Ursolic acid piperazine dithioformic acid-pyridine ruthenium complexes as well as preparation method and application thereof

A technology of ursolic acid piperazine dithiocarboxylic acid and dithiocarboxylic acid, which is applied in the directions of ruthenium organic compounds, pharmaceutical formulations, steroids, etc. The preparation method of ruthenium complexes has the problems of cytotoxicity and other problems, and achieves the effects of significant inhibitory activity, simple preparation method and low cost

Active Publication Date: 2021-02-05
GUILIN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are no relevant reports on ursolic acid piperazine dithioformic acid

Method used

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  • Ursolic acid piperazine dithioformic acid-pyridine ruthenium complexes as well as preparation method and application thereof
  • Ursolic acid piperazine dithioformic acid-pyridine ruthenium complexes as well as preparation method and application thereof
  • Ursolic acid piperazine dithioformic acid-pyridine ruthenium complexes as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1: the preparation of ligand L

[0039] Get compound UAP (5.24g, 10mmol, 1.0equiv), 4mmol / L sodium hydroxide (2.5mL, 10mmol, 1.0equiv) and carbon disulfide (5mL) and place in the round bottom flask, after adding 100mL of methylene chloride (at this time the system pH>9), stirred the reaction at room temperature for 4h, stopped the reaction, evaporated the solvent, and purified the residue by silica gel column chromatography (dichloromethane / methanol=250:3, volume ratio) to obtain 4.53g of white powdery solid , yield 72.8%. HRMS(m / z)(ESI):C 35 h 55 N 2 NaO 2 S 2 [L+Na] + calcd for: 645.3500, found: 645.3601; C 35 h 55 N 2 NaO 2 S 2 [L-Na] - calcd for:599.3705,found:599.3714. 1 H NMR (500MHz, DMSO-d 6 )δ5.30(s,1H,OH),5.09(s,1H,12-H),4.35–3.51(br,9H,3-H and 4×CH 2 in piperazine),3.04–2.94(br,1H),2.35(d,J=10.5Hz,1H),2.00(dd,J=69.7,59.1Hz,6H),1.57–1.13(m,14H),1.03( s,3H,27-CH 3 ), 0.92 (d, J=5.1Hz, 4H, 26-CH 3 and CH),0.88(s,3H,25-CH 3 ),0.86–...

Embodiment 2

[0042] Embodiment 2: Preparation of Ligand L

[0043] Get compound UAP (2.62g, 5mmol, 1.0equiv), 4mmol / L sodium hydroxide (1.25mL, 5mmol, 1.0equiv) and carbon disulfide (4mL) are placed in the round bottom flask, after adding 50mL ethanol (the pH of this moment system >9), stirred the reaction at room temperature for 2h, stopped the reaction, evaporated the solvent, and purified the residue by silica gel column chromatography (dichloromethane / methanol=250:3, volume ratio) to obtain 1.82g of white powdery solid, product The rate is 58.4%.

[0044] The structure of the product obtained in this example was characterized by high-resolution mass spectrometry, proton nuclear magnetic resonance spectrum, and carbon nuclear magnetic resonance spectrum, and it was determined that the product obtained in this example was ligand L.

Embodiment 3

[0045] Embodiment 3: Preparation of Ligand L

[0046] Example 2 was repeated, except that methanol, tetrahydrofuran, dioxane, chloroform or cyclohexane were used instead of ethanol, and potassium carbonate was used to adjust the pH of the system to 10. Finally, a colored powdery solid was obtained. The products obtained from the reaction in different solvents were characterized by high-resolution mass spectrometry, proton nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, etc., and it was confirmed that the obtained products were all ligand L.

[0047] The following examples prepare complex I, complex II and complex III according to the following synthetic routes:

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Abstract

The invention discloses three ursolic acid piperazine dithioformic acid-pyridine ruthenium complexes as well as a preparation method and application thereof. The preparation method of the ursolic acidpiperazine dithioformic acid-pyridine ruthenium complexes comprises the steps: respectively putting ligand ursolic acid piperazine dithioformic acid sodium and tris(2,2'-dipyridyl)ruthenium dichloride, tris(1,10-phenanthroline)ruthenium dichloride or tris(4,7-diphenyl-1,10-phenanthroline)ruthenium dichloride into a first organic solvent for coordination reaction, and thus obtaining a corresponding target crude product. Tests of the applicant show that the complexes have extremely remarkable inhibitory activity on certain tumor cell strains, the inhibitory activity is greatly higher than thatof parent nucleus and cis-platinum of the complexes, meanwhile, the inhibitory activity of the complexes on cis-platinum drug-resistant strain cells is remarkably superior to that of cis-platinum, andthe complexes are expected to be used for preparing anti-tumor drugs.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a piperazine ursolic acid dithioformic acid-pyridine ruthenium complex and a preparation method and application thereof. Background technique [0002] Ruthenium metal-based anti-tumor complexes are considered to be one of the most promising anti-cancer drugs besides platinum-based metal-based anti-tumor complexes (Mestroni G, Alessio E. Metal Based Drugs, 1994, 1:41-48), Its representative compounds NAMI2A and [ImH][trans2 RuCl 4 (dmso 2 S)(Im)] (Im=imidazole) has excellent anticancer activity. Because ruthenium metal-based anti-tumor complexes have the advantages of low toxicity, easy absorption, fast excretion and easy tumor tissue absorption (SavaG, Alessio E, Bergamo A, Mestroni G. Topics in Biological Inorganic Chemistry, Vol.1. Berlin: Springer, 1999.143-169), the design and screening of new high-efficiency and low-toxic ruthenium-based metal-based anti-tumor complexes ...

Claims

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Application Information

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IPC IPC(8): C07J63/00C07F15/00A61P35/00A61K31/58
CPCA61P35/00C07F15/0053C07J63/008
Inventor 张业韦健华马献力姜红廖永志
Owner GUILIN MEDICAL UNIVERSITY
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