CN106866955B - A kind of isoalantolactone derivative containing polyethylene glycol groups and its preparation and application - Google Patents

A kind of isoalantolactone derivative containing polyethylene glycol groups and its preparation and application Download PDF

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CN106866955B
CN106866955B CN201710029437.1A CN201710029437A CN106866955B CN 106866955 B CN106866955 B CN 106866955B CN 201710029437 A CN201710029437 A CN 201710029437A CN 106866955 B CN106866955 B CN 106866955B
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mmo1
preparation
isoalantolactone
polyethylene glycol
containing polyethylene
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CN106866955A (en
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史兰香
刘斯婕
张冀男
张宝华
郭瑞霞
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SHENYANG SUNSHINE PHARMACEUTICAL Co.,Ltd.
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Shijiazhuang University
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/337—Polymers modified by chemical after-treatment with organic compounds containing other elements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/334—Polymers modified by chemical after-treatment with organic compounds containing sulfur
    • C08G65/3348—Polymers modified by chemical after-treatment with organic compounds containing sulfur containing nitrogen in addition to sulfur

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
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  • Epidemiology (AREA)
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  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to a kind of isoalantolactone derivative and its preparation method and application containing polyethylene glycol groups.The beneficial effects of the present invention are provide a kind of new isoalantolactone derivative, with anti-tumor activity；Isoalantolactone derivative containing polyethylene glycol groups of the invention has hydrophily, is applicable in preparation several formulations, the bioavilability of isoalantolactone can be improved.

Description

A kind of isoalantolactone derivative containing polyethylene glycol groups and its preparation and application
Technical field
The present invention relates to the derivatives of isoalantolactone, and its application in pharmacy, belong to pharmaceutical technology field.
Background technique
Quercetin is the important component of flavone compound, has extensive pharmacological action and bioactivity, such as anti- Oxidation and scavenging activated oxygen, blood pressure lowering, Ischemic myocardium, avoid ischemia-reperfusion damage funeral, enhancing immune function and anticancer, Antiviral and analgesic activity etc..In recent years, Quercetin is to human ovarian cancer, breast cancer, the proliferation of leucocyte, gastroenteric tumor cell Inhibiting effect, be concerned.Using Quercetin as parent, structural modification is carried out to it, improves its pharmaceutical activity, it is novel to finding Drug has important meaning.
Elecampane (Inula helenium) alias Qi's radix aucklandiae is composite family (Compositae) Inulaplants, for many years Sward sheet, root hyoscine.Elecampane is used for eliminating the phlegm, antibechic and antibacterial in ancient prescription.Recent study discovery, times in elecampane Hemiterpene-isoalantolactone constituents have the new roles such as anti-tumour cell proliferative effect and Ad tuberculosis.But due to Isoalantolactone is not soluble in water, and bioavilability in vivo is low, limits its application.
Isoalantolactone physiological activity is extensive, and internal position is more, and specificity is poor.Poly- second two is introduced in its structure Alcohol can form hydrophilic compounds, improve its absorption, meanwhile, the access of the polyethylene glycol of high molecular weight, it is possible to change its Dynamic metabolism mode improves its antitumaous effect.
Summary of the invention
The purpose of the present invention is to provide a kind of isoalantolactone derivative containing polyethylene glycol groups, with anticancer Effect, be hydrophilic compounds.
The preparation of another object of the present invention is to provide the above-mentioned isoalantolactone derivative containing polyethylene glycol groups Method.
The purposes of a further object of the present invention is to provide the above-mentioned isoalantolactone derivative containing polyethylene glycol groups.
The present invention will be described in detail below.
Isoalantolactone derivative provided by the invention containing polyethylene glycol groups, including its stereoisomer and interconversion Isomers, structure are as follows:
In formula, R is alkyl, the alkyl replaced by halogen, hydroxyl, carboxyl, ester group, amino, acyl group, aryl, substituted virtue Base, aromatic heterocyclic, heterocycle, ghiourea group, urea groups.
The isoalantolactone derivative specific example structure containing polyethylene glycol groups is as follows:
。
The present invention also provides the preparation methods of above compound:
In formula, R is alkyl, the alkyl replaced by halogen, hydroxyl, carboxyl, ester group, amino, acyl group, aryl, substituted virtue Base, aromatic heterocyclic, heterocycle, ghiourea group, urea groups.
Isoalantolactone derivative containing polyethylene glycol groups of the invention has anticancer activity, and what is had is water-soluble Property, it is applicable in several formulations.
The present invention is further illustrated by following embodiment, but should be noted that the scope of the present invention is not implemented by these Any restrictions of example.
Specific embodiment
Embodiment 1
The preparation of compound (1)
Benzylamine (23.5mg, 0.22 mmo1) is dissolved in 5mL dehydrated alcohol, is stirred at room temperature, and isoalantolactone is added (46.4mg, 0.2mmo1) reacts at room temperature 6h, and end of reaction is concentrated under reduced pressure, and solid, filtering is precipitated, and acetone recrystallization obtains intermediate Body (a), yield 80%, by intermediate (a) (33.9mg, 0.1 mmo1), K2CO3(27.6mg, 0.2 mmo1) and PEG600 (60.0mg, 0.1 mmo1) is added in 10mL dehydrated alcohol, and mustargen phosphinylidyne dichloro (28.9mg, 0.1 mmo1) is added dropwise in stirring 5mL ethanol solution reacts at room temperature 3h, filtering, and filtrate decompression is concentrated into certain volume, the ether of 10 times of volumes is added, and analyses It crystallizes, filters out, ether washing is dry, obtains crude product.Crude product plus a certain amount of ethyl alcohol are dissolved, the second of 10 times of volumes is added Ether crystallization, is filtered, dry, obtains compound (1).
Embodiment 2
The preparation of compound (2)
The benzylamine (21.4mg, 0.2 mmo1) in embodiment 1 is replaced with l-Alanine methyl esters (25.9mg, 0.22 mmo1), Other operations obtain intermediate (b) with embodiment 1, and yield 83% replaces embodiment 1 with intermediate (b) (36.6mg, 0.1 mmo1) Intermediate (a) (33.9mg, 0.1 mmo1), it is other operation with embodiment 1, obtain compound (2).
Embodiment 3
The preparation of compound (3)
The benzylamine (21.4mg, 0.2 mmo1) in embodiment 1, Qi Tacao are replaced with ethanol amine (13.4mg, 0.22 mmo1) Make to obtain intermediate (c), yield 78%, with intermediate (c) (29.3mg, 0.1 mmo1) and PEG2000 with embodiment 1 (200.0mg, 0.1 mmo1) replace embodiment 1 intermediate (a) (33.9mg, 0.1 mmo1) and PEG600 (60.0mg, 0.1 Mmo1), other operations obtain compound (3) with embodiment 1.
Embodiment 4
The preparation of compound (4)
The benzylamine (21.4mg, 0.2 mmo1) in embodiment 1 is replaced with 2-chloroethyl amine (17.5mg, 0.22 mmo1), it is other Operation obtains intermediate (d) with embodiment 1, and yield 78% is replaced in embodiment 1 with intermediate (d) (31.1mg, 0.1 mmo1) Mesosome (a) (33.9mg, 0.1 mmo1), other operations obtain compound (4) with embodiment 1.
Embodiment 5
The preparation of compound (5)
The benzylamine (21.4mg, 0.2 mmo1) in embodiment 1 is replaced with 4-aminopyridine (20.7mg, 0.22 mmo1), It is operated with embodiment 1, obtains intermediate (e), yield 43%, with intermediate (e) (32.6mg, 0.1 mmo1) and PEG4000 (400.0mg, 0.1 mmo1) replace embodiment 1 intermediate (a) (33.9mg, 0.1 mmo1) and PEG600 (60.0mg, 0.1 Mmo1), other operations obtain compound (5) with embodiment 1.
Embodiment 6
The preparation of compound (6)
The benzylamine (21.4mg, 0.2 mmo1) in embodiment 1 is replaced with 40% methylamine (17.0mg, 0.22 mmo1), it is other Operation obtains intermediate (f), yield 74%, with intermediate (f) (32.6mg, 0.1 mmo1) and PEG4000 with embodiment 1 (400.0mg, 0.1 mmo1) replace embodiment 1 intermediate (a) (26.3mg, 0.1 mmo1) and PEG600 (60.0mg, 0.1 Mmo1), other operations obtain compound (6) with embodiment 1.
Embodiment 7
The preparation of compound (7)
The benzylamine (21.4mg, 0.2 mmo1) in embodiment 1, Qi Tacao are replaced with semicarbazides (16.5mg, 0.22 mmo1) Make to obtain intermediate (g), yield 85%, with intermediate (g) (30.7mg, 0.1 mmo1) and PEG4000 with embodiment 1 (400.0mg, 0.1 mmo1) replace embodiment 1 intermediate (a) (33.9mg, 0.1 mmo1) and PEG600 (60.0mg, 0.1 Mmo1), other operations obtain compound (7) with embodiment 1.
Embodiment 8
The preparation of compound (8)
The benzylamine (21.4mg, 0.2 mmo1) in embodiment 1 is replaced with thiosemicarbazides (20.0mg, 0.22 mmo1), it is other Operation obtains intermediate (h), yield 86% with embodiment 1.
Embodiment 1 is replaced with intermediate (h) (32.3mg, 0.1 mmo1) and PEG6000 (600.0mg, 0.1 mmo1) Intermediate (a) (33.9mg, 0.1 mmo1) and PEG600 (60.0mg, 0.1 mmo1), other operations obtain chemical combination with embodiment 1 Object (8).
Embodiment 9
The preparation of compound (9)
The benzylamine (21.4mg, 0.2 mmo1) in embodiment 1 is replaced with glycine methyl ester (19.6mg, 0.22 mmo1), It is operated with embodiment 1, obtains intermediate (i), yield 79%, with intermediate (i) (32.1mg, 0.1 mmo1) and PEG4000 (400.0mg, 0.1 mmo1) replace embodiment 1 intermediate (a) (33.9mg, 0.1 mmo1) and PEG600 (60.0mg, 0.1 Mmo1), other operations obtain compound (9) with embodiment 1.
Embodiment 10
Isoalantolactone derivative anti-tumor activity containing polyethylene glycol groups
Isoalantolactone derivative containing polyethylene glycol groups stores liquid with the raw medicine that aqua sterilisa is configured to 10mg/ml: 4 DEG C of preservations face the used time with the dilution of RPMI-1640 culture medium, 0.22 μm of filtering with microporous membrane.HO-8910 (Proliferation of Human Ovarian Cell), U251 (human glioma cell line cell), T-98(human brain neuroglial cytoma), MCF-7 (human breast cancer cell), KT (people Breast cancer cell), HEC-1(people's endometrial carcinoma cell) purchase in Shanghai Inst. of Life Science, CAS cell Library.Each cell line is with the RPMI-1640 culture medium culture containing 10% top grade fetal calf serum, condition of culture 5%C02、37 ℃。
Isoalantolactone and its derivative are detected to HO-8910 cell, U251 cell, T-98 cell, MCF- with mtt assay 7 cells, KT cell, HEC-1 cell Proliferation inhibiting effect.Logarithmic growth phase cell, adjustment concentration are 6x103A/every hole, It is inoculated in 96 well culture plates, every hole 200 μ l, 5%C02, cultivate in 37 DEG C of incubators of saturated humidity.It is adherent to cell, experiment Group be added the diluted isoalantolactone derivative of RPMll640 culture medium to final concentration respectively O.5, l, 2,4,8,16,32,64, Complete medium is respectively added in 100 μ g/ml, solvent control group, and every hole final volume is 200 μ 1, and every group sets 6 multiple holes.After culture for 24 hours Culture plate is taken out, morphological observation and is taken pictures under inverted microscope.5mg/ml MTT (the every hole 20 μ 1/) is added to continue to cultivate 4h is outwelled and is cleaned every hole with PBS after original fluid, is added in DMSO (150 hole μ L/), shake it is even dissolve precipitating, 20min at room temperature 96 orifice plates are placed in microplate reader after (purplish red solution), survey each hole OD value (OD value) at 492nm wavelength with microplate reader, Calculate each class mean.By formula:
The growth inhibition ratio of GI (growth inhibition ratio)=l- (medicine group OD value/control group OD value) × 100% calculating each group. According to as a result, calculating IC using SPSSl9.050 (table 1).As the result is shown: compared with isoalantolactone and cis-platinum, the different soil Increasing of the constuslactone derivative to HO-8910 cell, U251 cell, T-98 cell, MCF-7 cell, KT cell, HEC-1 cell Growing has inhibiting effect.

Claims (3)

1. a kind of isoalantolactone derivative containing polyethylene glycol groups, the derivative be it is below any one:
2. the isoalantolactone derivative described in claim 1 containing polyethylene glycol groups, preparation method include following step It is rapid:
In formula, RNH2For benzylamine, l-Alanine methyl esters, ethanol amine, 2-chloroethyl amine, 4- amido pyridine, methylamine, semicarbazides, amido sulphur Urea or glycine methyl ester.
3. the isoalantolactone derivative described in claim 1 containing polyethylene glycol groups, in preparation for treating cancer Application in preparation.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101869560A (en) * 2009-04-22 2010-10-27 刘华 Isoalantolactone amino derivative and application of salt thereof in preparing anti-tumor medicament
WO2015130081A1 (en) * 2014-02-25 2015-09-03 서울대학교산학협력단 Pharmaceutical composition for preventing and treating breast cancer containing inula helenium hexane fraction having stat3 inhibitory activity or compound isolated therefrom as active ingredient
CN105287627A (en) * 2015-10-23 2016-02-03 武汉大学 Unsaturated lactone ingredient and chemotherapy drug composition and application thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101681973B1 (en) * 2014-05-30 2016-12-05 경북대학교 산학협력단 Composition for preventing or treating memory, cognition or learning disorder comprising sesquiterpene

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101869560A (en) * 2009-04-22 2010-10-27 刘华 Isoalantolactone amino derivative and application of salt thereof in preparing anti-tumor medicament
WO2015130081A1 (en) * 2014-02-25 2015-09-03 서울대학교산학협력단 Pharmaceutical composition for preventing and treating breast cancer containing inula helenium hexane fraction having stat3 inhibitory activity or compound isolated therefrom as active ingredient
CN105287627A (en) * 2015-10-23 2016-02-03 武汉大学 Unsaturated lactone ingredient and chemotherapy drug composition and application thereof

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