Ruthenium complex, ruthenium-RGD (arginine-glycine-aspartic acid) peptide conjugate and preparation method and application thereof

A ruthenium complex and peptide coupling technology, which is applied in the preparation method of peptides, ruthenium organic compounds, platinum group organic compounds, etc., can solve the problem that metal complexes are in their infancy, and achieve the effect of inhibiting proliferation

Active Publication Date: 2018-09-21
GUANGDONG PHARMA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, the international research on RGD peptide targeted coupling is mostly focused on platinum anticancer drugs and some...

Method used

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  • Ruthenium complex, ruthenium-RGD (arginine-glycine-aspartic acid) peptide conjugate and preparation method and application thereof
  • Ruthenium complex, ruthenium-RGD (arginine-glycine-aspartic acid) peptide conjugate and preparation method and application thereof
  • Ruthenium complex, ruthenium-RGD (arginine-glycine-aspartic acid) peptide conjugate and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] The synthesis of embodiment 1 ruthenium-RGD conjugate RuM-RGD

[0023] The conjugate is obtained by coupling and synthesizing two parts of ruthenium complex (RuM) and RGD peptide (RGDfK). Wherein the general formula of ruthenium complex RuM is: [Ru(dmp) 2 (X-COOH)](PF 6 ) 2 , where the ligand represented by X is: 1,2-dimethyl-1H-imidazol[4,5-f][1,10]phenanthroline. RGD peptide is a commercial reagent (RGDfK, Shanghai Qiangyao Biotech). The conjugate RuM-RGD is obtained by condensation reaction of ruthenium complex RuM and RGD peptide RGDfK. (The synthesis process of RuM ruthenium complex is shown in formula I, and the conjugate RuM-RGD is shown in formula II):

[0024]

[0025] Wherein ligand preparation method is as follows:

[0026] (1) Preparation method of ligand L1: Weigh 0.093g aniline (1mmol), 0.150g 4-formylbenzoic acid (1mmol), 1.542g ammonium acetate (20mmol), 0.21g of 1,10-phenanthroline- 5,6-Diketone (1 mmol), dissolved in 10 mL of glacial acetic a...

Embodiment 2

[0031] Example 2 Conjugate RuM-RGD Targeted Recognition of U87 Tumor Cells

[0032] The conjugate RuM-RGD (100 μM) was co-incubated with U87 (human glioma) cells with high expression of integrin αvβ3 and normal liver cell L02 with low expression of integrin αvβ3 for 6 hours, and the cytoplasm of U87 showed obvious red No obvious fluorescence was observed in L02 cells, indicating that the conjugate RuM-RGD can target and recognize tumor cell U87 that highly expresses integrin αvβ3, as shown in the attached figure 1 shown.

Embodiment 3

[0033] Example 3 The ruthenium-RGD conjugate RuM-RGD targets the mitochondria distributed in U87 tumor cells

[0034] In order to further clarify whether the conjugate RuM-RGD can target mitochondria after entering the cells, fluorescence colocalization of organelles was detected by fluorescence microscopy. The mitochondria-specific dye Mitotracker with green fluorescence and the conjugate RuM-RGD (100 μM) with red fluorescence were added to U87 tumor cells and incubated for 6 h. If the two fluorescent substances colocalize in the same cell site, the green fluorescence and red fluorescence will overlap and become orange-yellow. The results showed that the fluorescence of the two substances turned orange after being superimposed, indicating that the two fluorescent substances were colocalized on the mitochondria, and proved that the conjugate RuM-RGD could target the mitochondria of U87 tumor cells after entering the cells, as shown in the attached figure 2 shown.

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Abstract

The invention relates to a ruthenium complex, a ruthenium-RGD (arginine-glycine-aspartic acid) peptide conjugate and a preparation method and application thereof. The conjugate is obtained by couplingtwo parts including the ruthenium complex (RuM) and RGD peptide (RGDfK). A general formula of the ruthenium complex RuM is as follows: [Ru(dmp)2(X-COOH)](PF6)2, wherein X represents a ligand: 1,2-dimethyl-1H-imidazole[4,5-f][1,10]phenanthroline. The RGD peptide is a commercial reagent (RGDfK, Shanghai Qiangyao Biotechnology Company). The conjugate RuM-RGD is obtained by taking the ruthenium complex RuM and the RGD peptide RGDfK and carrying out condensation reaction. The RuM-RGD conjugate provided by the invention has a strong inhibition effect on glioma cells U87, and can be used for accumulating mitochondria of the U87 tumor cells and inhibiting tumor cell proliferation; the RuM-RGD conjugate can be used as a novel anti-tumor medicine taking a tumor cell mitochondrion as a target spot.

Description

technical field [0001] The invention discloses a ruthenium complex and the preparation and application of a ruthenium-RGD peptide conjugate RuM-RGD that can target the mitochondria of U87 tumor cells. Anticancer Drugs Targeting Cell Mitochondria Background technique [0002] Compared with other metal anticancer drugs, ruthenium (Ruthenium) complexes have higher cytotoxicity and less toxic side effects, showing broad development prospects, especially the three ruthenium complexes have entered phase II (NAMI-A ) or phase I (KP1019 and NKP1339) clinical research, so various modification designs on ruthenium complexes have become research hotspots at home and abroad in order to further enhance their anti-tumor activity and targeting (Mini Rev.Med.Chem. , 16:787-95, 2016.). Recently, Simone Fulda et al. proposed a new design direction of anticancer drugs: mitochondria-targeted anticancer drugs. The mitochondria of tumor cells and normal cells are quite different in structure a...

Claims

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Application Information

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IPC IPC(8): C07F15/00A61P35/00C07K7/64C07K1/107
CPCA61P35/00C07F15/0053C07K7/64
Inventor 王金全薄华本
Owner GUANGDONG PHARMA UNIV
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