WO2022143183A1 - Dérivé de pérylène diimide pdic-nc, procédé de préparation associé et son application - Google Patents

Dérivé de pérylène diimide pdic-nc, procédé de préparation associé et son application Download PDF

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WO2022143183A1
WO2022143183A1 PCT/CN2021/138620 CN2021138620W WO2022143183A1 WO 2022143183 A1 WO2022143183 A1 WO 2022143183A1 CN 2021138620 W CN2021138620 W CN 2021138620W WO 2022143183 A1 WO2022143183 A1 WO 2022143183A1
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pdic
preparation
cells
perylene
lung
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黄永伟
刘中华
王颖哲
马翡雁
高一剑
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河南大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
    • C09K2211/10—Non-macromolecular compounds
    • C09K2211/1018—Heterocyclic compounds
    • C09K2211/1025—Heterocyclic compounds characterised by ligands
    • C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms

Definitions

  • the invention belongs to the field of biomedicine and relates to a peryleneimide derivative, in particular to a peryleneimide derivative PDIC-NC and a preparation method and application thereof.
  • the etiology and pathogenesis of lung cancer are complex. Most of the clinically diagnosed patients are patients with advanced lung cancer.
  • the main treatment plan is based on platinum-based chemotherapy.
  • platinum-based compounds are non-predominant drugs for lung cancer, and patients are prone to drug resistance during treatment. And liver, kidney toxicity and other side effects, the damage to normal tissues and organs is greater.
  • drugs with predominant distribution in the lung and organelles can be prepared.
  • the enrichment of drugs in the lungs is enhanced and the uptake of drugs in the lungs is increased; Therefore, designing and preparing drugs that can simultaneously achieve the superior distribution of lung and organelles is the premise and basis for improving lung cancer chemotherapy.
  • Perylene imide derivatives are a class of organic semiconductor molecules with excellent chemical and thermal stability, which are widely used in the fields of optoelectronics and biomaterials.
  • peryleneimide derivatives are easy to prepare, and the photoelectricity of peryleneimide derivatives can be regulated by introducing various types of substituent groups at the perylene bay carbon atom, imide position and carbonyl oxygen position of perylenetetracarboxylic dianhydride. properties, to achieve its wide application in the biomedical field.
  • researchers have prepared a variety of peryleneimide derivative molecules to achieve photothermal or photodynamic therapy of tumors guided by photoacoustic imaging, but the application of peryleneimide derivatives to tumor chemotherapy remains to be studied.
  • Pulmonary surfactant is a phospholipid protein mixture synthesized and secreted by type II alveolar epithelial cells, consisting of 70% to 80% phospholipids (the main component is saturated dipalmitoyl phosphatidylcholine), 10% protein and 10% neutral. It is composed of phospholipids and is distributed on the surface of alveoli. Based on the fact that pulmonary surfactants are mainly phospholipids, the electrostatic interaction between phosphate anions and positively charged drug molecules can be used to drive the predominant accumulation of drugs in the lungs and realize the predominant distribution of drugs in the lungs.
  • the mitochondrial double-layer membrane structure is rich in cardiolipin, and a large amount of exposed phosphate anions can bind positively charged drugs through the electrostatic interaction of positive and negative charges, increasing the concentration of drugs and improving the treatment efficiency.
  • the mitochondrial transmembrane potential is internally negatively charged, which can further increase the uptake of positively charged drugs and improve the therapeutic effect.
  • quaternary ammonium ions can be introduced at the imide position of perylene tetracarboxylic dianhydride to increase the electrostatic interaction between it and type II alveolar epithelial cells and mitochondrial bilayer membrane phosphate anions, and increase the perylene imide derivatives in the lung and the lungs. Mitochondrial enrichment. However, not all derivatives with perylene imide achieve lung-dominant distribution. Therefore, it is necessary to introduce substituent groups to achieve the predominant distribution of peryleneimide derivatives in the lung and mitochondria.
  • the present application discloses a perylene imide derivative PDIC-NC and its preparation method and application.
  • the applicant has found for the first time in practice that the introduction of halogen atoms at the carbon atom of the perylene bay reduces the electron cloud of perylene nucleus.
  • ⁇ - ⁇ conjugation effect through regulating the intramolecular ⁇ - ⁇ conjugation effect and quaternary ammonium ion hydrophilic effect of perylene imide derivatives to achieve its advantages in the lung and mitochondria, by regulating mitochondrial function to achieve excellent anti-lung cancer properties, for the preparation of High-efficiency, low-toxicity, and tunable performance of lung cancer therapeutic drugs provide theoretical basis and material basis.
  • a perylene imide derivative PDIC-NC contains a perylene bay chlorine atom, and its general structural formula is as follows:
  • the above-mentioned preparation method of perylene imide derivative PDIC-NC comprises the following steps: dissolving N,N'-dimethylethylenediamine in N-methylpyrrolidone, then adding 1,6,7,12-tetrachloroethylene -3,4,9,10-Perylenetetracarboxylic dianhydride, reacted to completion under argon protection, cooled to room temperature, added acetone, stirred at room temperature for 2 hours, filtered with suction, washed with water until neutral, added 2M HCl and reacted at room temperature for 24 hours , cooling and standing, suction filtration, drying, dissolving in water for dialysis for 24h, and freeze-drying the dialysate to obtain the peryleneimide derivative PDIC-NC.
  • the material ratio of N,N'-dimethylethylenediamine, 1,6,7,12-tetrachloro-3,4,9,10-perylenetetracarboxylic dianhydride and HCl is :2.5:1:40.
  • the concentration of the N,N'-dimethylethylenediamine solution in N-methylpyrrolidone is 0.05mol/L.
  • reaction conditions under argon protection were the temperature of 80°C and the reaction time of 24h.
  • the anti-lung cancer drug is specifically a drug for inhibiting tumor cell proliferation.
  • the lung cancer cells are A549 and/or H446 cells.
  • the present invention provides a peryleneimide derivative diagnostic and therapeutic agent that can realize the advantageous distribution of the lung and mitochondria and has excellent anti-lung cancer performance by changing the molecular structure.
  • the prepared peryleneimide derivative PDIC-NC has fluorescence imaging and anti-tumor properties. PDIC-NC affects mitochondrial function, kills tumor cells through the apoptosis pathway, and has high selective killing of A549 cells.
  • the perylene imide derivatives containing chlorine atoms in the perylene bay of the present application can achieve a dominant distribution in the lung.
  • Cell experiments show that PDIC-NC can effectively inhibit the proliferation of tumor cells.
  • the results of tumor-bearing animal experiments show that PDIC-NC has excellent anti-lung cancer. performance.
  • Preliminary molecular mechanism studies have shown that PDIC-NC molecules can localize in mitochondria and kill tumor cells by generating reactive oxygen species, providing a theoretical basis and material basis for the preparation of high-efficiency, low-toxicity, and tunable performance-adjustable lung cancer drugs.
  • Figure 1 shows the fluorescence comparison of PDIC-NC and PDI-NC in different tissues, in which (a) structural formula of PDIC-NC and PDI-NC; (b) fluorescence imaging of heart, liver, spleen, lung and kidney tissue and (c) Fluorescence intensity quantification results; (d) Fluorescence quantitative analysis of heart, liver, spleen, lung and kidney tissue fluids; (e) Fluorescence imaging of frozen sections of heart, liver, spleen, lung and kidney tissues and (f) fluorescence intensity quantification results; Fluorescence images Scale bar: 50 ⁇ m;
  • Figure 2 shows the effects of different concentrations of PDIC-NC and PDI-NC on the proliferation of A549/H446 cells;
  • (a) and (b) are the curves of the proliferation rate of A549 cells changing with the concentrations of PDIC-NC and PDI-NC;
  • (c) H1299, B16, SW480, DLD-1, HeLa, 4T1 and BEAS-2B cell proliferation rates (cell concentration 5 ⁇ 10 4 per mL, peryleneimide derivative concentration 0.50 ⁇ g mL -1 );
  • (e) the images and statistical results of H446 plate clone cells with the changes of PDIC-NC concentration. Compounds were incubated with cells for 24h, and the experiment was repeated three times, *p ⁇ 0.05;**p ⁇ 0.01;***p ⁇ 0.001.
  • Figure 3 shows the protein signaling pathway detection of PDIC-NC in A549 and H446;
  • Figure 4 shows the immunoblotting and quantification results related to apoptosis of A549 and H446 cells; the detected proteins are Cl.Caspase 9, Cl.Caspase 7, Cl.Caspase 3, Bax, Bcl2, PARP1, and Cl.PARP1.
  • Figure 5 is a graph showing the anti-tumor effect of A549 subcutaneous tumor model;
  • Figure 6 is a graph showing the anti-tumor effect of lung cancer in situ induced model; wherein (a) model design experimental scheme, tail vein injection, dose: 2 mg Kg -1 , 5 days/time, treatment cycle 120 days; (b) lung cancer in situ carcinoma Lung specimen images, white circles are lung tumor nodules and (c) statistics on the number of tumor nodules; (d) H&E, PCNA and TUNEL staining images of lung tissue sections, image scale: 40 ⁇ m; (e) PCNA and (f) TUNEL Relative positive rate statistics. Data statistics are 3 or 6 mouse specimens, *p ⁇ 0.05;**p ⁇ 0.01;***p ⁇ 0.001.
  • the preparation method of perylene imide derivative PDIC-NC the steps are: dissolving N,N'-dimethylethylenediamine (2.5mmol) in N-methylpyrrolidone (50mL), then adding 1,6,7 , 12-tetrachloro-3,4,9,10-perylenetetracarboxylic dianhydride (1mmol), under argon protection, react at 80°C for 24h, cool to room temperature, add 100mL of acetone, stir at room temperature for 2h, suction filter, wash with water To neutrality, add 2M HCl at room temperature (20mL) to react for 24h, cool and stand, suction filter, dry, dissolve in water for 24h (dialysis bag specification: 500-1000Da), freeze-dry the dialysate (-62°C, 24h) , get PDIC-NC.
  • PDI-NC was prepared according to literature reports. Xu,Z.,Cheng,W.,Guo,K.,Yu,J.,Shen,J.,Tang,J.,...Yin,M.(2015).Molecular Size,Shape,and Electric Charges:Essential for Perylene Bisimide-Based DNA Intercalator to Localize in Cell Nuclei and Inhibit Cancer Cell Growth, ACS Applied Materials & Interfaces, 7(18), 9784–9791.
  • the peryleneimide derivatives PDI-NC and PDIC-NC solutions are both aqueous solutions of PDI-NC and PDIC-NC.
  • Fig. 1a The PDI-NC and PDIC-NC structures are shown in Fig. 1a.
  • PDIC-NC and PDI-NC were injected into the tail vein at a dose of 2 mg Kg -1 , the injection frequency, 5 days/time, and the injection duration was 120 days, and the mice were euthanized.
  • Fig. 1b,c PDIC-NC was injected into normal mice via tail vein, and the lungs showed strong fluorescence detected by organ imaging.
  • the results of fluorescence intensity quantification showed that the content of PDIC-NC in lung tissue was 5, 30, 36, and 42 times that in liver, heart, kidney, and spleen, respectively.
  • the liver, heart, kidney, spleen and lung of equal mass were further weighed, crushed and extracted tissue fluid for fluorescence quantitative analysis.
  • the PDIC-NC content in the lung tissue was 2.5-6 times that of the liver, heart, kidney and spleen (Fig. 1d). ).
  • Fluorescence images of cryosections also showed that the content of PDIC-NC in lung tissue was 5 times higher than that in liver, heart, kidney, and spleen (Fig. 1e,f).
  • Non-small cell lung adenocarcinoma cells A549 and small cell lung cancer cells H446 were used as tumor cell models, while normal bronchial epithelial cells BESA-2B and human normal lung fibroblasts HFL-1 were selected as cell comparison models. All cells were purchased from the ATCC cell bank in the United States. After the cells reached about 80% confluence, they were subcultured with 0.25% trypsin, and the cells in logarithmic growth phase were used for in vitro cell viability experiments.
  • the median inhibitory concentration (IC 50 ) of PDIC-NC compound A549 is about 0.48 ⁇ 0.02 ⁇ g mL -1 , which is 16-48% of that of the first-line clinical anti-lung drug cisplatin (Table 1).
  • PDIC-NC can effectively inhibit the growth of A549 cells.
  • the IC 50 of PDI-NC is about 2.43 ⁇ 0.25 ⁇ g mL -1 (A549), which is 5 times higher than the half-inhibitory concentration of PDIC-NC, indicating that the perylene bay chlorine atom can significantly affect the perylene imide derivatives in inhibiting tumor cell proliferation.
  • Fig. 2a,b the applicant also tested the inhibitory properties of PDIC-NC on other tumor cells and normal human bronchial epithelial cells.
  • the log-phase cell suspension (5 ⁇ 10 5 cells) was placed in a 12-well plate, and a perylene imide derivative solution (1 mL) was added, incubated for 6 h, the medium was discarded, and the PBS was rinsed.
  • DCFH-DA (1 mL, 10 ⁇ M) was added to each well, incubated for 20 min, washed 3 times with PBS buffer, observed by laser confocal microscope, photographed, and quantified fluorescence intensity.
  • the cells were placed in a six-well plate (10,000 cells/well), 20 ⁇ L of peryleneimide derivatives were added to each well, and incubated for 4 h. The cells were collected and placed in a 15 mL centrifuge tube for centrifugation (4° C., 5 min), and washed twice with cold PBS. Add 500 ⁇ L buffer solution to each tube, then add 10 ⁇ L V-APC and 5 ⁇ L 7-AAD in turn, mix for 10 min in the dark, and detect by flow cytometry.
  • the cells were placed in a cell culture flask, the culture medium was removed at 75% confluency, washed twice with PBS, and fixed with 5% glutaraldehyde (pH 7.2) for 2 h.
  • the monolayer cells were scraped and transferred to a centrifuge tube, centrifuged for 3 min (800 rpm), and the pelleted cells were washed with 0.1 M phosphoric acid rinse solution and PBS (3 ⁇ 15 min), and fixed with 1% osmic acid for 1 h.
  • Tumor cell apoptosis pathway and endoplasmic reticulum stress pathway were detected by Western blot assay.
  • the compound (1 mL) was incubated with A549 or H446 cells (both cell numbers were 5 ⁇ 10 5 , when the compound was incubated with A549, the compound concentration was 0, 0.1 ⁇ g mL -1 , 0.3 ⁇ g mL -1 , the compound When incubated with H446, the compound concentration was 0, 0.2 ⁇ g mL -1 , 0.6 ⁇ g mL -1 ), the culture medium was removed, washed 3 times with cold PBS, 100 ⁇ L protein lysis buffer and 1% protease inhibitor were added, and lysed for 30 min (0°C).
  • Subcutaneous tumor model According to the preliminary experimental results, 16-18g SPF grade BALB/c nude mice (adapted to A549 and H446 cells) were selected, and 100 ⁇ L of cell suspension (2.5 ⁇ 10 7 cells) was injected into the right upper limb to track the tumor volume. The tumor volume was increased to 60 mm 3 , and the perylene acyl derivative compound was injected into the tail vein.
  • Mouse lung carcinoma in situ model According to the preliminary experimental results, BALB/c mice were selected, and each mouse was intraperitoneally injected with body weight urethane (0.6g/Kg/week) for 12 consecutive weeks, and the mice formed lung cancer. The peryleneimide derivatives were injected into the tail vein to track the therapeutic effect.
  • model mice were randomly divided into a control group and an experimental group (8 mice per group). brine. Different treatment measures are taken for different model mice:
  • Subcutaneous tumor model tail vein administration for 7 days/time, injection dose: 2 mg Kg -1 , experimental time 28 days.
  • the body weight and tumor volume of the mice were recorded for 3 days/time. After 28 days, the mice were euthanized, the tumor weight was recorded, the orbital blood was collected for analysis of blood biochemical indicators, and the heart, liver, spleen, lung and kidney were collected for biocompatibility analysis.
  • Lung carcinoma in situ model tail vein administration for 5 days/time, injection dose: 2 mg Kg -1 , experiment time 120 days, mouse body weight was recorded for 7 days/time, mice were euthanized after 120 days, and lung weight and lung nodules were recorded Orbital blood was taken for blood biochemical index analysis, heart, liver, spleen, lung and kidney were taken for biocompatibility analysis.
  • peryleneimide derivatives were evaluated according to tumor mass in subcutaneous tumor model, tumor/body weight ratio and number of tumor nodules collected in metastatic model and orthotopic model.
  • mice The orbital arterial blood of mice was collected, and its biochemical indexes were detected to evaluate the biosafety of the compounds.
  • Mouse tumors, hearts, livers, spleens, lungs, and kidneys were collected for paraffin sections, and stained with hematoxylin and eosin (H&E) to analyze and evaluate compound efficacy and biosafety; terminal deoxynucleotide transfer was performed on mouse tumors Enzyme-mediated dUTP-biotin nick end labeling (TUNEL) staining was used to assist in the analysis of compound treatment effects; tissue sections were dehydrated with gradient alcohol and then reacted with 3% H 2 O 2 for 20 min, washed 3 times with PBS, and placed in antigen retrieval solution Microwave repaired for 15 min, naturally cooled at room temperature, washed 3 times with PBS, blocked with 5% BSA for 30 min, dropped with primary antibody (Ki67) and placed in a refrigerator at 4°C to block overnight, washed with PBS three times
  • Ki67 and TUNEL staining also showed that PDIC-NC could efficiently inhibit the proliferation of A549 tumor cells and induce their obvious apoptosis (Figure 5f-g), proving that PDIC-NC has excellent anti-tumor effect.
  • the results of the lung cancer orthotopic model showed (Fig. 6) that the number of lung cancer nodules in the PDIC-NC treatment group was reduced by 55% compared with the control group (Fig. 6b, c).
  • Hematoxylin and eosin (H&E) staining showed that PDIC-NCs significantly inhibited tumor proliferation with regular nucleus size (Fig. 6d).

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Abstract

La présente invention concerne le domaine de la biomédecine et concerne un dérivé de pérylène diimide et concerne en particulier un dérivé de pérylène diimide PDIC-NC, un procédé de préparation associé et son application. La formule générale de sa structure est la suivante : le demandeur a découvert pour la première fois dans la pratique que par introduction d'un atome d'halogène sur une position d'atome de carbone de pérylène, on a un affaiblissement de l'effet de conjugaison π-π d'un nuage d'électrons d'un cœur de pérylène; par ajustement de l'effet de conjugaison π-π dans une molécule d'un dérivé de pérylène diimide et de l'effet hydrophile d'un ion ammonium quaternaire, on obtient les avantages d'une molécule de dérivé de pérylène diimide sur le poumon et les mitochondries; de plus, par ajustement de la fonction mitochondriale, on obtient une excellente résistance au cancer du poumon, ce qui fournit une base théorique et une base matérielle à la préparation d'un médicament pour le traitement du cancer du poumon présentant une grande efficacité, une faible toxicité et des performances ajustables.
PCT/CN2021/138620 2020-12-30 2021-12-16 Dérivé de pérylène diimide pdic-nc, procédé de préparation associé et son application WO2022143183A1 (fr)

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CN115181065A (zh) * 2022-08-08 2022-10-14 河南大学 一种苝酰亚胺衍生物及应用

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