CN105884853B - Phospholipid analogues, Preparation method and use containing betulinic acid - Google Patents

Phospholipid analogues, Preparation method and use containing betulinic acid Download PDF

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Publication number
CN105884853B
CN105884853B CN201610217261.8A CN201610217261A CN105884853B CN 105884853 B CN105884853 B CN 105884853B CN 201610217261 A CN201610217261 A CN 201610217261A CN 105884853 B CN105884853 B CN 105884853B
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Prior art keywords
betulinic acid
phospholipid analogues
phosphocholines
glycerine
acid
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CN201610217261.8A
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Chinese (zh)
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CN105884853A (en
Inventor
丁为民
李雪薇
李坤骐
毕远桐
白林涛
谈东升
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Harbin University of Science and Technology
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Harbin University of Science and Technology
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J63/00Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008Expansion of ring D by one atom, e.g. D homo steroids

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

The invention provides formula(1)R in the shown phospholipid analogues containing betulinic acid, formula1It is selected from.Purposes present invention also offers the preparation method of such phospholipid analogues and on antineoplastic is prepared.

Description

Phospholipid analogues, Preparation method and use containing betulinic acid
Technical field
The present invention relates to pharmaceutical chemistry and therapeutic field, and in particular to phospholipid analogues, preparation method containing betulinic acid And its it is used as the purposes of antineoplastic.
Background technology
Betulinic acid(Betulinic acid write a Chinese character in simplified form BA)(Also known as Betulinic Acid, betulic acid)For acicular crystal, molecular formula: CR30RHR48RO3, molecular weight 456.71, molecular structural formula:
Betulinic acid belongs to the pentacyclic triterpene alkenes compound of lupinane type, and betulinic acid is a kind of substantially nontoxic antitumor Compound, what is carried out by lead compound of betulinic acid is semi-synthetic, obtains the excellent derivative of bioactivity.But, birch The problem of acid derivative slightly water-soluble, not yet solve so far, seriously hamper birch acid derivative pushing away in clinic Wide application.Part document given below is used as reference.
PCT/US2005/041043 2005.11.14
PCT/US2005/032363 2005.9.12
PCT/US2005/032460 2005.9.12
PCT/FI2007/050318 2007.6.1
PCT/AT2004/000045 2004.2.11
US5962527A 1999.10.5
US20020052352 2002.5.2
WO9629068A 1996.9.26
PCT/IN1999/000043 1999.9.9
Bioorganic & Medicinal Chemistry Letters 19 (2009) 4814-4817
Bioorganic & Medicinal Chemistry 17 (2009) 6241-6250
Bioorganic & Medicinal Chemistry 18 (2010) 4385-4396
Chemistry of Natural Compounds 6(2005) 692-700
Bioorganic & Medicinal Chemistry 13 (2005) 3447-3454。
The design feature of phosphatide is the hydrophilic radical of a phosphate and quaternary ammonium salt base composition, and by two compared with The hydrophobic group of long alkyl composition.Phospholipid molecule can in water self-assembling formation multilayer micro-capsule, every layer is double points of lipid Sublayer, micro-capsule is central to be separated between each layer by aqueous phase, due to the similar biomembrane of its structure, enters group easily by cell membrane Knit cell.
Single fatty acyl choline glycerophosphatide is combined with betulinic acid by chemical bonding effect, form betulinic acid-phosphatide multiple Compound, corresponding liposome medicament transmission system is made by self assembly.Betulinic acid can be solved to be insoluble in water, be difficult to by body The problem of absorption.
The content of the invention
It is an object of the present invention to provide the new antitumor activity of a class is strong, bioavilability is significantly improved contains birch The phospholipid analogues of wood acid.
It is a further object to provide the preparation method of such phospholipid analogues containing betulinic acid.
It is also another object of the present invention to provide application of such phospholipid analogues containing betulinic acid as antineoplastic.
To achieve these goals, the present invention is to provide with formula(1)The phospholipid analogues containing betulinic acid
(1)
Wherein, R1It is selected from
Present invention also offers the method for the phospholipid analogues containing betulinic acid described in preparation:Betulinic acid enters with succinic anhydride After row acylation, then the reaction with corresponding 1- fatty acyls-Sn- glycerine -3- phosphocholines, it is made and contains birch accordingly The phospholipid analogues of acid;Described 1- fatty acyl-Sn- glycerine -3- phosphocholines are selected from 1- stearoyl-Sn- glycerine -3- phosphorus Sour choline, 1- oleoyl-Sn- glycerine -3- phosphocholines, 1- palmityl-Sn- glycerine -3- phosphocholines.
The invention further relates to application of the phospholipid analogues containing betulinic acid in antineoplastic is prepared.
External activity screening experiment show the described phospholipid analogues containing betulinic acid have obvious antitumor action and Good dose-dependence.Using abortion syndrome HXB1309H as subject cell strain, betulinic acid is determined, containing betulinic acid Phospholipid analogues half-inhibition concentration(IC50), the results are shown in Table 1.
Table 1:The half-inhibition concentration of betulinic acid, the phospholipid analogues containing betulinic acid to XB1309
Embodiment
Elaboration is further retouched in detail to present invention work with reference to embodiment:
With formula(1)The phospholipid analogues containing betulinic acid
(1)
Wherein, R1It is selected from
The preparation method of the described phospholipid analogues containing betulinic acid:Betulinic acid carries out acylation with succinic anhydride Afterwards, then the reaction with corresponding 1- fatty acyls-Sn- glycerine -3- phosphocholines, the corresponding phosphatide containing betulinic acid is made similar Thing;Described 1- fatty acyl-Sn- glycerine -3- phosphocholines are selected from 1- stearoyl-Sn- glycerine -3- phosphocholines, 1- oil Acyl-Sn- glycerine -3- phosphocholines, 1- palmityl-Sn- glycerine -3- phosphocholines.
Application of the described phospholipid analogues containing betulinic acid in antineoplastic is prepared.
The phospholipid analogues containing betulinic acid and preparation method of the present invention are described in more detail in the following example, but real Example is applied not to be construed as limiting the invention.
Embodiment 1 prepares 3-O- succinic acid list acyl betulinic acids
By 4.57 grams(0.01 mole)Betulinol is dissolved in 200 milliliters of dichloromethane, adds 5 milliliters of triethylamines, 0.98 gram (0.01 mole)Succinic anhydride, is heated to reflux 8 hours, cooling, recovery section solvent, and Liquid Residue adds 200 milliliters of ethanol, 3 millis The aqueous hydrochloric acid solution of 5 mol/Ls is risen, stirring adds frozen water after 1 hour, separate out a large amount of white solids, use dichloromethane(100 millis Rise × 3)Extract, washing, anhydrous sodium sulfate drying, filtering, steaming vibrating dichloromethane, residue silica gel column chromatography(Dichloromethane:Second Acetoacetic ester=1:1), obtain 3.82 grams of milky 3-O- succinic acid list acyls betulinic acid, yield 69%.
1- stearoyls-the 2- of embodiment 2(3-O- succinyl betulinic acids)Glycerine -3- phosphocholines(Phosphatide containing betulinic acid Analog)
By 0.557 gram(0.001 mole)3-O- succinic acid list acyl betulinic acids are dissolved in 50 milliliters of dichloromethane, are added 0.288 gram(0.0015 mole)1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, 0.01 gram of 4- dimethylamino pyrrole Pyridine, at room temperature, stirring add 0.523 gram after 3 hours(0.001 mole)1- stearoyl-Sn- glycerine -3- phosphocholines, room temperature Under, stir 48 hours, vacuum distillation steams dichloromethane, and residue washs 5 times, silica gel column layer with 10% aqueous citric acid solution Analysis(Methanol:Chloroform:Water=25:65:4), obtain white 1- stearoyls -2-(3-O- succinyl betulinic acids)Glycerine -3- phosphocholines 0.78 gram(That is phospholipid analogues containing betulinic acid), yield 73%.

Claims (3)

1. formula(1)The shown phospholipid analogues containing betulinic acid
(1)
Wherein, R1Selected from-OCOCH2(CH2)15CH3、—OCOCH2(CH2)6CH=CH(CH2)7CH3
—OCOCH2(CH2)13CH3
2. a kind of method of the phospholipid analogues containing betulinic acid prepared described in claim 1, it is characterised in that:Betulinic acid and fourth Dicarboxylic anhydride is carried out after acylation, then is reacted with corresponding 1- fatty acyls-Sn- glycerine -3- phosphocholines, is made corresponding Phospholipid analogues containing betulinic acid;Described 1- fatty acyl-Sn- glycerine -3- phosphocholines are selected from 1- stearoyls-Sn- the third three Alcohol -3- phosphocholines, 1- oleoyl-Sn- glycerine -3- phosphocholines, 1- palmityl-Sn- glycerine -3- phosphocholines.
3. application of the phospholipid analogues containing betulinic acid in antineoplastic is prepared as claimed in claim 1.
CN201610217261.8A 2016-04-11 2016-04-11 Phospholipid analogues, Preparation method and use containing betulinic acid Expired - Fee Related CN105884853B (en)

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Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1869063A2 (en) * 2005-03-29 2007-12-26 Regents Of The University Of Minnesota Methods of manufacturing bioactive 3-esters of betulinic aldehyde and betulinic acid
CN102603858B (en) * 2012-03-02 2014-07-02 东北林业大学 Azacycle-containing derivative of betulinol, preparation method thereof, and purpose thereof
EP2680005A1 (en) * 2012-06-28 2014-01-01 Rheinische Friedrich-Wilhelms-Universität Bonn Lipid analysis

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