All-trans retinoic acid-aryl metal complex as well as preparation method and application thereof

A technology of all-trans retinoic acid and metal complexes, applied in the field of biochemistry, can solve the problems of difficult metabolism, large toxic and side effects, and achieve the effects of high cellular uptake, low drug resistance, and high yield

Pending Publication Date: 2022-05-24
NANJING NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Purpose of the invention: The present invention aims at the problems of large toxic and side effects and difficult metabolism when the commonly used aryl metal complexes in the prior art are used as anticancer drugs or components of anticancer drugs, and provides a method that not only has good therapeutic activity on cancer cells , and an all-trans retinoic acid-aryl metal complex that has no toxic and side effects on normal cells; a preparation method of the complex is also provided

Method used

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  • All-trans retinoic acid-aryl metal complex as well as preparation method and application thereof
  • All-trans retinoic acid-aryl metal complex as well as preparation method and application thereof
  • All-trans retinoic acid-aryl metal complex as well as preparation method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0035]

[0036] The preparation method of the metal complex Ret-Ru of the present invention comprises the following steps:

[0037] Step 1, under argon atmosphere, dissolve retinoic acid, N-hydroxybenzotriazole and N,N-diisopropylethylamine in DMF, react for 5min at a certain temperature, and mix a certain amount of 1-(3 -Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was dissolved in DMF and added dropwise to the reaction mixture. After the mixture was reacted at 0°C for a period of time, propargylamine was added dropwise to the mixed solution. The reaction mixture was allowed to warm to room temperature overnight. After stirring overnight, the organic solvent was removed and the resulting residue was dissolved in ethyl acetate, followed by 5% NaHCO 3(3 x 20 mL) and 0.5 mol / L HCl (3 x 20 mL). Leave the aqueous hydrochloric acid phase, by adding Na 2 CO 3 The pH of the aqueous solution was adjusted to around 8.0 and extracted with dichloromethane (3 x 20 mL) to...

Embodiment 2

[0044]

[0045] The preparation method of the metal complex Ret-Ir of the present invention comprises the following steps:

[0046] Step 1, under argon atmosphere, dichloro(pentamethylcyclopentadienyl)iridium(III) dimer and 4-azidomethyl-4'-methyl-2,2'-linked Pyridine (Example 1) was dissolved in methanol solution, reacted at room temperature for 48 hours, the solvent was removed by rotary evaporation, 10 times equivalent saturated methanol solution of ammonium hexafluorophosphate was added, and column chromatography was performed to obtain a bright yellow powder product with a yield of 86 %, named Ir-N 3 . 1 H NMR (400MHz, DMSO-d 6 )δ8.95(d, J=5.9Hz, 1H), 8.82(d, J=5.8Hz, 1H), 8.73(d, J=5.6Hz, 2H), 7.79(d, J=5.8Hz, 1H) , 7.71(s, 1H), 4.95(s, 2H), 2.64(s, 3H), 1.65(s, 15H).

[0047] Step 2, under argon atmosphere, mix 0.05mmol Ret-alkyne, 0.15mmol Ir-N prepared above 3 , 0.01mmol of copper sulfate pentahydrate and 0.02mmol of sodium ascorbate were dissolved in DMF and ...

Embodiment 3

[0049]

[0050] The preparation method of metal complex Per-Ru of the present invention comprises the following steps:

[0051] Step 1, under argon atmosphere, dissolve 1 mmol of perillyl alcohol, 1 mmol of bromopropyne and 2 mmol of potassium carbonate in DMF, and react at 80 °C for 10-16 h. After the reaction, the reaction solution is washed with an equal volume of ethyl acetate. It was diluted with water solvent, the organic layer was separated, and the aqueous phase was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, the solvent was removed, and the pure product was obtained by column chromatography with a yield of 56%. Named Per-alkyne. 1 H NMR (400MHz, DMSO-d 6)δ5.48(m,1H),5.11(d,J=3.2Hz,1H),4.92(d,J=4.6Hz,1H),4.15(m,2H),4.04(m,2H),3.32( s, 1H), 2.33(dd, J=2.2Hz, 1H), 2.09 -7.61(d, J=5.8Hz, 2H), 1.99(dd, J=12.1Hz, 2H), 1.79(s, 3H), 1.77 (dd, J=2.2Hz, 2H).

[0052] Step 2, under argon atmosphere, mix 0.05mmol ...

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Abstract

The invention discloses all-trans retinoic acid-aryl metal complexes which are obtained by combining small molecules with anti-leukemia activity with aryl ruthenium and iridium metal precursors through a click reaction, and the complexes have the characteristics of corresponding active molecules and also have the anti-leukemia activity. The aromatic metal has the characteristics of good solubility, small toxicity, low drug resistance, high cell intake, easy metabolism and the like, and can realize targeted treatment on leukemia cells; the complex is simple in preparation process, easy to operate and high in yield, and has very high commercial value and application prospect in the aspect of preparing anti-leukemia drugs.

Description

technical field [0001] The invention belongs to the technical field of biochemistry, relates to a class of all-trans retinoic acid-aryl metal complexes, and also relates to a preparation method and application of the metal complexes. Background technique [0002] Leukemia, also known as blood cancer, is a malignant tumor of the hematopoietic system. The main treatment methods include chemotherapy, radiotherapy and bone marrow transplantation. The treatment process has strong toxic and side effects. So far, more than a dozen drugs (natural or synthetic) have been used to treat cancer. At present, new metal anticancer drugs such as ruthenium and iridium have gradually entered people's field of vision. Among them, organometallic complexes with a semi-sandwich configuration It is because of its structural diversity, easy control of aromatic hydrocarbons and hydrophobicity of cyclopentadienyl groups. In chemotherapy research, simple aryl metal complexes are commonly used as antic...

Claims

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Application Information

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IPC IPC(8): C07F15/00C07J63/00A61P35/00A61P35/02C07D213/42C12P17/18C12P17/16C12P33/20
CPCC07F15/0046C07F15/0033C07J63/008A61P35/00A61P35/02C07D213/42C12P17/165C12P17/182C12P33/20Y02P20/584
Inventor 刘红科王裙薛旭玲
Owner NANJING NORMAL UNIVERSITY
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