CN104257641B - A kind of C36Polyacetylene compound and preparation thereof and application - Google Patents

A kind of C36Polyacetylene compound and preparation thereof and application Download PDF

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Publication number
CN104257641B
CN104257641B CN201410392554.0A CN201410392554A CN104257641B CN 104257641 B CN104257641 B CN 104257641B CN 201410392554 A CN201410392554 A CN 201410392554A CN 104257641 B CN104257641 B CN 104257641B
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compound
preparation
formula
tumour
application
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CN104257641A (en
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海萍
高原
任福才
魏国柱
王飞
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Yunnan Biobiaopha Technology Co Ltd
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Yunnan Biobiaopha Technology 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 kind of C with antitumor activity36Polyyne class native compound (formula I compound), its preparation method, and this compound and the application of pharmaceutical composition aspect the medicine of preparation treatment tumour thereof.

Description

A kind of C36Polyacetylene compound and preparation thereof and application
Technical field
The invention belongs to medical compounds and field of pharmacology, particularly, relate to a kind of C36Polyacetylene compound BBP865, its preparation method, the pharmaceutical composition taking this compound as active component, and this compound and the application of pharmaceutical composition aspect the medicine of preparation treatment tumour thereof.
Background technology
White bright levisticum 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. Conventionally grow in hillside sylvan life and roadside, 4200 meters of regions of height above sea level 2000 –. The characteristic constituents of this plant is furocoumarin.
Tumour be phalangeal cell under the effect of tumorigenesis factor, gene changes, and loses the normal regulation of cell growth, causes paraplasm. Tumour can be divided into the optimum and large class of malignant tumour two, and the latter grows rapidly, can be transferred to other position of health, destroys normal organ 26S Proteasome Structure and Function, life-threatening.
The treatment means of tumour are mainly comprised to operation, radiotherapy, chemotherapy. In recent years advancing by leaps and bounds along with nano molecular medical science and Protocols in Molecular Biology, the elaboration of tumour mechanism, the searching of antitumor target spot, the exploitation of new type antineoplastic medicine and the innovation for the treatment of means and integrated use have had significant progress, and tumor patient life span obviously extends. But the treatment that accounts for more than 90% solid tumor of malignant tumour of serious threat human life health not yet reaches satisfied curative effect, still have massive tumor patient because finally causing treating unsuccessfully to treating reactionless or resistance. Therefore, find that also development of new antineoplastic remains the problem that people will continue to face.
In prior art, have no compd B BP865 involved in the present invention and as active ingredient in treatment the report aspect tumour, and this compound has the report of antitumor activity.
Summary of the invention
The object of the present invention is to provide a kind of C with medical value36Polyacetylene compound BBP865.
Another object of the present invention is to provide a kind of method of extracting the compounds of this invention from white bright levisticum (Heracleumcandicans) plant.
A further object of the present invention is to provide a kind of being used for the treatment of and the pharmaceutical composition of pre-preventing tumor taking formula I compound as active component, and this compound and the application of composition aspect the medicine of preparation treatment tumour.
To achieve these goals, the invention provides following technical scheme:
Be used for the treatment of the medicine of tumour, wherein contain formula I compound and pharmaceutically suitable carrier and/or the excipient for the treatment of tumour effective dose.
The compounds of this invention BBP865 can be converted into pharmaceutically acceptable derivates. As α, beta-unsaturated aldehyde can be introduced the chain containing 4～10 carbon by reversal of the Michael addition (Michaelreaction); Hydroxyl can adopt known method carry out acidylate (as formylated, acetylation, benzoylation, sulfonylation), halogenation or be oxidized to ketone group, and ketone group can further form acetal with ethylene glycol effect; Can adopt the method esterification in document to form amino-acid ester (amino in amino acid can be protected, and goes protection after esterification).
When the compounds of this invention is used as on medicine, can directly use, or use with the form of pharmaceutical composition. This pharmaceutical composition contains 0.1～99%, is preferably 0.5～90% the compounds of this invention, and all the other are acceptable salt on materia medica, or and pharmaceutically suitable carrier and/or excipient inertia nontoxic to humans and animals.
Described pharmaceutical carrier or excipient are that one or more are selected from solid, semisolid and liquid diluent, filler and pharmaceutical preparation assistant agent. Described pharmaceutical composition is used with the form of per weight dose. Medicine of the present invention can oral administration and two kinds of form administrations of injection (quiet note, intramuscular injection).
Oral available its solid or liquid preparation, as pulvis, tablet, sugar-coat agent, capsule, solution, syrup, pill etc.
Inject available its solid or liquid preparation, as powder-injection, solution shape injection etc.
In order to understand better essence of the present invention, the biologically active result with formula I compound of the present invention is illustrated to its application in field of medicaments below.
Mtt assay cytoactive detects:
MTT full name is 3-(4,5-dimethylthiazol-2-yl)-2, and 5-diphenyltetrazoliumbromide is a kind of dyestuff of yellow color. In living cells mitochondria succinate dehydrogenase can metabolism reduction MTT, simultaneously under the effect of cromoci, (content of Formazan) ， formazan can be measured at 570nm place with ELIASA to generate blue (or bluish violet) water-fast formazan. Under normal conditions, formazan growing amount is directly proportional to viable count, therefore can infer the number that living cells according to optical density OD value.
Experimental technique:
1. inoculating cell: use containing the nutrient solution (DMEM or RMPI1640) of 10% hyclone and be made into individual cells suspension, be inoculated into 96 orifice plates with every hole 10000-20000 cell, every pore volume 100 μ l, attached cell is 12 hours inoculated and cultured in advance.
2. add testing compound solution (fixed concentration 40 μ M primary dcreening operations are suppressed near compound 50% in this concentration to growth of tumour cell and establish 5 concentration and enter gradient and sieve again), every hole final volume 200 μ l, 3 multiple holes are all established in every kind of processing.
3. colour developing: 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 that in hole, culture supernatant 100 μ l are to avoid cell loss, and every hole adds 20% SDS100 μ l, and night incubation (37 DEG C of temperature), fully melts crystal.
4. colorimetric: select 595nm wavelength, enzyme-linked immunosorbent assay instrument (Bio-Rad680) reads each hole absorbance value, record result, taking concentration as abscissa, cell survival rate is that ordinate is drawn cell growth curve, and application two-point method (ReedandMuench method) calculates the IC of compound50Value.
Experimental result is in table 1:
The half growth inhibitory concentration IC of table 1.BBP865 to tumor cell line50(μM)
Above-mentioned result of the test shows, compd B BP865 has significant antitumor activity, but particularly the inhibition activity of breast cancer, liver cancer, colon cancer cell has been exceeded to clinical antineoplastic cis-platinum.
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 to this.
Embodiment 1:
The preparation method of the compounds of this invention and structural characterization:
1. preparation method:
The white bright levisticum dry rhizome of 9.0kg, after crushed with extracting 3 times under 95% ethanol room temperature, extracts 3 to 4 days at every turn, merges extract, and reduced pressure concentration, obtains 980g medicinal extract. Gained medicinal extract separates through silica gel column chromatography again, carries out gradient elution, in benzinum/acetone (5:1) wash-out Duan get Yi component with benzinum/acetone solvent system. This component further, through silica gel (chloroform/acetone=100:1) and SephadexLH-20 (methyl alcohol) column chromatography for separation, obtains compd B BP865 sterling 23mg.
2. structural characterization:
Colorless oil; Molecular formula C36H46O5；ESIMS(pos.):m/z581[M+Na]+；HRESIMS:m/z581.3239[M+Na]+(581.3243calcdforC36H46O5Na)；+128.2(c0.10,CHCl3)；IR(KBr)νmax3431,2927,2855,1707,1635,1462,1406,1384,1300,1262,1116,1022,988,934,574cm–1; Nmr spectrum data is in table 2.
Nmr spectrum data (the CDCl of table 2.BBP8653Middle mensuration)
The chemical structural formula of compd B BP865 is:
Embodiment 2:
Tablet: embodiment 1 gained compound 10mg, lactose 180mg, starch 55mg, dolomol 5mg;
Preparation method: compound, lactose, starch are mixed, and water is evenly moistening, and the mixture after moistening is sieved and is dried, and after sieve, adds dolomol, then by mixture compressing tablet, every heavy 250mg, wherein compounds content 10mg.
Embodiment 3:
Capsule: embodiment 1 gained compound 100mg, starch 100mg, dolomol is appropriate;
Preparation method: compound is mixed with auxiliary agent, sieve, evenly mix in suitable container, pack gained mixture into 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 packs in ampoule bottle under aseptic condition.

Claims (4)

1. following structural formula I compound:
2. the preparation method of formula I compound claimed in claim 1, the method comprises the following steps:
Get white bright levisticum (Heracleumcandicans) plant, with organic solvent extraction, extract obtained column chromatography repeatedly dividesFrom, obtain formula I compound.
3. be used for the treatment of the pharmaceutical composition of tumour, wherein contain treat effective dose formula I compound claimed in claim 1 and can medicineUse carrier.
4. formula I compound claimed in claim 1 is in preparation treatment breast cancer, lung cancer, liver cancer, colon cancer, leukemic medicine sideThe application of face.
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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