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3-deazaneplanocin derivatives

A technology for deazapyridine and drugs, which can be applied in the directions of sugar derivatives, drug combinations, active ingredients of heterocyclic compounds, etc., and can solve the problems of poor bioavailability, short half-life, and not being a candidate drug.

Inactive Publication Date: 2012-03-07
AGENCY FOR SCI TECH & RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, DZNep itself may not be an ideal drug candidate due to its short half-life and poor bioavailability

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] Example 1: 2', 3'-O-isopropylidene-3-deazifialin A

[0130] A mixture of 3-deazifiadin A hydrochloride (DZnep) (20 mg, 0.067 mmol), 0.5 mL of DMF, and 1 mL of 1 M HCl in diethyl ether was stirred in 5 mL of acetone for 18 h at room temperature, then washed with tris Ethylamine (TEA) for neutralization. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, MeOH / TEA / DCM = 10:10:80) to afford 18 mg (89%) of the title compound. 1 H NMR (MeOD, 400MHz): δ8.175(s, 1H), 7.68(d, J=6.4Hz, 1H), 7.12(d, J=6.4Hz, 1H), 5.55(s, 1H), 5.36( d,J=6.0Hz,1H), 4.68(d,J=6.0Hz,1H), 4.365(s,2H), 1.48(s,3H), 1.35(s,3H); 15 h 18 N 4 o 3 ESI MS m / z calcd: 302.14, found: 303.13 (M+H) +

Embodiment 2

[0131] Embodiment 2: 3-deazamonocycin hydrochloride (D2)

[0132] To a solution of 3-denitrovialin A hydrochloride (DZnep) (15 mg, 0.05 mmol) in 2 mL of MeOH was added 10 mg of 10% palladium on charcoal. The suspension was stirred at room temperature for 18 hours under hydrogen atmosphere. The mixture was filtered through a pad of celite to remove palladium. The product was purified by pre-prepared LCMS in 50% yield (ratio of two enantiomers = 1:1). C 12 h 16 N 4 o 3 ESI MS m / z calcd: 264.12, found: 265.11 (M+H) +

Embodiment 3

[0133] Example 3: (1R, 4R, 5S)-9-N-[3-(hydroxymethyl)-4,5-O,O-isopropylidene-2-cyclopentenyl-L-yl]-N 6 , N 6 -Bis-(tert-butoxycarbonyl)adenine

[0134]

[0135] At room temperature, to (1R,4R,5S)-9-N-[3-(trityloxymethyl)-4,5-O,O-isopropylidene-2-cyclopentene-L -base]-N 6 , N 6 -Bis-(tert-butoxycarbonyl)adenine [Tetrahedron lett.2006, (47) 9187-9189.] (225 mg, 0.45 mmol) in 20 mL of acetone was added 2,2-dimethoxypropane (20 mL) and p-Toluenesulfonic acid monohydrate (42.8 mg, 0.225 mmol). The acidic solution was stirred at room temperature for 18 hours. The reaction mixture was quenched with 300 mg of solid sodium bicarbonate. The solvent was evaporated in vacuo, and water (20 mL) and DCM (20 mL) were added to the residue. The two phases were separated. The aqueous phase was extracted by DCM (3 x 20 mL). with MgSO 4 The combined organic layers were dried and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether / EtOAc = 2:...

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Abstract

This invention describes the series of compounds based on the 3-deazaneplanocin A (DZNep) core structure designed to inhibit the function of Polycomb repressive complex 2 (PRC2) proteins.

Description

technical field [0001] The present invention relates to the synthesis and application of 3-deazavidin derivatives. Background of the invention [0002] Cancer epigenetic regulation involves complex biological processes including DNA methylation and histone modifications, such as histone deacetylation and histone methylation. Small molecules targeting epigenetic processes such as histone deacetylation are emerging as a new class of anticancer agents with satisfactory effects in clinical studies. In 2006, the histone deacetylase inhibitor (HDI) vorinostat (also known as SAHA) was approved for the treatment of cutaneous T-cell lymphoma, a type of skin cancer. In addition to histone deacetylation, histone methylation also plays an important role in cancer epigenetics. In particular, histone methylation induced by polycomb family (Pcg) (Polycomb group) proteins such as EZH2, which are overexpressed in various human cancers, is thought to be part of the mechanism that triggers c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/34A61K31/52C07D495/04C07H19/167A61K31/7076A61K31/437A61P35/00C07D471/04
CPCC07D471/04C07D473/34A61K31/437A61K31/52A61K31/7076A61P35/00A61P43/00C07H15/04
Inventor 蔡丽玲谭国伟杨海燕于强阮遵明
Owner AGENCY FOR SCI TECH & RES
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