A kind of ring metal iridium metformin complex and its preparation method and application

Abstract

The invention discloses a cyclometalated iridium metformin complex and a preparation method and application thereof. Firstly the cyclometalated iridium metformin complex is provided, and the complex not only can be rapidly absorbed by tumor cells, but also has a phosphorescence tracing characteristic; the complex has excellent hypoxic anti-tumor activity, compared with the complex under a normal oxygen condition, the cytotoxicity of the complex to tumor cells under the hypoxic condition is enhanced, ROS can be better induced to be generated in the tumor cells, the complex has good inhibitory activity to HIF-1 alpha, and finally apoptosis of the tumor cells is induced. The invention further provides a preparation method of the complex. The preparation method is simple and low in cost. Therefore, the complex has a good application prospect in preparation of hypoxic antitumor drugs.

Description

technical field

[0001] The invention belongs to the technical field of medicinal chemistry. More specifically, it relates to a ring metal iridium metformin complex and its preparation method and application. Background technique

[0002] Hypoxia is a prominent feature of most solid tumors. Due to the rapid proliferation of tumor cells, incomplete development and uneven distribution of blood vessels in solid tumors, the supply of oxygen and nutrients in the tumor tissue is insufficient, which eventually leads to the existence of hypoxic areas in the tumor. Hypoxic microenvironment can induce tumor tissue resistance to traditional chemotherapy drugs such as cisplatin, making chemotherapy effect worse, and will reduce the therapeutic effect of photosensitizers in tumor hypoxic areas, and will increase tumor recurrence, metastasis and invasion ability. Therefore, the development of new metal antitumor drugs with different antitumor mechanisms is of great significance for impr...

Examples

Embodiment 1

[0054] The preparation of embodiment 1 ring metal iridium metformin complex Ir1

[0055] The preparation method of ring metal iridium metformin complex Ir1 comprises the following steps:

[0056]S1. After mixing iridium trichloride hydrate and ligand at a molar ratio of 1:2.2, dissolve it in a mixed solvent of ethylene glycol ether and ultrapure water (volume ratio: 3:1), and stir at 135°C under reflux The coordination reaction was carried out for 24 hours, cooled to room temperature and suction filtered, and the obtained solid product was washed three times with ultrapure water and diethyl ether, and dried in vacuum to obtain an iridium precursor;

[0057] S2. After mixing the iridium precursor (121.4mg, 0.1mmol) obtained in step S1 with metformin (66.2mg, 0.4mmol), dissolve in dichloromethane / methanol mixed solvent (volume ratio is 1.5:1), in N 2 Potassium tert-butoxide (89.8mg, 0.8mmol) was added under protection, and the reaction was carried out at 35°C for 25h. After the...

Embodiment 2

[0063] The preparation of embodiment 2 ring metal iridium metformin complex Ir2

[0064] The preparation method of ring metal iridium metformin complex Ir2 comprises the following steps:

[0065] S1. After mixing iridium trichloride hydrate and ligand at a molar ratio of 1:2.5, dissolve it in a mixed solvent of ethylene glycol ether and ultrapure water (volume ratio: 2:1), and stir at 130°C under reflux Carry out the coordination reaction for 22 hours, cool to room temperature and suction filter, the obtained solid product is washed 3 times with ultrapure water and diethyl ether, and vacuum-dried to obtain the iridium precursor;

[0066] S2. After mixing the iridium precursor (121.4mg, 0.1mmol) obtained in step S1 with metformin (66.2mg, 0.4mmol), dissolve in dichloromethane / methanol mixed solvent (volume ratio is 2:1), in N 2 Potassium tert-butoxide (89.8mg, 0.8mmol) was added under protection, and the reaction was carried out at 40°C for 30h. After the reaction was complete...

Embodiment 3

[0072] The preparation of embodiment 3 ring metal iridium metformin complex Ir3

[0073] The preparation method of ring metal iridium metformin complex Ir3 comprises the following steps:

[0074] S1. After mixing iridium trichloride hydrate and ligand at a molar ratio of 1:3, dissolve it in a mixed solvent of ethylene glycol ether and ultrapure water (volume ratio: 4:1), and stir at 140°C under reflux Carry out the coordination reaction for 26 hours, cool to room temperature and suction filter, the obtained solid product is washed 3 times with ultrapure water and diethyl ether, and vacuum-dried to obtain the iridium precursor;

[0075] S2. After mixing the iridium precursor (121.4mg, 0.1mmol) obtained in step S1 with metformin (66.2mg, 0.4mmol), dissolve in dichloromethane / methanol mixed solvent (volume ratio is 1:1), in N 2 Potassium tert-butoxide (89.8mg, 0.8mmol) was added under protection, and the reaction was carried out at 30°C for 20h. After the reaction was completed,...

technical field

[0001] The invention belongs to the technical field of medicinal chemistry. More specifically, it relates to a ring metal iridium metformin complex and its preparation method and application. Background technique

[0002] Hypoxia is a prominent feature of most solid tumors. Due to the rapid proliferation of tumor cells, incomplete development and uneven distribution of blood vessels in solid tumors, the supply of oxygen and nutrients in the tumor tissue is insufficient, which eventually leads to the existence of hypoxic areas in the tumor. Hypoxic microenvironment can induce tumor tissue resistance to traditional chemotherapy drugs such as cisplatin, making chemotherapy effect worse, and will reduce the therapeutic effect of photosensitizers in tumor hypoxic areas, and will increase tumor recurrence, metastasis and invasion ability. Therefore, the development of new metal antitumor drugs with different antitumor mechanisms is of great significance for impr...

Examples

Embodiment 1

[0054] The preparation of embodiment 1 ring metal iridium metformin complex Ir1

[0055] The preparation method of ring metal iridium metformin complex Ir1 comprises the following steps:

[0056]S1. After mixing iridium trichloride hydrate and ligand at a molar ratio of 1:2.2, dissolve it in a mixed solvent of ethylene glycol ether and ultrapure water (volume ratio: 3:1), and stir at 135°C under reflux The coordination reaction was carried out for 24 hours, cooled to room temperature and suction filtered, and the obtained solid product was washed three times with ultrapure water and diethyl ether, and dried in vacuum to obtain an iridium precursor;

[0057] S2. After mixing the iridium precursor (121.4mg, 0.1mmol) obtained in step S1 with metformin (66.2mg, 0.4mmol), dissolve in dichloromethane / methanol mixed solvent (volume ratio is 1.5:1), in N 2 Potassium tert-butoxide (89.8mg, 0.8mmol) was added under protection, and the reaction was carried out at 35°C for 25h. After the...

Embodiment 2

[0063] The preparation of embodiment 2 ring metal iridium metformin complex Ir2

[0064] The preparation method of ring metal iridium metformin complex Ir2 comprises the following steps:

[0065] S1. After mixing iridium trichloride hydrate and ligand at a molar ratio of 1:2.5, dissolve it in a mixed solvent of ethylene glycol ether and ultrapure water (volume ratio: 2:1), and stir at 130°C under reflux Carry out the coordination reaction for 22 hours, cool to room temperature and suction filter, the obtained solid product is washed 3 times with ultrapure water and diethyl ether, and vacuum-dried to obtain the iridium precursor;

[0066] S2. After mixing the iridium precursor (121.4mg, 0.1mmol) obtained in step S1 with metformin (66.2mg, 0.4mmol), dissolve in dichloromethane / methanol mixed solvent (volume ratio is 2:1), in N 2 Potassium tert-butoxide (89.8mg, 0.8mmol) was added under protection, and the reaction was carried out at 40°C for 30h. After the reaction was complete...

Embodiment 3

[0072] The preparation of embodiment 3 ring metal iridium metformin complex Ir3

[0073] The preparation method of ring metal iridium metformin complex Ir3 comprises the following steps:

[0074] S1. After mixing iridium trichloride hydrate and ligand at a molar ratio of 1:3, dissolve it in a mixed solvent of ethylene glycol ether and ultrapure water (volume ratio: 4:1), and stir at 140°C under reflux Carry out the coordination reaction for 26 hours, cool to room temperature and suction filter, the obtained solid product is washed 3 times with ultrapure water and diethyl ether, and vacuum-dried to obtain the iridium precursor;

[0075] S2. After mixing the iridium precursor (121.4mg, 0.1mmol) obtained in step S1 with metformin (66.2mg, 0.4mmol), dissolve in dichloromethane / methanol mixed solvent (volume ratio is 1:1), in N 2 Potassium tert-butoxide (89.8mg, 0.8mmol) was added under protection, and the reaction was carried out at 30°C for 20h. After the reaction was completed,...

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