CN104257641A - C36 polyacetylene compound and preparation and application of C36 polyacetylene compound - Google Patents

C36 polyacetylene compound and preparation and application of C36 polyacetylene compound Download PDF

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Publication number
CN104257641A
CN104257641A CN201410392554.0A CN201410392554A CN104257641A CN 104257641 A CN104257641 A CN 104257641A CN 201410392554 A CN201410392554 A CN 201410392554A CN 104257641 A CN104257641 A CN 104257641A
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preparation
formula
tumor
compound
polyacetylene compound
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CN201410392554.0A
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CN104257641B (en
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海萍
高原
任福才
魏国柱
王飞
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BIOBIOPHA Co Ltd
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BIOBIOPHA Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
    • C07C47/26—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups
    • C07C47/263—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups acyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption

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

Abstract

The invention provides a C36 polyacetylene compound (as shown in the formula I) with the anti-neoplastic activity, a preparation method of the C36 polyacetylene compound and application of the C36 polyacetylene compound and pharmaceutical compositions of the C36 polyacetylene compound to preparing medicine for treating cancers.

Description

A kind of C 36polyacetylene compound and Synthesis and applications thereof
Technical field
The invention belongs to medical compounds and field of pharmacology, particularly, relate to a kind of C 36polyacetylene compound BBP865, its preparation method, the pharmaceutical composition being active component with this compound, and the application in the medicine of preparation treatment tumor of this compound and pharmaceutical composition thereof.
Background technology
White bright Radix Angelicae Pubescentis is Umbelliferae (Umbelliferae) heracleum hemsleyanum michaux (Heracleum) herbaceos perennial, and China is mainly distributed in the provinces and regions such as Tibet, Sichuan, Yunnan; Mainly be distributed in the ground such as Nepal, Pakistan abroad.Usually hillside sylvan life and roadside is grown on, height above sea level 2000 – 4200 meters of regions.The characteristic constituents of this plant is furocoumarin.
Tumor be phalangeal cell under the effect of tumorigenesis factor, gene changes, and loses the normal regulation of cell growth, causes paraplasm.Tumor can be divided into the optimum and large class of malignant tumor two, and the latter grows rapidly, can be transferred to other position of health, destroys normal organ 26S Proteasome Structure and Function, life-threatening.
Surgical operation, X-ray therapy, chemotherapy are mainly comprised to the treatment means of tumor.Advancing by leaps and bounds in recent years along with nano molecular medical science and Protocols in Molecular Biology, innovation and the integrated use of the elaboration of tumor mechanism, the searching of antitumor target spot, the exploitation of new type antineoplastic medicine and treatment means have had significant progress, and tumor patient life span obviously extends.But the treatment accounting for the solid tumor of malignant tumor more than 90% of serious threat human life health not yet reaches satisfied curative effect, still have massive tumor patient because finally causing Endodontic failure to the reactionless or drug resistance for the treatment of.Therefore, find and development of new antitumor drug remain people to continue faced by problem.
Have no compd B BP865 involved in the present invention in prior art and treating the report in tumor as effective ingredient, and this compound has the report of anti-tumor activity.
Summary of the invention
The object of the present invention is to provide a kind of C with medical value 36polyacetylene compound BBP865.
Another object of the present invention is to provide a kind of method extracting the compounds of this invention from white bright Radix Angelicae Pubescentis (Heracleum candicans) plant.
A further object of the present invention is to provide that a kind of to be active component with formula I be used for the treatment of the pharmaceutical composition with prophylaxis of tumours, and this compound and the application of compositions in the medicine of preparation treatment tumor.
To achieve these goals, the invention provides following technical scheme:
Be used for the treatment of the medicine of tumor, wherein containing the treatment formula I of anti-tumor effective amount and pharmaceutically suitable carrier and/or excipient.
The compounds of this invention BBP865 can be converted into pharmaceutically acceptable derivates.As α, beta-unsaturated aldehyde introduces the chain containing 4 ~ 10 carbon by reversal of the Michael addition (Michael reaction); Hydroxyl can adopt known method carry out acidylate (as formylated, acetylation, benzoylation, sulfonylation), halogenation or be oxidized to ketone group, and ketone group can form acetal with ethylene glycol effect further; The method esterification in document can be adopted to form amino-acid ester (amino in aminoacid can be protected, and goes protection after esterification).
When the compounds of this invention is used as on medicine, directly can uses, or use with the form of pharmaceutical composition.This pharmaceutical composition contains 0.1 ~ 99%, and be preferably the compounds of this invention of 0.5 ~ 90%, all the other are acceptable salt on materia medica, or pharmaceutically suitable carrier of and inertia nontoxic to humans and animals and/or excipient.
Described pharmaceutical carrier or excipient are that one or more are selected from solid, semisolid and liquid diluent, filler and pharmaceutical preparation adjuvant.Described pharmaceutical composition is used with the form of per weight dose.Medicine of the present invention can oral administration and injection (quiet note, intramuscular injection) two kinds of form administrations.
Oral its solid available or liquid preparation, as powder, tablet, sugar-coat agent, capsule, solution, syrup, drop pill etc.
Inject its solid available or liquid preparation, as injectable powder, solution shape injection etc.
In order to understand essence of the present invention better, its application in field of medicaments will be described by the biological activity result of formula I of the present invention below.
Mtt assay cytoactive detects:
MTT full name is 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, is a kind of dyestuff of yellow color.In living cells mitochondrion succinate dehydrogenase can metabolism reduction MTT, simultaneously under the effect of cytochrome C, (content of Formazan) ， formazan can measure at 570nm place by microplate reader to generate blue (or bluish violet) water-fast formazan.Under normal conditions, formazan growing amount is directly proportional to viable count, therefore can infer according to optical density OD value the number living cells.
Experimental technique:
1. inoculating cell: be made into individual cells suspension with the culture fluid (DMEM or RMPI1640) containing 10% hyclone, be inoculated into 96 orifice plates with every hole 10000-20000 cell, every pore volume 100 μ l, attached cell shifts to an earlier date 12 hours inoculated and cultured.
2. add testing compound solution (fixed concentration 40 μMs of primary dcreening operations suppress the compound near 50% to establish 5 concentration to enter gradient in this concentration to growth of tumour cell and sieve again), every hole final volume 200 μ l, 3 multiple holes are all established in often kind of process.
3. develop the color: cultivate after 48 hours for 37 degrees Celsius, every hole adds MTT solution 20 μ l.Continue to hatch 4 hours, stop cultivating, careful suction abandons in hole that culture supernatant 100 μ l is to avoid cell loss, and every hole adds the SDS100 μ l of 20%, and night incubation (temperature 37 DEG C), makes crystal fully melt.
4. colorimetric: select 595nm wavelength, enzyme-linked immunosorbent assay instrument (Bio-Rad680) reads each hole absorbance value, record result, take concentration as abscissa, cell survival rate is that vertical coordinate draws cell growth curve, the IC of application two-point method (Reed and Muench method) computerized compound 50value.
Experimental result is in table 1:
Table 1.BBP865 is to the half growth inhibitory concentration IC of tumor cell line 50(μM)
Above-mentioned result of the test shows, compd B BP865 has significant anti-tumor activity, has but particularly exceeded clinical antitumor agents cisplatin to the inhibit activities of breast carcinoma, hepatocarcinoma, colon cancer cell.
Detailed description of the invention
Further flesh and blood of the present invention is described below in conjunction with embodiment, but content of the present invention is not limited thereto.
Embodiment 1:
The preparation method of the compounds of this invention and structural characterization:
1. preparation method:
The white bright Radix Angelicae Pubescentis dry rhizome of 9.0kg extracts 3 times with under 95% ethanol room temperature after crushed, and each extraction 3 to 4 days, merge extractive liquid, concentrating under reduced pressure, obtains 980g extractum.Gained extractum is separated through silica gel column chromatography again, carries out gradient elution, in petroleum ether/acetone (5:1) eluting Duan get Yi component with petroleum ether/acetone solvent system.This component through silica gel (chloroform/acetone=100:1) and Sephadex LH-20 (methanol) column chromatography for separation, obtains compd B BP865 sterling 23mg further.
2. structural characterization:
Colorless oil; Molecular formula C 36h 46o 5; ESIMS (pos.): m/z581 [M+Na] +; HRESIMS:m/z581.3239 [M+Na] +(581.3243calcd for C 36h 46o 5na); + 128.2 (c0.10, CHCl 3); IR (KBr) ν max3431,2927,2855,1707,1635,1462,1406,1384,1300,1262,1116,1022,988,934,574cm – 1; Nmr spectrum data is in table 2.
Nmr spectrum data (the CDCl of table 2.BBP865 3middle mensuration)
The chemical structural formula of compd B BP865 is:
Embodiment 2:
Tablet: embodiment 1 gained compound 10mg, lactose 180mg, starch 55mg, magnesium stearate 5mg;
Preparation method: by compound, lactose, starch mixing, evenly moistening with water, sieves the mixture after moistening drying, after sieve, adds magnesium stearate, then by mixture tabletting, and every sheet heavy 250mg, wherein compounds content 10mg.
Embodiment 3:
Capsule: embodiment 1 gained compound 100mg, starch 100mg, Magnesium Stearate proper quantity;
Preparation method: mixed with auxiliary agent by compound, sieves, Homogeneous phase mixing in suitable container, and gained mixture is loaded hard gelatin capsule.
Embodiment 4:
Ampulla: embodiment 1 gained compound 2mg, sodium chloride 10mg;
Preparation method: compound and sodium chloride are dissolved in appropriate water for injection, filter, gained solution aseptically loads in ampoule bottle.

Claims (4)

1. following structural formula I:
2. the preparation method of formula I according to claim 1, the method comprises the following steps:
Get white bright Radix Angelicae Pubescentis (Heracleum candicans) plant, with organic solvent extraction, extract obtained column chromatography for separation repeatedly, obtains formula I.
3. be used for the treatment of the pharmaceutical composition of tumor, the formula I according to claim 1 wherein containing treatment effective dose and pharmaceutically suitable carrier.
4. the application of formula I according to claim 1 in the medicine of preparation treatment tumor.
CN201410392554.0A 2014-08-11 2014-08-11 A kind of C36Polyacetylene compound and preparation thereof and application Active CN104257641B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107840836A (en) * 2016-09-18 2018-03-27 云南西力生物技术股份有限公司 Icariine K and preparation method thereof and the application on medicine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101240002A (en) * 2007-02-07 2008-08-13 首都医科大学 Fatty acylaminoacylcytarabine conjugate, preparation method and application thereof
CN102234259A (en) * 2010-04-23 2011-11-09 天津尚德药缘科技有限公司 Sphaelactone derivatives, their pharmaceutical compositions, preparation method thereof and application thereof
CN102775427A (en) * 2012-07-04 2012-11-14 中国科学院南海海洋研究所 Antibiotic Tetrathiazomycin A and preparation method thereof and application in preparing antineoplastic drugs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101240002A (en) * 2007-02-07 2008-08-13 首都医科大学 Fatty acylaminoacylcytarabine conjugate, preparation method and application thereof
CN102234259A (en) * 2010-04-23 2011-11-09 天津尚德药缘科技有限公司 Sphaelactone derivatives, their pharmaceutical compositions, preparation method thereof and application thereof
CN102775427A (en) * 2012-07-04 2012-11-14 中国科学院南海海洋研究所 Antibiotic Tetrathiazomycin A and preparation method thereof and application in preparing antineoplastic drugs

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107840836A (en) * 2016-09-18 2018-03-27 云南西力生物技术股份有限公司 Icariine K and preparation method thereof and the application on medicine

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