CN101511355A - Application of (2Z)-2-(3, 4-dihydroxy bezilidene)-1-benzofuran-3(2H)-ketone for preparation of anti-cancer medicine - Google Patents
Application of (2Z)-2-(3, 4-dihydroxy bezilidene)-1-benzofuran-3(2H)-ketone for preparation of anti-cancer medicine Download PDFInfo
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- CN101511355A CN101511355A CNA2007800330141A CN200780033014A CN101511355A CN 101511355 A CN101511355 A CN 101511355A CN A2007800330141 A CNA2007800330141 A CN A2007800330141A CN 200780033014 A CN200780033014 A CN 200780033014A CN 101511355 A CN101511355 A CN 101511355A
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- cancer
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
The use of (2Z)-2-(3,4-dihydroxybenzylidene)-1-benzofuran-3(2H)-one in manufacture of medicaments for treating cancers. The compound demonstrates inhibition towards liver, colon, lung and stomach cancer cells and phosphokinase Aurora-B. The compound of the present invention can be formulated into anticancer pharmaceutical compositions with pharmaceutically acceptable carriers to suppress the continuous growth of tumors.
Description
(2Z) -2- (3,4- dihydroxy benzal) -1- benzofurans -3 (2H) -one
Application in cancer therapy drug is prepared
Technical field
Application the present invention relates to cell biology there is provided compound s6 in cancer therapy drug is prepared.Background technology
Tumour is the disease for seriously endangering human health.The incidence of disease of tumour day by day increases in recent years, and the current whole world has more than 600 ten thousand people to die from cancer every year, and new cases 8,000,000, this numeral is also increasing year by year.There are million new cancer patients every year in the population of China 1,300,000,000, patient to be treated about 2,000,000, death about 1,300,000.The end of the year in 2006 is expected, China there will be 1,700,000 people to die from cancer, and cancer turns into first cause of the death.
Malignant tumour is commonly called as cancer, is lump unrestrictedly grown caused by after the organ and histocyte of human body morph and diffusion.It can destroy finite energy in organ and the function of organization of human body, consumer, and the vital movement of people is suffered damage, and even result in death.
Mitosis is a critically important stage in cell cycle process.The difference of tumour and normal cell is exactly that unrestricted hyperplasia, i.e. mitosis lose normal regulation.Its occurrence cause of most tumour is the unstability of the genome caused by mitosis, genome unstable and from the unstable of chromosome, chromosome it is unstable be cancer characteristic mark.The separation of chromosome, the duplication of centriole and separation occur abnormal, the exception of each cell chromosome number can be caused, that is aneuploid, increase the chance of loss of heterozygosity, the missing of tumor suppressor gene or the number increase of proto-oncogene can all make cell life metabolism and signal transduction get muddled, and increase the chance of canceration.Kinases plays an important role in mitosis and cell cycle regulating is completed, so that the study hotspot as current molecular biology.
In order to treat tumour, this area can effectively suppress the compound of growth of tumour cell in the urgent need to exploitation.The content of the invention
It is an object of the invention to provide applications of the compound s6 in cancer therapy drug is prepared.In the first aspect of the present invention, there is provided the compound shown in a kind of Formulas I, i.e. (2Z) -2- (3,4- dihydroxy benzals;) (2H ketone, or its pharmaceutically acceptable salt or ester are preparing composition (such as cancer therapy drug of anticancer to -1- benzofurans -3;) in application.
In another preference, described composition is pharmaceutical composition, and Halth-care composition or dietary supplement combination are in another preference, and described medicine is used for the growth for killing cancer cell or suppressing cancer cell.
In another preference, described cancer therapy drug contain 0.001-99wt% (；Preferably 0.01-90wt%；) Formulas I compound and carrier or excipient pharmaceutically.
In another preference, described medicine is additionally operable to suppress phosphokinase Aurora-B.
In another preference, the cancer therapy drug is injection, granule, capsule, solution or tablet.
In another preference, described cancer is selected from：Liver cancer, colon cancer, stomach cancer and lung cancer.
In the second aspect of the present invention, there is provided a kind of method that extracorporeal suppression tumor cell grows, including step：Compound (2 Ζ) -2- is added in the cultivating system of the tumour cell<;(2 Η) -one of 3,4- dihydroxy benzal 1- benzofurans -3.
In another preference, described tumour cell is selected from：Liver cancer cells, colon cancer cell, stomach cancer cell and lung carcinoma cell.
In the third aspect of the present invention, there is provided a kind of method for the treatment of cancer, including step：(2 Ζ) -2- (3,4- dihydroxy benzal) -1- benzofurans -3 (2 Η) -one or its pharmaceutically acceptable salt are applied to the mammalian object for needing to treat.
In another preference, described amount of application is daily 0.1 mg/kg to 20 mg/kg body weight.Brief description of the drawings
Fig. 1 is s6 pairsSW620 Carbazole alkaloid result figures.It can be seen that, the IC50 (median lethals of s6 of the invention to human colon cancer cells' strain (sw620)）It is about 1 μM of o
Fig. 2 is s6 tumor killing effect figures.It can be seen that, after s6 administrations, mouse knurl weight is decreased obviously.
Embodiment
Entitled-2- (3,4-dihydroxybenzyl idene)-1-benzofuran-3 (2^-one [(2-2- (3,4- dihydroxy benzals of the compound）- 1- benzofurans-3 (2 -one], referred to as s6, molecular weight is 254, can be prepared by commercially available acquisition or conventional method.Present invention additionally comprises the resulting compound of conventional replacement is carried out to the compound.
The s6 compounds of the present invention can be with as pharmaceutically or derived from the acceptable acid of physiology or alkali salt or ester-formin are used.These salt include（But it is not limited to）The salt or ester formed with following acid：Hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, butanedioic acid, oxalic acid, fumaric acid, maleic acid, oxaloacetic acid, methanesulfonic acid, ethyl sulfonic acid, benzene sulfonic acid or isethionic acid.The salt of halide is equally applicable.Other salt include：With alkali metal or alkaline-earth metal（Such as sodium, potassium, calcium or magnesium）The salt of formation, and in the form of " pro-drugs " of ester, carbamate or other routines（When being administered in this form, active part can be changed into vivo）.In the present invention, compound s6 can be used for preparing cancer therapy drug.
The present invention have detected compound s6 for tumour cell and the operative condition of cancer cell by standard MTS experiments, as a result show, the s6 of the present invention is to kinds of tumor cells and cancer cell, such as liver cancer cells, colon cancer cell, stomach cancer cell and lung carcinoma cell, there are killing or inhibition.
The compound s6 of the further studies have shown that present invention has inhibitory action to phosphokinase Aurora-B.This further demonstrates that the compound s6 of the present invention has the effect for suppressing malignant tumour.
Malignant tumour is commonly called as cancer, is lump unrestrictedly grown caused by after the organ and histocyte of human body morph and diffusion.Kinases plays an important role in mitosis and cell cycle regulating is completed, so that the study hotspot as current molecular biology. AIK (Aur0Ra/Ipl l Kinase) it is that the big modulability of five be currently known swashs
One of enzyme family.Up to the present, mankind Aiks families find three members altogether：Aikl, Aik2 (Aurora-B) and Aik3.Wherein, Aik2 mainly works in the cell mitogen phase.It participates in the interaction of regulation centromere and spindle microtubule as chromosome with albumen, in mid-term to later stage, this is instantaneous, Aik2 is migrated to cell middle area band by centromere, latter stage is distributed in cell dish and rear mitosis bridge, mitosis event after participation, thus it is relevant with the separation and cytokinesis of chromosome.Aik2 mutation is suppressed the formation of division ditch, and results in apocyte.Aik2 is positioned at 17ql3, and exception occurs in a variety of cancer cells of the mankind in this region, and Aik2 height is expressed in the colon cancer cell line of abnormal ploidy.Therefore, scientific research personnel finds the molecule acted on Aik2 one after another, and studies as antineoplastic.
The present invention has also set up transplantable tumor mouse model, for detecting effects of the s6 to in-vivo tumour and cancer cell.As a result display that s6 can suppress tumor growth in vivo.In the present invention, the pharmaceutical composition that the cancer therapy drug prepared by compound s6 is made up of the compound s6 containing effective therapeutic dose and carrier or excipient pharmaceutically.
In the present invention, described effective application amount is daily 0. 1 mg/kg to 20 mg/kg body weight.In the present invention, prepared antineoplastic can be injection or tablet etc..
S6 of the present invention and the like etc., when being administered in the treatment（Administration）When, it is possible to provide different effects.Generally, these materials can be formulated in nontoxic, inert and pharmaceutically acceptable aqueous carrier medium, wherein pH ordinarily be about 5-8, and preferably pH is about 6-8, although pH value can be varied from the property that is formulated material and illness to be treated.The pharmaceutical composition prepared can be administered by conventional route, including（But it is not limited to）：Intramuscular, intraperitoneal, subcutaneous, intracutaneous, knurl are interior or part is administered.
By taking the s6 of the present invention as an example, it can be combined with suitable pharmaceutically acceptable carrier.This kind of pharmaceutical composition contains the compound and pharmaceutically acceptable carrier or excipient of therapeutically effective amount.This kind of carrier includes (but being not limited to）：Salt solution, buffer solution, glucose, water, glycerine, ethanol, and combinations thereof.Pharmaceutical preparation should match with administering mode.The s6 of the present invention can be made into injection form, and such as aqueous solution with physiological saline or containing glucose and other assistant agents is prepared by conventional method.The pharmaceutical composition of such as tablet and capsule etc, can be prepared by conventional method.Pharmaceutical composition such as injection, solution, tablet and capsule are preferably aseptically manufactured.The dosage of active component is therapeutically effective amount, such as the daily mg/kg body weight of about 1 microgram/kg body weight-about 5.In addition, the s6 of the present invention can be also used together with other therapeutic agents.
When the s6 of the present invention is used as medicine, the s6 for the treatment of effective dose can be applied to mammal, its
In the treatment effective dose typically at least about 10 micrograms/kg body weight, and in most cases be no more than about 80 mg/kg body weight, preferably the dosage is the mg/kg body weight of about 500 micrograms/kg body weight-about 2.Certainly, specific dosage is also contemplated that the factors such as method of administration, patient health situation, within the scope of these are all skilled practitioners technical ability.Cancer turns into first cause of the death, kills the material of tumour and growth of cancer cells and also thus becomes the study hotspot of current biological medicine circle.The s6 of the present invention has killing or inhibition to kinds of tumor cells and cancer cell；Meanwhile, compound s6 of the invention has inhibitory action to phosphokinase Aurora-B.This compound s6 for demonstrating the present invention has the effect for suppressing malignant tumour.The compound s6 of the present invention can be used for prepare cancer therapy drug with suitable pharmaceutically acceptable carrier combination, to suppress continued tumor growth.With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are only illustrative of the invention and is not intended to limit the scope of the invention.The experimental method of unreceipted actual conditions in the following example, generally according to normal condition such as Sambrook et al., molecular cloning：Laboratory manual（New York :Cold Spring Harbor Laboratory Press, 1989) described in condition, or according to the condition proposed by manufacturer.The external enzyme activity Inhibition test of embodiment 1
Using escherichia expression system, clone, express and purify having obtained people source Aurora-B protein kinases (the NCBI numbers of logging in are NP -004208), for high flux screening screening experiment.Using radio isotope technique, AUR0RAB Pity acidifying substrate MBP (UPSTATE companies, CAT#13- 110, lot#27845), by solution [γ-33Ρ] γ on-Α Τ Ρ-33Ρ transfers are covalently bound to substrate, make its Ser phosphorylation, produce the substrate with isotope marks33P-MBP.It is eventually adding scintillation solution and the enzymatic activity is detected by liquid scintillation counter counting, different compounds can be observed to its active suppression situation, with the activity of preliminary assessment compound.
Parallel laboratory test result shows that the IC50 that compound s6 of the invention suppresses to Aurora-B protein kinase activities is 15 59nM.The inhibition of cancer cell of embodiment 2 is tested
Test and carry out according to standard MTS, wherein design parameter is as follows：
Plant plate：1000 cells/wells
Compound： s6
Incubation time： 96h
Dosing product finishing time： 3h
Compound concentration gradient：Unit： uM
Repeat to test：6 groups
Data provide form：Average value scholar's standard deviation
Cell line：Human colon cancer cells' strain（sw620)
As a result show, compound s6 of the invention is about 1 μ Μ to the sw620 IC50 suppressed.Specifically it see the table below:
Embodiment 3 is to rat liver cancer H22 tumor killing effects
Experimental animal and its strain：Kunming mouse
Source：Shanghai Si Laike experimental animal responsibilities Co., Ltd
Production licence number：SCXK (Shanghai） 2003-0003
Use credit number：SYXK (Shanghai） 2004-0015
Body weight： 19-21g
Sex：Male
Every group of number of animals：8（Control group 16）Transplanted tumor：Rat liver cancer H22 test methods：
Well-grown rat liver cancer H22 ascites is taken, with physiological saline with 1：4 dilutions（Cell concentration about 1-2X107Individual/ml), the right 2ml of armpit subcutaneous vaccination 0. of every mouse, random packet, if：
1) blank control group
2) s6 (12. 5mg/kg, ipx7)
3) s6 (25mg/kg, ipx7)
It is administered after inoculation from next day, administered volume is 0. 5ml/20g body weight, continuous intraperitoneal injection 7 days.De- neck on the 10th puts to death animal after inoculation, and solution takes tumor mass, claims knurl weight, result judgement results as shown in Fig. 2 after inoculation s6, the knurl weight of mouse is decreased obviously, and the s6 of inoculation is more, and knurl weight declines more obvious.Embodiment 4
Pharmaceutical composition (tablet）Preparation
Using routine techniques, following components is mixed, then direct tablet compressing, prepares the pharmaceutical composition of tablet form, and its formula is as follows：
All documents referred in the present invention are all incorporated as reference in this application, are individually recited just as each document as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims limited range.
Claims (1)
- Claim1. compound (2 Ζ the 2- ((applications of 2H ketone or its pharmaceutically acceptable salt or ester in cancer therapy drug is prepared of 3,4- dihydroxy benzal 1- benzofurans -3 shown in a kind of Formulas I.2. application as claimed in claim 1, it is characterised in that described medicine is used to kill cancer cell or suppresses the growth of cancer cell.3. application as claimed in claim 1, it is characterised in that described cancer therapy drug contains 0.001-99wt% compound of formula I and carrier or excipient pharmaceutically.4. application as claimed in claim 1, it is characterised in that described medicine is additionally operable to suppress phosphokinaseAurora-B。5. application as claimed in claim 1, it is characterised in that the cancer therapy drug is injection, granule, capsule, solution or tablet.6. application as claimed in claim 1, it is characterised in that described cancer is selected from：Liver cancer, colon cancer, stomach cancer and lung cancer.7. a kind of method of extracorporeal suppression tumor cell growth, it is characterised in that including step：Compound (2Z) -2- (3,4- dihydroxy benzal) -1- benzofurans -3 (2H) -one is added in the cultivating system of the tumour cell.8. method as claimed in claim 7, it is characterised in that described tumour cell is selected from：Liver cancer cells, colon cancer cell, stomach cancer cell and lung carcinoma cell.9. a kind of method for the treatment of cancer, it is characterised in that including step：(2Z) -2- (3,4- dihydroxy benzal) (2H) -one of -1- benzofurans -3 or its pharmaceutically acceptable salt are applied to the mammalian object for needing to treat.10. method as claimed in claim 9, it is characterised in that described amount of application is daily 0.1 mg/kg to 20 mg/kg body weight.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007800330141A CN101511355B (en) | 2006-09-07 | 2007-09-07 | Application of (2Z)-2-(3, 4-dihydroxy bezilidene)-1-benzofuran-3(2H)-ketone for preparation of anti-cancer medicine |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610030918.6 | 2006-09-07 | ||
| CNA2006100309186A CN101011377A (en) | 2006-09-07 | 2006-09-07 | Application of compound s6 in the process for preparing anti-cancer medicament |
| CN2007800330141A CN101511355B (en) | 2006-09-07 | 2007-09-07 | Application of (2Z)-2-(3, 4-dihydroxy bezilidene)-1-benzofuran-3(2H)-ketone for preparation of anti-cancer medicine |
| PCT/CN2007/070651 WO2008040208A1 (en) | 2006-09-07 | 2007-09-07 | (2z)-2-(3,4-dihydroxybenzylidene)-1-benzofuran-3(2h)-one in manufacture of medicaments for treating cancers |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101511355A true CN101511355A (en) | 2009-08-19 |
| CN101511355B CN101511355B (en) | 2012-11-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006100309186A Pending CN101011377A (en) | 2006-09-07 | 2006-09-07 | Application of compound s6 in the process for preparing anti-cancer medicament |
| CN2007800330141A Expired - Fee Related CN101511355B (en) | 2006-09-07 | 2007-09-07 | Application of (2Z)-2-(3, 4-dihydroxy bezilidene)-1-benzofuran-3(2H)-ketone for preparation of anti-cancer medicine |
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| Application Number | Title | Priority Date | Filing Date |
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| CNA2006100309186A Pending CN101011377A (en) | 2006-09-07 | 2006-09-07 | Application of compound s6 in the process for preparing anti-cancer medicament |
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| Country | Link |
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| CN (2) | CN101011377A (en) |
| WO (1) | WO2008040208A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101011377A (en) * | 2006-09-07 | 2007-08-08 | 复旦大学 | Application of compound s6 in the process for preparing anti-cancer medicament |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05509078A (en) * | 1990-05-17 | 1993-12-16 | ベイラー カレッジ オブ メディシン | Growth inhibitory factors and the Act on Measures against Cancer and Cell Proliferative Diseases |
| CA2441274A1 (en) * | 2001-04-18 | 2002-10-24 | Pharmacia Italia S.P.A. | Aurones as telomerase inhibitors |
| US7220764B2 (en) * | 2002-06-17 | 2007-05-22 | The Pennsylvania State University Research Foundation | Sphingosine kinase inhibitors |
| CN101011377A (en) * | 2006-09-07 | 2007-08-08 | 复旦大学 | Application of compound s6 in the process for preparing anti-cancer medicament |
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2006
- 2006-09-07 CN CNA2006100309186A patent/CN101011377A/en active Pending
-
2007
- 2007-09-07 CN CN2007800330141A patent/CN101511355B/en not_active Expired - Fee Related
- 2007-09-07 WO PCT/CN2007/070651 patent/WO2008040208A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008040208A1 (en) | 2008-04-10 |
| CN101511355B (en) | 2012-11-21 |
| CN101011377A (en) | 2007-08-08 |
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Granted publication date: 20121121 Termination date: 20160907 |