Phenanthroline derivative, as well as preparation method and application thereof

A technology of o-phenanthroline and its derivatives, applied in o-phenanthroline derivatives and its preparation, as an anti-tumor drug, achieving high selectivity, high stability, and the effect of inhibiting growth and reproduction

Inactive Publication Date: 2013-04-17
SHANXI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, telomerase in 85-90% of tumor cells exhibits a very high activity, which can continuously extend the shortened telomere DNA ends after cell division, resulting in the proliferation of cancer cells

Method used

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  • Phenanthroline derivative, as well as preparation method and application thereof
  • Phenanthroline derivative, as well as preparation method and application thereof
  • Phenanthroline derivative, as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: a kind of preparation of o-phenanthroline derivative

[0029] (1) Dissolve (1.0 g, 3.7 mmol) 2,9-dicarboxylic acid-1,10-phenanthroline in 100 mL of anhydrous DMF, add (0.85 g, 7.8 mmol) 2,6-diaminopyridine to it Stir until dissolved, add (1.5 g, 7.8 mmol) EDCI and (0.1 g, 0.7 mmol) HOAT in sequence, stir at room temperature for 3 hours, add 100 mL of 1% (m / V) NaHCO to the reaction solution 3 solution, the precipitate was collected by filtration, washed with ether to obtain N,N'-bis(2-amino-6-pyridyl)-2,9-diamide-1,10-o-phenanthroline;

[0030] (2) Under ice-salt bath conditions, (0.5g, 1.1mmol) 2,9-diamidino-1,10-phenanthroline was dissolved in 20mL of anhydrous DMF, N 2 Add (0.5 mL, 6.2 mmol) pyridine and (0.5 mL, 6.5 mmol) 3-chloropropionyl chloride under protection, react in ice bath for half an hour, then warm to 40 °C and continue stirring for 48 hours. After the reaction was completed, it was cooled to 0 °C, and (2.5 g) of ice was added to precipit...

Embodiment 2

[0038] Embodiment 2: a kind of preparation of o-phenanthroline derivative

[0039] (1), (2) The process is the same as in Example 1

[0040] (3) The piperidine (0.8 mL, 8.1 mmol) in the step (3) of Example 1 was replaced with pyrrolidine (0.67 mL, 8.1 mmol), and the obtained substance was separated by column chromatography. The developing solvent was dichloromethane: methanol= 6:1, the o-phenanthroline derivative is obtained, and the structural formula is:

[0041]

[0042] Its physical constants and spectral data are as follows:

[0043] Off-white powder, molecular formula: C 38 H 40 N 10 O 4 2HCl 2H 2 O(801.76) (%): calcd.C 56.92, H 5.78, N 17.47; found C 57.09, H 5.98, N 17.21;

[0044] ESI(+)-MS(m / z): [M+H]+701.58 (100%);

[0045] 1 H-NMR (300MHz, DMSO-d 6 ): δ(ppm) 10.80(s, 2H), 10.14(s, 2H), 8.89(d, J=8.1Hz, 2H), 8.62(d, J=8.1Hz, 2H), 8.28(s, 2H) , 8.04(d, J=7.5Hz, 2H), 7.91(m, 4H), 2.73(s, 4H), 2.55(s, 8H), 2.32(s, 4H), 1.68(s, 8H);

[0046] 13 C-NMR (75...

Embodiment 3

[0047] Embodiment 3: a kind of preparation of o-phenanthroline derivative

[0048] (1), (2) The process is the same as in Example 1

[0049] (3) (0.8 mL, 8.1 mmol) piperidine in step (3) of Example 1 was replaced with (0.7 g, 8.1 mmol) piperazine, and the resulting substance was separated by column chromatography, and the developing solvent was dichloromethane: methanol: Triethylamine=4:1:0.02, obtain o-phenanthroline derivative, the structural formula is:

[0050]

[0051] Its physical constants and spectral data are as follows:

[0052] Light yellow powder, molecular formula: C 38 H 42 N 12 O 4 2HCl 2H 2 O(839.77)(%): calcd.C 54.35, H 5.79, N20.01; found C 54.56, H 5.88, N 19.81;

[0053] ESI(+)-MS(m / z): [M+H]+731.58 (100%);

[0054] 1 H-NMR (300MHz, DMSO-d 6 )δ(ppm): 11.81(s, 2H), 10.20(s, 2H), 8.91(d, J=8.1Hz, 2H), 8.64(d, J=8.1Hz, 2H), 8.30(s, 2H) , 8.06(s, 2H), 7.92(s, 4H), 2.85(s, 4H), 2.78(s, 8H), 2.44(s, 4H), 2.26(m, 8H);

[0055] 13 C-NMR (75MHz, DMSO...

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Abstract

The invention provides a phenanthroline derivative and a preparation method thereof. the method comprises the following steps: firstly, 2,9-dioctyl phthalate-1,10 phenanthroline and 2,6-diaminopyridine react to obtain N,N'-dual(2-amino-6-pyridyl)-2,9-diamide-1,10-phenanthroline under the condition that EDCI and HOAT exist; secondly, the N,N'-dual(2-amino-6-pyridyl)-2,9-diamide-1,10-phenanthroline and 3-chloropropionylchloride react to obtain N,N'-dual(2-(3chlorine propionamido)-6-pyridyl)-2,9-diamide-1,10-phenanthroline; and finally, the N,N'-dual(2-(3chlorine propionamido)-6-pyridyl)-2,9-diamide-1,10-phenanthroline forms the phenanthroline derivative with piperidine, pyrrolidine or diethylene diamine. The derivative represents higher stability and bonding appetency to human telomere and promoter G-four-helix DNAs and high selectivity relative to double-helix DNA, can induce human telomere and promoter G-four-helix DNA to form an antiparallel structure, can effectively inhibit telomerase activity as well as growth and reproduction of HepG2 cancer cells, and can be used for preparation of antitumor drugs.

Description

technical field [0001] The present invention relates to a heterocyclic compound, in particular to an o-phenanthroline derivative and its preparation method and use, especially as an antitumor drug. Background technique [0002] Tumor is a major disease that seriously threatens human health and life, and has become the second leading cause of human death. In recent decades, the research and development of new anti-tumor drugs has achieved remarkable success, and a large number of drugs with new targets have been gradually applied in clinical practice. Among them, the research on anti-tumor drugs targeting G-quad helix DNA has attracted widespread attention. [0003] Telomeres are the special ends of linear chromosomes in eukaryotic cells, in which telomeric DNA is rich in guanine (G). The G-rich repeat sequence of human telomeric DNA is 5'-TTAGGG-3', about 3-6 kb in length, and its 3'-end is a single-stranded region of 100-200 bases. Crystallographic and NMR studies have sh...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/496A61K31/4545A61K31/444A61P35/00
Inventor 魏春英王彦波
Owner SHANXI UNIV
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