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A mitochondria-targeted iridium-n-heterocyclic carbene complex and its preparation method and application

A technology of heterocyclic carbene and mitochondria, which is applied in the direction of medical preparations containing active ingredients, pharmaceutical formulas, and compounds containing elements of Group 8/9/10/18 of the periodic table, etc., can solve problems such as differences in functional activities, and achieve The effect of increasing water solubility

Inactive Publication Date: 2016-08-24
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have shown that N-heterocyclic carbene complexes of different metals have very different functional activities, and their anti-tumor mechanisms are also different due to different metal centers. For example, silver complexes are mediated by mitochondria. Cysteine-aspartate proteolytic enzyme)-independent pathway induces cancer cell apoptosis, while gold complex induces cancer cell apoptosis through mitochondria-mediated caspase-dependent pathway

Method used

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  • A mitochondria-targeted iridium-n-heterocyclic carbene complex and its preparation method and application
  • A mitochondria-targeted iridium-n-heterocyclic carbene complex and its preparation method and application
  • A mitochondria-targeted iridium-n-heterocyclic carbene complex and its preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] 1. Preparation of complex Ir-1

[0046] (1) Preparation of Ligand L1:

[0047] Add dichloromethane (1.699 g, 20 mmol) and 1-methylimidazole (4.926 g, 60 mmol) into the reaction flask, and react in a closed container at 75 °C for 24 h. After the reaction, cool to room temperature and spin After the solvent was evaporated to dryness, it was dissolved with a small amount of methanol, added to a large amount of tetrahydrofuran and stirred at room temperature for 2 h, a large amount of white solid was formed, filtered, washed with tetrahydrofuran, and dried in vacuum to obtain a white solid to obtain 2.123 g of the ligand, with a yield of 42.6%.

[0048] 1 H NMR (300 MHz, DMSO) δ 9.86 (s, 2H), 8.27 (s, 2H), 7.79 (s, 2H), 6.89 (s, 2H), 3.88 (s, 6H). 13 C NMR (75 MHz, DMSO) δ 138.69, 124.60, 122.53, 57.99, 36.66.

[0049] ESI-MS: Theoretical: m / z 177.2 [M-Cl-H] + and 89.1 [M-2Cl] + ;Experimental value: m / z [M-Cl-H] + 177.1 and 89.0 [M-2Cl] + .

[0050] Elemental Anal...

Embodiment 2

[0078] Example 2 Mitochondrial targeting and mitochondrial swelling induced by iridium-N-heterocyclic carbene complexes

[0079] 1. Measure the mitochondrial targeting and mitochondrial swelling tracking of the iridium-N-heterocyclic carbene complex prepared by the present invention by laser confocal fluorescence microscopy. The assay method is as follows:

[0080] The cells were digested with 0.25% trypsin into a single-cell suspension, and the number of viable cells was recorded using a hemocytometer. About 200,000 cells per well were seeded in a confocal culture dish, and after 24 hours of culture, mitochondrial probes were added Mito-tracker Red (purchased from Invitrogen) and 20 μM iridium-N-heterocyclic carbene complex, at 37 °C, in 5% (volume concentration) CO 2 Incubated in an incubator for 30 min. Then suck up and discard the old medium, wash twice with phosphate buffered saline (PBS), add 1 mL of PBS, and immediately observe under a confocal laser microscope.

[00...

Embodiment 3

[0082] Example 3 Antitumor Activity and Phototoxicity to Tumor Cells of Iridium-N-Heterocyclic Carbene Complexes

[0083] 1. In this example, the antitumor activity of the iridium-N-heterocyclic carbene complexes prepared in the present invention is evaluated, and the drug cisplatin is used as a control, and the grouping conditions are as follows:

[0084] Control group: drug cisplatin (cisplatin); experimental group: iridium-N-heterocyclic carbene complex.

[0085] 2. Cytotoxicity was determined by tetrazolium salt (MTT) colorimetric method, the specific determination method is as follows:

[0086] The cells were digested with trypsin with a mass volume ratio of 0.25% into a single cell suspension, and the number of viable cells was recorded using a hemocytometer, and the concentration of viable cells was adjusted to 5×10 4 / mL, inoculated in a 96-well culture plate, 160 μL per well, after 24 hours of culture, then added different concentrations of drugs, placed at 37 ℃, in ...

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Abstract

The invention discloses a mitochondria-targeted iridium-N-heterocyclic carbene complex, the structural formula of which is shown in formula (I), (II) or (III): , wherein the compounds represented by formulas (I), (II) and (III) are respectively named as complex Ir-1, complex Ir-2, and complex Ir-3. The present invention studies the mitochondrial targeting and anticancer activity of such iridium-N-heterocyclic carbene complexes, and the results show that it can quickly enter cells and specifically target the mitochondria of cancer cells, and has excellent anti-tumor Activity and phototoxicity of tumor cells, can be used as a potential mitochondrial antitumor drug and photodynamic therapy drug.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry. More specifically, it relates to a mitochondria-targeted iridium-N-heterocyclic carbene complex and its preparation method and application. Background technique [0002] Platinum drugs have made remarkable achievements in the treatment of cancer, but they still have not fully resolved many shortcomings similar to cisplatin, and their serious side effects and drug resistance limit the scope of clinical application of platinum drugs . Therefore, it is a current research hotspot to search for new metal anticancer drugs with different mechanisms of action to improve or supplement the performance of existing platinum-based drugs. Because most of the traditional metal anti-tumor drugs target double-stranded DNA, it is difficult to break through the limitations of platinum-based drugs. [0003] Mitochondria are important organelles in cells and participate in many important physiological and bioche...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F15/00A61K41/00A61K31/555A61P35/00
Inventor 毛宗万李毅谭彩萍黄华珍计亮年
Owner SUN YAT SEN UNIV
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