CN101444501A - Application of mother-nucleus conjugated iridoid in preparing anti-tumor medicine - Google Patents

Abstract

The invention belongs to the medication technical field, in particular relates to application of a mother-nucleus conjugated iridoid in preparing anti-tumor medicine. Animal experiments proves the compound has obvious inhibiting effect to various cancer cells without toxic or side effect, so that the compound can be used for preparing the anti-tumor medicine. The invention further provides a medicine composition using the mother-nucleus conjugated iridoid as an active composition for treating tumor. The compound can either be extracted from plants, or obtained by a chemical synthesizing method.

Description

The application of mother-nucleus conjugated iridoid in the preparation antitumor drug

Technical field

The invention belongs to medical technical field, be specifically related to the application of mother-nucleus conjugated iridoid in the preparation antitumor drug.

Background technology

Tumor is to cause one of human main causes of death.Ministry of Health of China is announced urban and rural residents' major causes of death in 2006 a few days ago.Statistics shows that malignant tumor has become the primary cause of the death.As seen the prevention of tumor and treatment are very urgent.Drug therapy is one of main treatment means of tumor.At present, though developed tens kinds of antitumor drug, effectively prolonged patient's life or improved patient's life quality.Some anti-tumor drugs treatment curative effect highly significant wherein is as the Drug therapy acute leukemia of children etc.But the drug research of tumor and exploitation also face huge challenge, mostly are cell toxicity medicament as antitumor drug, and its side effect is obvious, has limited the performance of these curative effect of medication.Famous tumor aetiology man, member of Chinese Academy of Engineering's journey book an ancient unit of weight are thought: current medical science still is in the junior stage for the control of tumor.Chinese medicine has the basis of human toxicity experiment in several thousand, and perhaps Chinese medicine can be walked prostatitis in the world at anti-tumor aspect.The lead compound of seeking the anti-tumor activity of high-efficiency low-toxicity from natural product is the focus of new drug research always.

Rhizoma valerianae latifoliae has another name called Herba Asari, tiger seven, Indian Rhizoma et radix valerianae, is the Valerianaceae valerian." Rhizoma valerianae latifoliae goes out in the another name for Sichuan Province Xi Mao pine fence mountain in the Compendium of Material Medica record.Grass roots also, black has thick palpus, shape such as Aranea and Rhizoma Ligustici, vault Rhizoma Chuanxiong, fragrant odour ".Chinese Pharmacopoeia version in 1977 was once recorded, and Guizhou is among the people aches with its treatment trusted subordinate pain, rheumatic numbness and muscles, and can be calm, pleasant, helps digestion, and controlled sun stroke, sealing is let out, and transferred to apply with vegetable oil and controlled herpes zoster etc.Kunming etc. areas is before and after the annual Dragon Boat Festival, among the peoplely likes making fumigant with Rhizoma valerianae latifoliae, is used for disinfesting.Chemical constitution study shows that Rhizoma valerianae latifoliae contains volatile oil, iridoid and flavones ingredient.Pharmacological experiments shows that Aranea perfume extract has sedative-hypnotic effect, antibiotic and virus function, simultaneously dog, rabbit etc. is had hypotensive activity.Studies show that valepotriate, dihydro valepotriate and valdrinal have cytotoxicity, wherein valepotriate all has killing effect to squamous carcinoma of the cervix cell, adenocarcinoma of stomach cell and lung adenocarcinoma cell.

Although the research to Rhizoma valerianae latifoliae has had certain scale,, especially get thorough inadequately to wherein iridoids composition Study to the research of its chemical constituent etc. still system comprehensively inadequately.Therefore we have carried out the deep chemical constitution study of system to Rhizoma valerianae latifoliae, in the hope of further clear and definite its chemical constituent, are the research stockpile of Natural Medicine Chemistry; From wherein finding to have the especially natural product of anti-tumor activity of excellent activity, for the follow-up developmental research of going deep into provides material base.

Summary of the invention

The objective of the invention is to propose the application of mother-nucleus conjugated iridoid in the preparation antitumor drug.

It is active component that the present invention further also provides with this mother-nucleus conjugated iridoid, is used for the treatment of the pharmaceutical composition of tumor.

The mother-nucleus conjugated iridoid that is used to prepare antitumor drug that the present invention proposes has following general structure:

R in the formula ₁Alkyl, acetyl group, isovaleryl, alpha-substituted acetoxyl group isovaleryl, β-replacement acetoxyl group isovaleryl or alpha-substituted isoamyl acyloxy isovaleryl for hydrogen, 1～4 carbon;

R ₂Be acetyl group or isovaleryl;

R ₃Be hydrogen, acetyl group, isovaleryl or β-replacement acetoxyl group isovaleryl;

R ₄Be acetyl group, β-replacement acetoxyl group isovaleryl, alpha-substituted isoamyl acyloxy isovaleryl or o-hydroxy formoxyl.

More than mother-nucleus conjugated iridoid respectively in Rhizoma valerianae latifoliae or other plant of Valerianaceae valeriana, can from plant, prepare by extraction separation, also can obtain by the chemosynthesis mode.

It is active component that the pharmaceutical composition that the present invention proposes contains the mother-nucleus conjugated iridoid for the treatment of effective dose, and contains one or more pharmaceutically acceptable carriers.Wherein, the weight content of active component is 5-95%.

Pharmaceutically acceptable carrier mentioned above is meant the pharmaceutical carrier of pharmaceutical field routine, for example: diluent, excipient such as water etc.; Filler such as starch, sucrose etc.; Binding agent such as cellulose derivative, alginate, gelatin and polyvinylpyrrolidone; Wetting agent such as glycerol; Disintegrating agent such as agar, calcium carbonate and sodium bicarbonate; Absorption enhancer such as quaternary ammonium compound; Surfactant such as hexadecanol; Absorption carrier such as Kaolin and soap clay; Lubricant such as Pulvis Talci, calcium stearate and magnesium and Polyethylene Glycol etc.Can also in compositions, add other adjuvant such as flavouring agent, sweeting agent etc. in addition.

The compounds of this invention can compositions form by oral, snuffing is gone into, the mode of rectum or parenteral is applied to the patient who needs this treatment.Be used for when oral, can be made into conventional solid preparation such as tablet, powder, granule, capsule etc. or make liquid preparation such as water or oil-suspending agent or other liquid preparation such as syrup, elixir etc.; When being used for parenteral, can be made into solution, water or the oiliness suspending agent etc. of injection.Preferred form is tablet, coated tablet, capsule, suppository, nasal spray and injection.

The various dosage forms of pharmaceutical composition of the present invention can be according to the conventional production method preparation of pharmaceutical field.Active component is mixed with one or more carriers, be made into required dosage form then.

The specific embodiment

The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.

Embodiment 1: the preparation of mother-nucleus conjugated iridoid

Exsiccant Rhizoma valerianae latifoliae medical material 25kg, pulverize the back with 95% ethanol percolate extraction, extracting solution decompression recycling ethanol to volume is 20L, filter, filtrate is successively with petroleum ether, chloroform, ethyl acetate and n-butanol extraction, collect each extraction part and also be condensed into extractum, chloroform extraction part extractum 120g wherein, ethyl acetate extraction part extractum 180g.The chloroform extraction part and the ethyl acetate extraction part that obtain are carried out silica gel column chromatography respectively, chloroform-methanol in varing proportions carries out gradient elution, thin layer chromatography detects, and chemical compound is carried out purification in conjunction with Sephadex LH-20, preparative liquid chromatography, obtain 42 of chemical compounds, employing UV, MS, ¹H NMR, ¹³Means such as C NMR, 2D NMR are carried out the structure evaluation, have identified 30 of iridoid constituents wherein, wherein have 9 of conjugated system in the mother nucleus structure.Its structural formula, title etc. see Table 1.

9 parent nucleus of table 1 contain the title and the structure of the iridoid chemical compound of conjugated system

Embodiment 2: the cytotoxic activity experiment of mother-nucleus conjugated iridoid chemical compound

1, experiment material

1.1, given the test agent

9 iridoids as described in Table 1 add PBS (-) after using DMSO (Merck) dissolving respectively

Be made into solution or the uniform suspension of 1000 μ g/ml, then with PBS (-) dilution that contains DMSO.

1.2, cell strain

A549 (human lung carcinoma cell)

PC3 (Human Prostate Cancer Cells)

HCT-8 (human colon adenocarcinoma cell)

Bel 7402 (human liver cancer cell)

1.3, culture fluid

RPMI1640+15%NBS+ is two anti-

1.4, other materials

Full-automatic microplate reader: model: WellscanMK-2, production firm: Labsystems

Import 96 well culture plates etc.

2, test method

Mtt assay: it is 4～6 * 10 that the every hole of 96 orifice plates adds concentration ⁴The cell suspension 100 μ l of individual/ml put 37 ℃, 5% CO ₂In the incubator.Behind the 24h, add sample liquid, two multiple holes are established in 10 μ l/ holes, and 37 ℃, 5% CO ₂Effect 72h.Every hole adds the MTT solution 20 μ l of 5mg/ml, adds lysate behind the effect 4h, and put in the incubator in 100 μ l/ holes, and 570nm OD value is surveyed with the full-automatic microplate reader of MK-2 in the dissolving back.

3, result of the test

The results are shown in Table 2, the result shows, contains the iridoid of conjugated system to human lung carcinoma cell in these 9 mother nucleus structures, Human Prostate Cancer Cells, the human colon adenocarcinoma cell, human liver cancer cell all has better inhibited activity, favorable anti-tumor effect has the excellent development prospect.

The mother-nucleus conjugated iridoid chemical compound of embodiment 3 is to the efficacy experiment of mice S180 sarcoma (solid type)

1, experiment material

1.1 given the test agent

After using a small amount of tween-80 hydrotropy respectively, 9 iridoids as described in Table 1 use the 0.5%CMC wiring solution-forming.

1.2 animal

Strain: Kunming mouse

The source: the The 2nd Army Medical College Experimental Animal Center provides.

The quality certification number: Shanghai is moving closes the card word No. 107

Body weight: 18-20g

Sex: female.

1.3 transplanted tumor

Mice S180 sarcoma is gone down to posterity by Shanghai Institute of Pharmaceutical Industry and to keep.

2, experimental technique

Get well-grown mice S180 sarcoma ascites, dilute with 1:4 with normal saline, every mice axil subcutaneous vaccination 0.2ml, random packet is divided into matched group, cyclophosphamide group (CTX group, 20mg/kg, ip * 7), administration (5mg/kg) group, next day is played administration in the inoculation back, the administration volume is the 0.5ml/20g body weight, continuous irrigation stomach 7 days.Inoculate back 10 days and take off neck execution animal, dissect behind the title the weight of animals and get the tumor piece, claim tumor heavy.The result judges according to following formula:

3, experimental result

The iridoid that contains conjugated system in 9 mother nucleus structures all has significant tumor-inhibiting action.Experimental result sees Table 3.

9 iridoid chemical compounds of table 3 are to the inhibitory action of mice S180 sarcoma

Claims (4)

1, a kind of mother-nucleus conjugated application of iridoid in the preparation antitumor drug, this iridoid has a kind of of following general structure:

R in the formula ₁Alkyl, acetyl group, isovaleryl, alpha-substituted acetoxyl group isovaleryl, β-replacement acetoxyl group isovaleryl or alpha-substituted isoamyl acyloxy isovaleryl for hydrogen, 1～4 carbon;

R ₂Be acetyl group or isovaleryl;

R ₃Be hydrogen, acetyl group, isovaleryl or β-replacement acetoxyl group isovaleryl;

R ₄Be acetyl group, β-replacement acetoxyl group isovaleryl, alpha-substituted isoamyl acyloxy isovaleryl or o-hydroxy formoxyl.

2, application according to claim 1 is characterized in that described mother-nucleus conjugated iridoid extracts or chemosynthesis obtains from plant.

3, a kind of antitumor medicine composition is characterized in that containing described mother-nucleus conjugated iridoid active component of claim 1 and pharmaceutically acceptable carrier.

4, pharmaceutical composition according to claim 3, the weight content that it is characterized in that active component is 5～95%.