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Phenanthroline derivative and preparation method and application thereof

A technology for o-phenanthroline and derivatives, which is applied in the field of o-phenanthroline derivatives and their preparation, can solve the problems of low G-quadruple helix DNase inhibitory activity and high price, and achieves inhibition of growth and reproduction and reduction of toxic and side effects. , the effect of increasing enzyme inhibitory activity

Inactive Publication Date: 2011-02-09
SHANXI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Its ability to stabilize G-quadruplex DNA and enzyme inhibitory activity are low, and Pt is a noble metal, which is expensive

Method used

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  • Phenanthroline derivative and preparation method and application thereof
  • Phenanthroline derivative and preparation method and application thereof
  • Phenanthroline derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Embodiment 1: the preparation of o-phenanthroline derivatives

[0023] (1) Dissolve (0.5026 g, 3.1 mmol) lithium perchlorate and (0.6667 g, 11.2 mmol) silicon dioxide in 10 mL of acetonitrile. Stir at room temperature for 1 hour, remove the solvent by rotary evaporation, and dry the solid in vacuo to obtain LP-SiO 2 .

[0024] (2) Add (1 g, 3.1 mmol) LP-SiO to 10 mL of dry dichloromethane 2 and (1.0913 g, 10 mmol) p-aminophenol. Under the protection of nitrogen, (3.228g, 20mmol) hexamethyldisilazane (HMDS) was slowly dropped into the above mixed solution, stirred at room temperature for 40 minutes, then added 10mL of dry dichloromethane, filtered to remove LP-SiO 2 , the filtrate rotary evaporation removes dichloromethane, and vacuum drying obtains protected p-aminophenol (yellow oily liquid);

[0025] (3) Dissolve (1g, 3.7mmol) 2,9-dicarboxylic acid-1,10-phenanthroline in 30mL dry DMF, then add (1.414g, 7.8mmol) the above-mentioned protected p-aminophenol, and stir...

Embodiment 2

[0032] Embodiment 2: the preparation of o-phenanthroline derivatives

[0033] (1), (2), (3) process is the same as embodiment 1

[0034] (4) Add (0.1g, 0.235mmol) amide and (0.0708g, 2.3mmol) 60% sodium hydride into 10mL of dry and degassed DMF, and heat to 110°C; (0.1616g, 0.95mmol) 1- (2-Chloroethyl)pyrrole hydrochloride was dissolved in 20 mL of dry and degassed DMF, stirred to dissolve, and then this solution was added dropwise to the above amide solution, and reacted at 110°C for 12 hours under the protection of nitrogen, and the reaction solution was Cool to room temperature, continue to stir at room temperature for 72 hours, filter, and the filtrate was rotovapped to obtain a yellow solid; this solid was dissolved in methanol, and the pH was adjusted to 7 with hydrochloric acid and triethylamine; the solvent was removed by rotovap, and the obtained product was separated by silica gel column chromatography , The developer is: ethyl acetate: ethanol: triethylamine = 10: ...

Embodiment 3

[0040] Example 3 Selective recognition and stability experiments of o-phenanthroline derivatives on human telomeric G-quadruplex DNA

[0041] In order to explore the recognition and stabilization of phenanthroline derivatives on G-quadruplex DNA, we carried out fluorescence resonance energy transfer-melting point (FRET-melting) experiments, the results are as follows figure 1 and shown in Table 1. The DNA sequence used is 5'-FAM-GGG (TTAGGG) 3 -TAMRA-3', the human telomere sequence 5'-GGG (TTAGGG) 3 The 5' and 3' ends of -3' were labeled with FAM and TAMRA, respectively. The buffer system is: 100 mM NaCl, 10 mM sodium cacodylate (pH 7.4). Table 1 has listed under different drug concentrations, o-phenanthroline derivatives make the melting point temperature increase value of G-quadruplex DNA (ΔT m ). The results showed that o-phenanthroline derivatives could interact with human telomere terminal G-quadruplex DNA and stabilize its structure.

[0042] Table 1 Effect of diff...

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Abstract

The invention provides a phenanthroline derivative. A preparation method for the phenanthroline derivative comprises the following steps of: under the condition of taking LP-SiO2 prepared by mixing lithium perchlorate and silicon dioxide according to proportion as a catalyst, preparing p-aminophenol into hydroxyl protection ether by using hexamethyldisilazane (HMDS), then preparing the protection ether and carboxylic acid into amide in the presence of EDCI (ethylcarbodiimide hydrochloride) condensation agent and HOAt catalyst, and finally adding 1-(2-chloroethane) piperidine hydrochloride or 1-(2-chloroethane) pyrrole hydrochloride into DMF (dimethyl formamide) to form the phenanthroline derivative. The prepared phenanthroline derivative can selectively identify and stabilize telomere G-four-helical DNA in the presence of excess double-helical DNA, nearly fully inhibits the activity of telomerase at low concentration, can remarkably inhibit the growth and reproduction of Hela cells, and can be used for preparation of anti-tumor medicaments.

Description

technical field [0001] The invention relates to an organic small molecule ligand, in particular to an o-phenanthroline derivative and a preparation method and use thereof. Background technique [0002] Telomere DNA at the end of eukaryotic chromosomes is composed of a series of repeat sequences rich in guanine (G), which has a protective effect on chromosomes. The repeat sequence of human telomere DNA is 5'-TTAGGG-3', about 3-6kb in length, and its 3'-end is a single-stranded region of 100-200 bases. Both NMR and crystal structure showed that in Na + or K + In the presence of this sequence, it folds into a G-quadruplex structure. [0003] For normal somatic cells, as the cells divide again and again, the DNA at the end of the telomere is gradually shortened, eventually leading to cell senescence or apoptosis. However, 85%-90% of cancer cells express highly active telomerase, a reverse transcriptase that continuously adds repeat sequences to shortened telomere ends. The ...

Claims

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Application Information

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IPC IPC(8): A61P35/00A61K31/4745C07D471/04
Inventor 魏春英王立华文烨
Owner SHANXI UNIV
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