications and variations are desired to be included within the scope of the invention described herein. Furthermore, the background art is intended to illustrate the status and meaning of the development of the technology and is not intended to limit the invention or the application and field of application of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs; the terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention; the term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The ligands QB1, QB2, QB3 and QB4 involved in the synthetic methods of the invention can be prepared by reference to the prior literature (Christie, R.M.; et al dyes and Pigments,2000,47:79-89. And Qin, Q.P.; et al European journal of medicinal chemistry,2019, 184:111751.).
The invention is further described below in connection with specific embodiments.
Example 1
The present embodiment provides a complex targeting human lung cancer drug-resistant cells, named RhN1 in the present embodiment, referring to fig. 2, and the preparation method thereof is as follows:
(1)preparation of ligand 3- (2' -pyridinyl) -6-chloro-2-iminobenzopyran (QB 1): 5-chloro-2-hydroxybenzaldehyde (0.01 mol,1.5657 g) and 2-pyridine acetonitrile (0.01 mol,1.1814 g) were added to a 250.0mL flask containing an ethanol-piperidine mixed solution (v: v=100 mL:1 mL), and reacted at 65℃with stirring for 24.0 hours with 50.0mL of methanol, CH, respectively 2 Cl 2 And diethyl ether to obtain yellow solid product QB1.
(2)Preparation of Complex RhN1: 1.0mmol of ligand QB1, 1.0mmol of RhCl 3 ·3H 2 O, 0.5mL of DMSO and 3.5mL of CH 3 OH was added to a dry 15.0mL high temperature pressure tube, the mixture was stirred three times, and then the lid of the high temperature pressure tube was screwed. Reflux the mixture at 90.0deg.C in the dark for 72.0h, then filter on filter paper to obtain RhN1 as reddish brown blocky crystals, and extract from n-hexane and CH at 37.0deg.C 2 Cl 2 The mixture was recrystallized from a solution (v: v=35 mL/5 mL) to yield 70.2%.
The resulting reddish brown product RhN1 was identified as follows:
(1) RhN1, the electrospray mass spectrum of which is shown in FIG. 3.
ESI-MS:m/z＝561.90[M+(H 2 O)+H] + M in the formula is the molecular weight of the complex RhN 1.
(2) RhN1 1 The H NMR spectrum is shown in fig. 4.
1 H NMR(500MHz,DMSO-d6)δ9.49(d,J＝5.3Hz,1H),9.30(s,1H),8.45–8.39(m,1H),8.30(d,J＝7.9Hz,1H),8.16(d,J＝2.3Hz,1H),7.98(dd,J＝9.0,2.4Hz,1H),7.94–7.90(m,1H),7.88(d,J＝9.0Hz,1H)。
(3) The elemental analysis results of RhN1 are shown below:
C 16 H 15 Cl 3 N 2 O 2 RhS theoretical value C35.32,H 2.78,N 5.15; experimental value C35.31,H 2.80,N 5.14.
(4) RhN1, as shown in FIG. 5.
Therefore, by combining the above identification results, it can be determined that the obtained reddish brown target product is rhodium (III) complex RhN1, the structural formula of which is shown in FIG. 1.
Example 2
The present example provides a complex targeting human lung cancer drug-resistant cells, named RhN2 in the present example, referring to fig. 2, prepared as follows:
(1)preparation of ligand 3- (2' -benzimidazolyl) -6-bromo-2-iminobenzopyran (QB 2): 5-bromo-2-hydroxybenzaldehyde (0.01 mol,2.0102 g) and benzimidazole-2-acetonitrile (0.01 mol,1.5717 g) were added to a 250.0mL flask containing an ethanol-piperidine mixed solution (v: v=100 mL:1 mL), and reacted at 65℃with stirring for 24.0 hours with 50.0mL of methanol, CH, respectively 2 Cl 2 And diethyl ether to obtain yellow solid product QB2.
(2)Preparation of Complex RhN2: 1.0mmol of QB2 ligand and 1.0mmol of RhCl are added 3 ·3H 2 O, 0.5mL of DMSO and 3.5mL of CH 3 OH was added to a dry 15.0mL high temperature pressure tube, the mixture was stirred three times, and then the lid of the high temperature pressure tube was screwed. Reflux the mixture at 90.0deg.C in the dark for 72.0h, then filter on filter paper to obtain RhN2 as reddish brown blocky crystals, and extract from n-hexane and CH at 37.0deg.C 2 Cl 2 The mixture was recrystallized from a solution (v: v=35 mL/5 mL) to give a yield of 68.1%.
The resulting reddish brown product was identified as follows:
(1) RhN2, the electrospray mass spectrum of which is shown in FIG. 6.
ESI-MS:m/z＝671.00[M+(3CH 3 OH)+H] + Wherein M is the molecular weight of complex RhN 2.
(2) The elemental analysis results of RhN are shown below:
C 17 H 14 BrCl 3 N 3 O 2 rh is theoretical value C35.11,H 2.43,N 7.23; experimental value C35.12,H 2.46,N 7.24.
(3) RhN2, as shown in fig. 7.
Therefore, by combining the above identification results, it can be determined that the obtained reddish brown target product is rhodium (III) complex RhN2, and the structural formula of the complex is shown in FIG. 1.
Example 3
The present example provides a complex targeting human lung cancer drug-resistant cells, named RhS in the example, referring to fig. 2, prepared as follows:
(1)preparation of the ligand 3- (2' -benzothiazolyl) -8-tert-butyl-2-imine benzopyran (QB 3): 3-tert-butyl-2-hydroxybenzaldehyde (0.01 mol,1.7823 g) and benzothiazole-2-acetonitrile (0.01 mol,1.7422 g) were added to a 250.0mL flask containing an ethanol-piperidine mixed solution (v: v=100 mL:1 mL) and reacted at 37℃with stirring for 24.0h with 50.0mL of methanol, CH, respectively 2 Cl 2 And diethyl ether to give the product (QB 3) as a yellow solid.
(2)Preparation of Complex RhS: 1.0mmol of QB3 ligand and 1.0mmol of RhCl are added 3 ·3H 2 O, 0.5mL of DMSO and 3.5mL of CH 3 OH was added to a dry 15.0mL high temperature pressure tube, the mixture was stirred three times, and then the lid of the high temperature pressure tube was screwed. Reflux the mixture at 90.0deg.C in the dark for 72.0h, then filter on filter paper to obtain RhS as reddish brown blocky crystals, and extract from n-hexane and CH at 37.0deg.C 2 Cl 2 The mixture was recrystallized from a solution (v: v=35 mL/5 mL) to give a yield of 76.3%.
The resulting reddish brown product was identified as follows:
(1) The electrospray mass spectrum of RhS is shown in fig. 8.
ESI-MS:m/z＝693.25[M+(DMSO)+(CH 3 CN)+H] + M in the formula is the molecular weight of a complex RhS.
(2) RhS 1 The H NMR spectrum is shown in FIG. 9.
1 H NMR(500MHz,DMSO-d6)δ9.36(s,1H),8.28(d,J＝7.8Hz,1H),8.14–8.05(m,1H),7.94–7.86(m,1H),7.69–7.54(m,3H),6.87(s,1H),1.52(d,J＝7.2Hz,9H).
(3) The elemental analysis results of RhS are shown below:
C 21 H 22 Cl 3 N 2 O 2 RhS theoretical value C43.81,H 3.85,N 4.87; experimental value C43.80,H 3.88,N 4.85.
(4) RhS, as shown in fig. 10.
Therefore, by combining the above identification results, it can be determined that the obtained reddish brown target product is rhodium (III) complex RhS, and the structural formula of the complex is shown in FIG. 1.
Example 4
The present example provides a complex targeting human lung cancer drug-resistant cells, named RhQ in the example, referring to fig. 2, prepared as follows:
(1)preparation of the ligand 3- (2' -quinolinyl) -8-tert-butyl-2-iminobenzopyran (QB 4): 3-tert-butyl-2-hydroxybenzaldehyde (0.01 mol,1.7823 g) and 2- (quinolin-2-yl) acetonitrile (0.01 mol,1.6819 g) were added to a 250.0mL flask containing an ethanol-piperidine mixed solution (v: v=100 mL:1 mL) and reacted at 37℃with stirring for 24.0h with 50.0mL of methanol, CH, respectively 2 Cl 2 And diethyl ether to give the product (QB 4) as a yellow solid.
(2)Preparation of Complex RhQ: 1.0mmol of QB4 ligand and 1.0mmol of RhCl are added 3 ·3H 2 O, 0.5mL of DMSO and 3.5mL of CH 3 OH was added to a dry 15.0mL high temperature pressure tube, the mixture was stirred three times, and then the lid of the high temperature pressure tube was screwed. Reflux the mixture at 90.0deg.C in the dark for 72.0h, filtering on filter paper to obtain RhQ in the form of reddish brown bulk crystals, and cooling at 37.0deg.CFrom n-hexane and CH 2 Cl 2 The mixture was recrystallized from a solution (v: v=35 mL/5 mL) to give a yield of 80.7%.
The resulting reddish brown product was identified as follows:
(1) The electrospray mass spectrum of RhQ is shown in FIG. 11.
ESI-MS:m/z＝681.35[M+2(CH 3 OH)+H] + ；m/z＝506.25[M-(DMSO)-Cl] + Wherein M is the molecular weight of complex RhQ.
(2) RhQ 1 The H NMR spectrum is shown in FIG. 12.
1 H NMR(500MHz,DMSO-d6)δ8.94(s,1H),8.49(d,J＝8.7Hz,1H),8.34(d,J＝8.7Hz,1H),8.12(d,J＝8.7Hz,1H),8.04(d,J＝8.1Hz,1H),7.88(d,J＝7.6Hz,1H),7.85–7.81(m,1H),7.66(t,J＝7.4Hz,2H),7.38(t,J＝7.7Hz,1H),1.52(s,9H).
(3) The elemental analysis results of RhQ are shown below:
C 24 H 26 Cl 3 N 2 O 2 RhS theoretical value C46.81,H 4.26,N 4.55; experimental value C46.78,H 4.30,N 4.56.
(4) RhQ, as shown in fig. 13.
Therefore, by combining the above identification results, it can be determined that the obtained reddish brown target product is rhodium (III) complex RhS, and the structural formula of the complex is shown in FIG. 1.
Comparative example 1
This comparative example provides a ligand 3- (2' -pyridyl) -6-chloro-2-iminobenzopyran (QB 1) and its preparation method, which is prepared in substantially the same manner as in example 1, and after the preparation is completed, it is directly subjected to a subsequent cancer cell inhibition experiment, as a reference group for comparison with the example.
Comparative example 2
This comparative example provides a ligand 3- (2' -benzimidazolyl) -6-bromo-2-iminobenzopyran (QB 2) and a method for preparing the same, which is substantially the same as example 2, and a subsequent cancer cell inhibition experiment is directly performed on the ligand after the preparation is completed, as a reference group for comparison with the example.
Comparative example 3
This comparative example provides a ligand 3- (2' -benzothiazolyl) -8-tert-butyl-2-iminobenzopyran (QB 3) and its preparation method, which is substantially the same as example 3, and the preparation method is directly carried out on the ligand after the preparation is completed for subsequent cancer cell inhibition experiments, and the ligand is used as a reference group to compare with the examples.
Comparative example 4
This comparative example provides a ligand 3- (2' -quinolinyl) -8-tert-butyl-2-iminobenzopyran (QB 4) and a method for preparing the same, which is substantially the same as example 3, and a subsequent cancer cell inhibition experiment is directly performed on the ligand after the preparation is completed, as a reference group for comparison with the example.
Comparative example 5
This comparative example provides RhCl 3 ·3H 2 O, which was directly subjected to subsequent cancer cell inhibition experiments, was compared with examples as a reference group.
Comparative example 6
This comparative example provides cisplatin (cispratin), which was directly subjected to a subsequent cancer cell inhibition experiment, as a reference group for comparison with the examples.
In order to fully illustrate the application of the complexes RhN1, rhN2, rhS and RhQ targeting human lung cancer drug-resistant cells in pharmacy, the applicant carried out in vitro and in vivo anti-tumor activity experiments.
1. Proliferation inhibition activity experiment of complexes RhN1, rhN2, rhS and RhQ targeting human lung cancer drug-resistant cells on various human tumor cell strains
1. Cell strain and cell culture
The experiment selects 3 human cell lines of human lung adenocarcinoma cisplatin drug-resistant cells A549/DDP, human lung adenocarcinoma A549 cells and human normal liver cells HL-7702.
All the human cell lines are cultured in RPMI-1640 culture solution containing 100U/mL penicillin, 10wt% calf blood and 100U/mL streptomycin, and the culture solution is placed at 37 ℃ and contains CO with the volume concentration of 5% 2 Is cultured in an incubator of (a).
2. Preparation of test Compounds
The ligands QB1, QB2, QB3, QB4 and the complexes RhN1, rhN2, rhS and RhQ all need to have a purity of 95% or more, and their DMSO stock solutions are diluted into a final solution of 20 mu mol/L (DMSO final concentration of 1% or less) by physiological buffer, and the inhibition degree of each compound on the growth of normal cells or selected tumor cells at the concentration is tested.
3. Cell growth inhibition experiment (MTT method)
(1) Taking normal cells or tumor cells in logarithmic growth phase, digesting the normal cells or tumor cells by trypsin, preparing a cell suspension with the concentration of 5000 cells/mL by using a culture solution containing 10% calf serum, inoculating 190 mu L of each well into a 96-well culture plate, enabling the density of cells to be detected to 1000-10000 cells/well, and filling the edge holes with sterile PBS.
(2)5％CO 2 Incubating at 37deg.C for 24 hr until cell monolayer is fully covered with the bottom of the well, adding 10 μl of drug with a certain concentration gradient into each well, and setting 4 multiple wells for each concentration gradient.
(3)5％CO 2 Incubation was carried out at 37℃for 24 hours and observation under an inverted microscope was carried out.
(4) mu.L of 5mg/mL MTT solution was added to each well and the incubation was continued for 4h.
(5) After the culture was terminated, the culture medium in the wells was carefully aspirated, 150. Mu.L of DMSO was added to each well to dissolve the formazan precipitate sufficiently, and after mixing with a shaker, the optical density value of each well was measured at a wavelength of 570nm for an microplate reader and at a reference wavelength of 450 nm.
(6) At the same time, zeroing wells (medium, MTT, DMSO), control wells (cells, medium, MTT, drug dissolution medium of the same concentration, DMSO) were set.
(7) The number of living cells is judged according to the measured optical density value, namely the OD value, and the larger the OD value is, the stronger the cell activity is. 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 using a Bliss method 50 Values. The results are shown in table 1 below.
TABLE 1 IC of complexes for various cell lines 50 Value (mu M)
IC from Table 1 50 From the results of the activity screening, examples 1 to 4 and comparative examples 1 to 6 were compared: the complexes RhN, rhN, rhS and RhQ all exhibit a certain proliferation inhibiting activity on selected cancer cells, all higher than the corresponding ligands QB1, QB2, QB3, QB4 and RhCl 3 ·3H 2 O activity, it shows that the ligand QB and rhodium (III) can effectively improve the synergistic performance of the two in cancer cell inhibition after being made into a complex. Wherein the complex RhQ prepared in the example 4 can effectively and effectively inhibit the proliferation of human lung adenocarcinoma cisplatin-resistant cells A549/DDP, and the IC thereof 50 The value is 0.08 plus or minus 0.02 mu M, and the activity is 812.75 times higher than that of cisplatin medicaments.
In addition, the complex RhQ prepared in example 4 has little cytotoxicity to human normal liver cells HL-7702 and IC 50 The value is larger than 80 mu M, which is a positive result, and shows that the complex RhQ prepared in the embodiment 4 can not only inhibit the growth of cisplatin-resistant cells A549/DDP of human lung adenocarcinoma in a targeted manner, but also has lower hepatotoxicity, namely the complex RhQ has certain cytotoxicity selectivity.
Wherein the complex RhQ prepared in example 4 is more active than RhN1 prepared in example 1, by comparison, benzopyrans possibly bearing a tert-butyl group at position 8 and/or a quinolinyl group at position 3 are presumed to have a more favourable synergistic effect with rhodium (III) in terms of cancer cell inhibition; whereas the complex RhS prepared in example 3 was more active than RhN2 prepared in example 2, by comparison, benzopyrans possibly bearing a tertiary butyl group at position 8 and/or a benzothiazolyl group at position 3 were presumed to have a more favourable synergistic effect with rhodium (III) in terms of cancer cell inhibition; in vivo tumor suppression experiments were subsequently continued for these two more active RhQ and RhS.
2. In vivo tumor inhibition experiment
(1) Animal requirements:
strain: BALB/c nude mice; grade: SPF stage; week-old: 6-8w; weight of: 18-22g; gender: male male
(2) Animal origin:
provided by the experimental animal company, karvens, usa, experimental animal production license: SCXK 2016-0010.
(3) The place of animal experiment:
the Changzhou Kavens laboratory animal Co., ltd., laboratory animal use license: SYXK 2017-0007
(4) Requirements of feeding environment:
SPF stage, IVC independent ventilation system; keeping constant temperature (26+ -2deg.C) and humidity (40-70%), turning on and off for 12h.
(5) Feed:
SPF mice were selected for breeding feed, purchased from Australian feed Co., ltd.
(6) The main reagents and instruments used in the experiment:
reagent: DMSO, 0.9% saline, 75% medical alcohol, 4% paraformaldehyde; an instrument: surgical scissors, forceps, trocars, and electronic vernier calipers.
(7) Basic procedure and operation of experiments
(1) Cell culture
The experimental cell lines and cell cultures were carried out as described above.
(2) Preparation and efficacy experiment of A549/DDP nude mice subcutaneous transplantation tumor model
Collecting A549/DDP cells in logarithmic growth phase, and modulating to 5×10 with 200 μl of serum-free medium 6 Viable cell concentration suspensions per mL 0.2mL of suspension was withdrawn with a 1.0mL syringe and then inoculated subcutaneously in the right armpit of nude mice. When xenograft tumors grow to about 1000mm 3 When the tumor is in volume, the tumor source is prepared as a subcutaneous tumor transplantation model, and the tumor source is passaged in nude mice. A549/DDP is uploaded on a nude mouse for 4 generations after the growth is stable, selecting tumor-bearing mice with vigorous tumor growth and no crumple, killing cervical vertebra dislocation, sterilizing animal skin with 75% medical alcohol, dissecting tissue block, removing necrotic part, cutting tumor tissue into 1.5mm pieces 3 Left and right small pieces were inoculated subcutaneously in the right armpit of nude mice with a trocar. By electricityMeasuring the diameter of the transplanted tumor by using a sub-vernier caliper, and when the tumor volume grows to 90-100mm 3 At that time, animals were randomly grouped. Mice were randomized into vehicle control and treatment groups (n=6/group), receiving the following treatments: (a) vehicle control, 5.0% v/v dimethyl sulfoxide/physiological saline vehicle, (b) RhS, at a dose of 5.0mg/kg, once every two days (10% v/v dimethyl sulfoxide/physiological saline), (c) RhQ (5.0 mg/kg), once every two days, percutaneous injection (q 2 d). Tumor diameter, body weight, tumor volume was determined by length (l) and width (w) using an electronic vernier caliper every three days, and volume, tumor volume, and tumor growth inhibition rates (1) - (3) were calculated using the formulas:
tumor volume: v= (w) 2 ×l)/2 (1)
Relative tumor proliferation rate: T/C (%) =t RTV /C RTV ×100％ (2)
Tumor growth inhibition rate: IR (%) = (W) c -W t )/W c ×100％ (3)
Wherein w and l represent the shorter and longer diameters of the tumor, respectively; t (T) RTV And C RTV RTV in the treatment and control groups, respectively. (RTV: relative tumor volume, rtv=v t /V 0 ，V t For the volume at each measurement, V 0 Volume when grouped); w (W) t And W is c Average tumor weights for the complex treated group and vehicle control group, respectively. In addition, all experimental procedures were performed according to NIH guidelines for laboratory animal care and use.
TABLE 2 in vivo tumor-inhibiting action of complexes on A549/DDP (%)
As shown in Table 2, the effect of complexes RhS and RhQ on tumor growth in vivo was studied in the A549/DDP model. When injected intraperitoneally every two days RhS (5.0 mg/kg) and RhQ (5.0 mg/kg), the tumor growth inhibition rates are as high as 46.4% and 55.3%, respectively, which produce remarkable tumor inhibition effects. Notably, the efficacy of RhQ was significantly higher than the tumor growth inhibition rate of the clinical drug cisplatin (33.1%).
In conclusion, the complex targeted to the human lung cancer drug-resistant cells provided by the invention has excellent in-vitro and in-vivo anti-tumor activity and good cancer cell selectivity, and the design thought and the synthesis method of the complex targeted to the human lung cancer drug-resistant cells are feasible. The complex RhQ prepared in the example 4 has good potential medicinal value due to the anti-tumor activity and low toxicity, and is expected to be used for preparing anti-tumor drugs.
The invention has been described in detail hereinabove with reference to specific exemplary embodiments thereof. It will be understood that various modifications and changes may be made without departing from the scope of the invention as defined by the appended claims. The detailed description and drawings are to be regarded in an illustrative rather than a restrictive sense, and if any such modifications and variations are desired to be included within the scope of the invention described herein. Furthermore, the background art is intended to illustrate the status and meaning of the development of the technology and is not intended to limit the invention or the application and field of application of the invention.
More specifically, although exemplary embodiments of the present invention have been described herein, the present invention is not limited to these embodiments, but includes any and all embodiments that have been modified, omitted, e.g., combined, adapted, and/or substituted between the various embodiments, as would be recognized by those skilled in the art in light of the foregoing detailed description. The limitations in the claims are to be interpreted broadly based on the language employed in the claims and not limited to examples described in the foregoing detailed description or during the prosecution of the application, which examples are to be construed as non-exclusive. Any steps recited in any method or process claims may be executed in any order and are not limited to the order presented in the claims. The scope of the invention should, therefore, be determined only by the appended claims and their legal equivalents, rather than by the descriptions and examples given above.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, definitions, will control. Where a molar amount, mass, concentration, temperature, time, volume, or other value or parameter is expressed as a range, preferred range, or a range bounded by a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. For example, a range of 1-50 should be understood to include any number, combination of numbers, or subranges of numbers selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all fractional values between the integers described above, such as 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. Regarding sub-ranges, specifically considered are "nested sub-ranges" that extend from any end point within the range. For example, the nested subranges of exemplary ranges 1-50 can include 1-10, 1-20, 1-30, and 1-40 in one direction, or 50-40, 50-30, 50-20, and 50-10 in another direction.
Claims (3)
1. A complex targeted to human lung cancer resistant cells, comprising RhN1 or RhQ; rhN1 is
The RhQ is
2. The method for preparing the complex targeted to the human lung cancer drug-resistant cells according to claim 1, which is characterized by comprising the following specific operation steps:
(1) QB and RhCl 3 ·3H 2 Mixing and dissolving O in a polar solvent comprising a ligand M to obtain a mixed solution; the saidQB comprises QB1 or QB4, wherein QB1 is
QB4 is->
M is (CH) 3 ) 2 SO；
(2) The obtained mixed solution reacts at the temperature of 80-100 ℃ to obtain a reaction product after the reaction is completed;
(3) The reaction product is filtered, recrystallized and dried to obtain the complex.
3. The method of claim 1 for preparing a complex targeted to human lung cancer resistant cells according to claim 2, wherein in the step (1), QB1 or QB4 and rhci 3 ·3H 2 The mol ratio of O is (0.8-1.2): 1, a step of; the polar solvent is one or a combination of more of methanol, acetonitrile, ethanol, dimethyl sulfoxide, acetone and water, and the volume of the polar solvent is 2-20 mL; in the step (2), the reaction time is 12-72 h; in the step (3), n-hexane and CH are used for the recrystallization 2 Cl 2 Recrystallizing the mixed solution, n-hexane and CH 2 Cl 2 The volume ratio of (20 mL-40 mL): (5 mL-10 mL); the drying temperature is 50-75 ℃.
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