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Ethylenediaminetetraacetic acid binuclear platinum complex and preparation method thereof

A technology of EDTA and disodium EDTA, applied in the field of EDTA binuclear platinum complex and its preparation, can solve the problem of large toxic and side effects, poor water solubility, safety evaluation to be further investigated, etc. problem, to achieve the effect of high safety

Active Publication Date: 2016-07-06
CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Although in vitro experiments have confirmed that the above-mentioned divalent dinuclear platinum has certain anticancer activity, the ligands used in it have yet to be further investigated in terms of safety evaluation.
In view of the current importance of platinum-based drugs in the field of anti-cancer, and the shortcomings of most existing divalent platinum-based anti-cancer drugs, such as poor water solubility and high toxicity and side effects, it is of great significance and value

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  • Ethylenediaminetetraacetic acid binuclear platinum complex and preparation method thereof
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  • Ethylenediaminetetraacetic acid binuclear platinum complex and preparation method thereof

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[0026] The invention also discloses a preparation method of the dinuclear platinum complex of ethylenediaminetetraacetic acid, which comprises the following steps:

[0027] (A) Dissolving ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid in the aqueous solution, and adjusting the pH of the aqueous solution to 6.0-9.0;

[0028] (B) adding cisplatin to the aqueous solution, stirring and reacting, and obtaining the dinuclear platinum complex of ethylenediaminetetraacetic acid as shown in formula (I) after purification;

[0029]

[0030] According to the present invention, first dissolving ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid in an aqueous solution to obtain an aqueous solution, and then adjusting the pH of the aqueous solution to 6.0-9.0, preferably adjusting the pH to 6.6-7.5. The mass percent concentration of the EDTA or disodium EDTA in the aqueous solution is not particularly limited, preferably 10-70%, more ...

Embodiment 1

[0034] Add 30.15 mg of ethylenediaminetetraacetic acid and 65 mL of pure water to the reaction flask, adjust the pH to 8.1 with 0.1 M NaOH, and add 61.91 mg of CDDP. After stirring and reacting for 72 hours, dialyze with a dialysis bag with a molecular weight cut-off of 500 for 36 hours, collect a transparent and colorless liquid, and store it in a refrigerator at 4°C.

[0035] A small amount of the liquid product was freeze-dried to obtain a pale yellow crystalline solid, namely the dinuclear platinum complex of ethylenediaminetetraacetic acid. H NMR spectrum ( 1 HNMR, 400MHz, D 2 O) The result shows: 2.97~3.08ppm (s,-NCH 2 CO-), 2.40~2.52ppm (s,-NCH 2 CH 2 The EDTA peak of N-) disappeared completely, and multiple peaks of the product appeared at 3.35-4.65ppm. The resulting solid was characterized by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), and the following data were obtained: 735.4, 730.2, 718.3, 713.2, 696.2. Both a...

Embodiment 2

[0037] Add 33.69 mg of ethylenediaminetetraacetic acid and 70 mL of pure water to the reaction flask, adjust the pH to 6.8 with 0.1 M NaOH, and add 69.18 mg of CDDP. After stirring and reacting at room temperature for 60 hours, dialyze for 30 hours with a dialysis bag with a molecular weight cut-off of 500, collect the liquid, and freeze-dry to obtain a pale yellow crystalline solid, which is the dinuclear platinum complex of ethylenediaminetetraacetic acid.

[0038] 1 HNMR (400MHz,D 2 O) The result shows: 2.97~3.08ppm (s,-NCH 2 CO-), 2.40~2.53ppm (s,-NCH 2 CH 2 The EDTA peak of N-) disappeared completely, and multiple peaks of the product appeared at 3.35-4.65ppm. The obtained solid was characterized by MALDI-TOF-MS, and the following data were obtained: 735.4, 730.2, 718.3, 713.2, 696.2. Both are fragment ion peaks of the complex. Thus, it can be confirmed that the target product was successfully synthesized.

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Abstract

The present invention provides the dinuclear platinum complex of ethylenediaminetetraacetic acid as shown in formula I. The preparation method is as follows: dissolving ethylenediaminetetraacetic acid or disodium ethylenediaminetetraacetic acid in an aqueous solution, adjusting the pH of the aqueous solution to 6.0-9.0; adding cisplatin to the aqueous solution, stirring and reacting, and obtaining A dinuclear platinum complex of ethylenediaminetetraacetic acid as shown in formula (I). The binuclear platinum complex uses ethylenediaminetetraacetic acid (EDTA) as a ligand, is formed through the coordination of two pairs of symmetrical carboxyl groups of EDTA and cisplatin, has a stable double-centered eight-membered ring structure, and is very easy to dissolve. In the low pH environment of tumor tissue, the compound with anticancer activity can be slowly released, so as to achieve the purpose of reducing the body toxicity of the original drug of cisplatin and maintaining its anticancer activity. The present invention uses clinically injectable EDTA as a ligand, and has high safety. The preparation method is simple and easy for industrialized production.

Description

technical field [0001] The invention relates to the field of metal platinum anticancer drugs, in particular to a dinuclear platinum complex of ethylenediaminetetraacetic acid and a preparation method thereof. Background technique [0002] Cisplatin has the characteristics of broad anti-cancer spectrum, strong effect, synergistic effect with various anti-tumors and no cross-resistance. It is one of the most commonly used drugs in combination chemotherapy. According to statistics, in my country's anticancer chemotherapy, cisplatin-based or cisplatin-based regimens account for 70% to 80% of all chemotherapy regimens. At present, cisplatin has a good effect on the treatment of lung cancer, reproductive system tumors, head and neck cancer, bladder cancer, lymphoma and so on. Oral administration of cisplatin is ineffective, and it is usually administered by intravenous infusion in clinical practice. After intravenous infusion, cisplatin is rapidly divided into the whole body, es...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F15/00
Inventor 汤朝晖李明强陈学思张影
Owner CHANGCHUN INST OF APPLIED CHEMISTRY - CHINESE ACAD OF SCI