WO2017148193A1 - Complexe de platine tétravalent contenant un groupe bioactif et son procédé de préparation - Google Patents
Complexe de platine tétravalent contenant un groupe bioactif et son procédé de préparation Download PDFInfo
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- WO2017148193A1 WO2017148193A1 PCT/CN2016/108275 CN2016108275W WO2017148193A1 WO 2017148193 A1 WO2017148193 A1 WO 2017148193A1 CN 2016108275 W CN2016108275 W CN 2016108275W WO 2017148193 A1 WO2017148193 A1 WO 2017148193A1
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- formula
- cisplatin
- platinum
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Images
Classifications
-
- 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
-
- 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 present invention relates to an antitumor tetravalent platinum complex, in particular to a bottom surface of a tetragonal platinum complex octahedral structure with a cisplatin backbone, a single biologically active group introduced at one axial position, and introduced at another axial position A hydroxy or chlorine atom provides a platinum (IV) complex having antitumor activity; the present invention also relates to a method and application for the preparation of such a platinum complex.
- Antitumor bivalent platinum drugs such as cisplatin, carboplatin and oxaliplatin have been widely used clinically for the treatment of related cancers.
- cisplatin mainly acts on the N7 target of guanine in DNA, and forms an adduct by cross-linking with DNA to cause apoptosis of tumor cells, leading to cell arrest and cells. death.
- transmembrane transport cell uptake by active diffusion and passive absorption
- hydration dissociation due to the difference in concentration of chloride ions inside and outside the cell, It is easy to form platinum (II) hydrated cations
- targeted migration platinum (II) ions form DNA Pt-DNA adducts
- DNA damage lethal by acting on DNA, leading to cancer cell death.
- cisplatin drugs are inactivated by toxic substances in the blood such as glutathione before they reach the tumor cells after intravenous injection. Therefore, existing cisplatin drugs have some serious defects: first, they show corresponding toxicity, mainly nephrotoxicity and bone marrow toxicity; second, drug resistance after drug administration. These deficiencies limit the application of these platinum (II) drugs to some extent.
- platinum (IV) complexes have good stability, can reduce the reaction with nucleophilic substances in the body, and introduce certain axial groups to adjust the hydrophilicity and lipophilicity of platinum (IV) complexes. Promote the absorption of drugs. Platinum (IV) ions can be reacted with cancer cell DNA after reduction to form platinum (II) ions in the body. If a biologically active group is introduced in the axial direction of the platinum (IV) complex, it may be produced with platinum (II) ions. Synergistic anti-tumor activity. Therefore, platinum (IV) complexes have attracted widespread attention as anti-tumor prodrugs.
- platinum (IV) complexes Despite some work on platinum (IV) drug research, many types of complexes have been designed and prepared. It is hoped that the space structure of the platinum (IV) complex can be used to obtain a drug which is highly effective and low in toxicity, has no cross-resistance with cisplatin drugs, or has a selective therapeutic effect. However, to date, platinum (IV) complexes that target or overcome cisplatin resistance have not been marketed as drugs.
- the object of the present invention is to utilize the spatial structure of a platinum (IV) complex, using cisplatin as an octahedral bottom surface, introducing a small molecule targeting or pharmaceutically active group in one axial position, and introducing a hydroxyl group in another axial position.
- a chlorine atom providing an antitumor tetravalent platinum complex having overcoming cisplatin resistance, in order to obtain a highly effective and low toxicity platinum (IV) drug;
- the present invention also provides a process for preparing the platinum (IV) complex, and In the preparation of anti-tumor drugs.
- the present invention is a kind of tetravalent platinum complex containing a biologically active group, and the tetravalent platinum complex is a platinum (IV) complex, and its structure is as shown in Formula II:
- the following method is employed: mixing equimolar reactant Bio-OH and coupling reagent TBTU in anhydrous DMF or DMSO, adding equimolar TEA under stirring at room temperature, and then adding equimolar Pt(IV) reactant A Or B, the reaction solution is stirred under nitrogen for 30-60 ° C for 12-48 hours, then the solvent is removed under reduced pressure, and the concentrate is separated by silica gel column chromatography, and the eluent is a mixed solvent of dichloromethane and methanol to obtain Yellow solid product;
- CUA-OH a carboxylic acid derivative
- CUT-OH a triazole fatty acid derivative of a natural product coumarin having an anti-oxidation and anti-cancer effect
- CUT-OH a triazole fatty acid derivative of a natural product coumarin having an anti-oxidation and anti-cancer effect
- CUT-OH a triazole fatty acid derivative of a natural product coumarin having an anti-oxidation and anti-cancer effect
- CUT-OH a known anti-tumor
- SAA-OH a PARP inhibitor
- human lung cancer cell A549, colon cancer cell HCT-116, liver cancer cell HepG2, breast cancer cell MCF-7 and MDA-MB-231, ovarian cancer cell A2780, pancreatic cancer cell PANC-1, gastric cancer cell SGC- 7901 was evaluated for in vitro anti-tumor activity with cisplatin-resistant gastric cancer cells SGC-7901/CCCP, glioma cell line U87 or glioma cell line U251, and cisplatin was used as a positive control. The inhibition of tumor cell growth by the compounds at different concentrations was observed.
- Figure 3 Inhibition of test sample on the growth of human gastric cancer cell SGC-7901 xenograft tumor in nude mice.
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Abstract
L'invention concerne un complexe de platine tétravalent contenant un groupe bioactif et son procédé de préparation, le complexe de platine tétravalent étant un complexe de platine (IV) et ayant une structure telle que représentée par la formule II. Dans la formule II, Y représente OH ou Cl; et Bio représente un groupe bioactif. Le complexe de platine (IV) est préparé selon l'équation telle que présentée par la formule III. Dans la formule III, Y représente un OH ou un Cl; Bio-OH représente un composé bioactif; TBTU représente un réactif de couplage tétrafluoroborate d'O-benzotriazole-N,N,N',N'-tétraméthyluronium; TEA représente une triéthylamine catalytique; DMF représente un solvant N,N-diméthylformamide; et DMSO représente un solvant diméthylsulfoxyde. Grâce à l'utilisation de cisplatine comme face inférieure d'un octaèdre, à l'introduction d'un groupe de ciblage micromoléculaire ou d'un groupe pharmaceutiquement actif dans une position axiale, et à l'introduction d'un groupe hydroxyle ou d'un atome d'hélium dans une autre position axiale, un complexe de platine tétravalent anti-tumoral apte à surmonter la résistance au cisplatine est fourni, de façon à obtenir un complexe de platine (IV) d'une efficacité élevée et d'une faible toxicité.
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