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Eucommia ulmoides lignans and application of Eucommia ulmoides in preparation of Hsp90alpha inhibitor and anti-tumor drug

An anti-tumor drug, Eucommia lignan technology, applied in anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve problems such as poor stability in vivo, hepatotoxicity, and unsatisfactory clinical efficacy, and achieve excellent anti-tumor activity, Prominent effect of inhibitory activity

Inactive Publication Date: 2018-05-18
CENT SOUTH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the first-generation inhibitors have two fatal shortcomings: poor stability in vivo and severe liver toxicity
At present, the HSP90 inhibitors that have entered the third phase of clinical development include Synta pharmaceutical’s Ganetespib and Infinity’s Retaspimycin, etc., but most of the clinical efficacy is not satisfactory, indicating that HSP90 inhibitors may not be a broad-spectrum anticancer drug

Method used

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  • Eucommia ulmoides lignans and application of Eucommia ulmoides in preparation of Hsp90alpha inhibitor and anti-tumor drug
  • Eucommia ulmoides lignans and application of Eucommia ulmoides in preparation of Hsp90alpha inhibitor and anti-tumor drug
  • Eucommia ulmoides lignans and application of Eucommia ulmoides in preparation of Hsp90alpha inhibitor and anti-tumor drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Take 2 kg of bark of Eucommia ulmoides (with the outer skin removed), extract twice with 8L of 65% ethanol under reflux, each time for 1 hour, filter, combine the two extracts and concentrate to 800ml. Mix and load the sample with D101 macroporous resin (column volume of macroporous resin is 3 L), wash with water for 3 times of column volume, continue to wash with 1% ammonia water for 3 times of column volume, and then wash with water until neutral. Elute with 20% ethanol for 2 column volumes and 45% ethanol for 2.5 column volumes. The 45% ethanol eluate was concentrated to 600ml. The eluate was concentrated and dried to a powder. Using pinoresinol diglucoside as a control, the content of lignans in the extract was 85% as detected by ultraviolet light, and the content of pinoresinol diglucoside as detected by HPLC was 12.5%.

Embodiment 2

[0030] After the bark of Eucommia ulmoides was crushed, add 9L of 60% ethanol to reflux for extraction for 1 hour, filter, add 7L of 60% ethanol to the filter residue, extract for 1 hour, filter, combine the two extracts, concentrate until there is no ethanol smell, and obtain a concentrated solution of about 3L. The concentrated solution was passed through an AB-8 macroporous adsorption resin column, first eluted with 5L of water, and then eluted with 7L of 60% ethanol, collected the 60% ethanol eluate, concentrated to 150ml, slowly added to 450ml of water, filtered, concentrated, A dry solid powder was obtained. Using pinoresinol diglucoside as a control, the content of lignans in the extract was 75% as detected by ultraviolet light, and the content of pinoresinol diglucoside as detected by HPLC was 9.5%.

[0031]The eucommia lignan extracts obtained in Examples 1 and 2 were used to prepare Hsp90α inhibitors respectively, and had good Hsp90α inhibitory effect.

Embodiment 3

[0033] Experimental Study on Inhibition of Recombinant Human Heat Shock Protein 90α C-terminal Enzyme Activity by Eucommia Lignans

[0034] 1. Experimental materials

[0035] Reagents: Eucommia lignans, novobiocin, DMSO, Hsp90αC-terminal, ST-labeled PPID cyclophilin D, Alphascreen Streptavidin-conjugated donor beads (donor), Alphascreen anti-GSTAcceptor beads (acceptor), hydroxyethyl Piperazineethanesulfonic acid, sodium chloride, bovine serum albumin.

[0036] Instruments: Tecan Infinite M1000 PRO multifunctional microplate reader, pipette.

[0037] 2. Experimental method

[0038] The enzymatic activity of recombinant human heat shock protein 90α was measured by TR-FRET technology, and the TR-FRET signal intensity was related to the number of PPID ligands bound to Hsp90α in the reaction system. The compound was dissolved in 10% DMSO, and 2 μl of the drug solution was added to a 20 μl reaction system (25 mM HEPES pH 7.4, 100 mM NaCl, 0.1% bovine serum albumin, Hsp90α) so th...

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Abstract

The invention discloses an eucommia ulmoides lignans and an application of eucommia ulmoides in preparation of Hsp90alpha inhibitor and anti-tumor drug, in particular to the application in preparationof heat shock protein 90 alpha (Hsp 90 alpha) selective C-terminal inbhibitor and use in preventing breast cancer and prostate cancer. The invention finds that the eucommia ulmoides lignans and its extractive extracted and prepared by using eucommia ulmoides as raw material can inhibit enzymatic activity of recombined human heat shock protein 90 alpha-C terminal; compared with a positive controldrug novobiocin, the eucommia ulmoides lignans show more excellent anti-cancer activity.

Description

technical field [0001] The invention belongs to the technical field of application of extracts of traditional Chinese medicines, and specifically relates to the application of eucommia lignans and eucommia extracts in the preparation of Hsp90α inhibitors and antitumor drugs, in particular to eucommia lignans and eucommia lignans prepared by extracting and preparing Eucommia ulmoides as raw materials Application of its extract in preparation of selective Hsp90α C-terminal inhibitor. Background technique [0002] Eucommia ulmoides Oliv., also known as Kapok, Sixian, Sizhong, and Sijinshu, is a deciduous tree of a single family and a single genus. It is a "living fossil" left over from the glacier movement in the third century. Eucommia ulmoides is a unique economic tree species in my country. Its wild distribution center is in the central region of China, and it is widely planted in Hunan, Hubei, Henan, Shanxi, Sichuan, Guizhou, Yunnan and other provinces. Eucommia has a medi...

Claims

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Application Information

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IPC IPC(8): A61K36/46A61P35/00A61K129/00
CPCA61K36/46
Inventor 周露萍欧阳冬生黄琪陈露露谭志荣周淦
Owner CENT SOUTH UNIV
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