WO2012155559A1 - Complexe de platine organique à quatre noyaux hybridés et son procédé de préparation ainsi que son utilisation dans la fabrication de médicaments anti-tumoraux - Google Patents

Complexe de platine organique à quatre noyaux hybridés et son procédé de préparation ainsi que son utilisation dans la fabrication de médicaments anti-tumoraux Download PDF

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Publication number
WO2012155559A1
WO2012155559A1 PCT/CN2012/071263 CN2012071263W WO2012155559A1 WO 2012155559 A1 WO2012155559 A1 WO 2012155559A1 CN 2012071263 W CN2012071263 W CN 2012071263W WO 2012155559 A1 WO2012155559 A1 WO 2012155559A1
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WIPO (PCT)
Prior art keywords
tetranuclear
platinum complex
formula
cisplatin
bridging ligand
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2012/071263
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English (en)
Chinese (zh)
Inventor
毛宗万
郑小辉
谭彩萍
黄华珍
计亮年
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Sun Yat Sen University
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Sun Yat Sen University
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Filing date
Publication date
Application filed by Sun Yat Sen University filed Critical Sun Yat Sen University
Publication of WO2012155559A1 publication Critical patent/WO2012155559A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • 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
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage

Definitions

  • the invention relates to a kind of tetranuclear platinum complex which synthesizes organic hybrids by using supramolecular self-assembly and has excellent anti-tumor activity, and a preparation method thereof, and particularly relates to a preparation method and a resistance of a tetranuclear platinum complex with an amino side arm Tumor activity.
  • the bridging ligand is a series of nitrogen-containing heterocycles which can be adjusted for the size of the entire Pt complex by varying the size of the bridging ligand.
  • the present invention has a high anticancer activity and targeting property by supramolecular self-assembly of an organic hybrid tetranuclear platinum complex.
  • the object of the present invention is to provide an organo-hybrid tetranuclear platinum complex having anticancer activity according to the deficiencies of the prior art, and the structural formula is as shown in the formula (I):
  • the bridging ligand is of the formula (11), the formula (111), and the formula
  • the invention of the formula (IV) also provides a preparation method of the organic hybrid tetranuclear platinum complex, which is a tetranuclear structure by using a supramolecular self-assembly to assemble a prosthetic ligand and a bridging ligand to obtain the organic hybrid.
  • Tetranuclear platinum complex The prosthetic ligand is cisplatin in which chloride ions are replaced by nitrate; the bridging ligand is one of the formulae (11), ( ⁇ ), (IV).
  • the reaction step is: dechlorination of cisplatin, addition of the bridging ligand, and obtaining the organic hybrid tetranuclear platinum complex at 50-100 degrees in the dark for 4-7 days.
  • cisplatin is dissolved in an appropriate amount of water and then added to the phase.
  • the reaction was protected from light for 15 hours under nitrogen protection, centrifuged in a low temperature centrifuge, and the precipitate was discarded, leaving the night.
  • the bridging ligand is added to the supernatant, and the molar ratio of cisplatin to bridging ligand is 1:1 - 1.1:1.
  • anhydrous ethanol is added to the reactor to obtain a precipitate, which is centrifuged.
  • the supernatant was washed 2-3 times with absolute ethanol and centrifuged to obtain a light-colored solid substance, that is, an organic hybrid tetranuclear platinum complex.
  • the organic hybrid tetranuclear platinum complex provided by the present invention can be used for the preparation of an antitumor drug. More specifically, it is used to prepare a drug for treating cisplatin-resistant tumors. These drugs may also contain a pharmaceutically acceptable adjuvant ⁇ .
  • the present invention has the following beneficial effects:
  • the present invention synthesizes and characterizes a series of tetranuclear Pt(II) complexes having a square configuration by supramolecular self-assembly by using cisplatin as a prosthetic ligand and a corresponding bridging ligand.
  • the data show that these compounds have excellent anti-tumor activity, especially the MTT experimental data of human lung cancer cell A549/cisR indicates that the anti-tumor activity of the compound is 10 times that of cisplatin.
  • Figure 1 MTT screening of tetranuclear complex I and cisplatin in cisplatin-resistant lung cancer cells (A549/cisR).
  • HepG2 human liver cancer cell line
  • Hela human cervical cancer cell line
  • MCF-7 human breast cancer cell line
  • A549 human lung cancer cell
  • A549/cisR resistant Platinum lung cancer cells are provided by the Experimental and Animal Center of Sun Yat-Sen University.
  • the cells were cultured in DMEM medium containing 10% fetal bovine serum containing 100 units of penicillin per ml and 100 ⁇ g of streptomycin.
  • the cells were seeded in a Petri dish with a diameter of 10 cm and cultured in a 37-degree, 5% C0 2 environment. When the cells are full, they are passaged by trypsinization.
  • Cytotoxicity test Cytotoxicity was determined by the MTT method. Digest the cells into single cells with 0.25% trypsin Suspension, using the blood cell calculation plate for the number of viable cells, adjusting the viable cell concentration to 5 X 10 4 per ml inoculated in a 96-well culture plate, 160 ⁇ L per well, after 24 hours of culture, then adding different concentrations of tetranuclear platinum The complexes (concentrations are shown in Figure 1), placed at 37 degrees, incubated in an incubator containing 5% C0 2 for 48 hours, added MTT 20 ⁇ l per well 4 hours before the end, and discarded the supernatant after 4 hours.
  • DMSO 100 ⁇ l per well shake for about 10 minutes, and measure the OD value by the microplate reader.
  • the wavelength is set to 570 nm and 607 nm dual wavelength.
  • the survival rate was calculated according to the following formula, and the cytotoxicity of the drug was evaluated by plotting and obtaining a half killing concentration (/C 50 ).
  • % survival average OD of the drug well / average OD of the control well X 100%
  • a/C 5Q value The concentration of the complex when the cell survival rate is only 50% compared with the blank. A total of 3 parallel experiments were performed to obtain the average.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un complexe de platine organique à quatre noyaux hybridés ayant une activité anti-tumorale. La formule de structure du complexe est représentée par la formule (I), dans laquelle (…) représente le même ligand ponté qui est un ligand des formules (II), (III) et (IV). Le composé possède une activité anti-tumorale, en particulier une activité contre le cancer du poumon.
PCT/CN2012/071263 2011-05-17 2012-02-17 Complexe de platine organique à quatre noyaux hybridés et son procédé de préparation ainsi que son utilisation dans la fabrication de médicaments anti-tumoraux Ceased WO2012155559A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2011101273708A CN102250150B (zh) 2011-05-17 2011-05-17 有机杂化四核铂配合物及其制备方法和在制备抗肿瘤药物中的应用
CN201110127370.8 2011-05-17

Publications (1)

Publication Number Publication Date
WO2012155559A1 true WO2012155559A1 (fr) 2012-11-22

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PCT/CN2012/071263 Ceased WO2012155559A1 (fr) 2011-05-17 2012-02-17 Complexe de platine organique à quatre noyaux hybridés et son procédé de préparation ainsi que son utilisation dans la fabrication de médicaments anti-tumoraux

Country Status (2)

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CN (1) CN102250150B (fr)
WO (1) WO2012155559A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016127681A1 (fr) * 2015-02-09 2016-08-18 中山大学 Utilisation de complexe de platine tétranucléaire ponté par 4,4'-bipyridine dans la préparation d'un médicament anti-cellules tumorales télomérase négatives

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102250150B (zh) * 2011-05-17 2013-11-06 中山大学 有机杂化四核铂配合物及其制备方法和在制备抗肿瘤药物中的应用
CN102408452B (zh) * 2011-12-13 2014-09-03 中山大学 四吡啶基卟啉桥联十字形四核铂配合物及其制备方法和抗肿瘤活性
CN102898478B (zh) * 2012-08-09 2017-10-10 中山大学 一种高效端粒酶抑制剂及其在抗肿瘤药物中的应用
CN103275077B (zh) * 2013-01-29 2015-07-15 中山大学 钌配合物及其制备方法和作为组蛋白脱乙酰基酶抑制剂的用途
CN115286662A (zh) * 2022-02-16 2022-11-04 温州医科大学附属第一医院 一种氨基酸杂化四核铂配合物、制备方法及应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101891769A (zh) * 2010-06-18 2010-11-24 河北大学 抗肿瘤药物铂配合物
CN102250150A (zh) * 2011-05-17 2011-11-23 中山大学 有机杂化四核铂配合物及其制备方法和在制备抗肿瘤药物中的应用技术领域

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4543253B2 (ja) * 2004-10-28 2010-09-15 Ｄｏｗａエレクトロニクス株式会社 蛍光体混合物および発光装置

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101891769A (zh) * 2010-06-18 2010-11-24 河北大学 抗肿瘤药物铂配合物
CN102250150A (zh) * 2011-05-17 2011-11-23 中山大学 有机杂化四核铂配合物及其制备方法和在制备抗肿瘤药物中的应用技术领域

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016127681A1 (fr) * 2015-02-09 2016-08-18 中山大学 Utilisation de complexe de platine tétranucléaire ponté par 4,4'-bipyridine dans la préparation d'un médicament anti-cellules tumorales télomérase négatives

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CN102250150A (zh) 2011-11-23
CN102250150B (zh) 2013-11-06

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