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WO2008040208A1 - (2z)-2-(3,4-dihydroxybenzylidene)-1-benzofuran-3(2h)-one utilisé pour la fabrication de médicaments destinés au traitement de cancers - Google Patents

(2z)-2-(3,4-dihydroxybenzylidene)-1-benzofuran-3(2h)-one utilisé pour la fabrication de médicaments destinés au traitement de cancers Download PDF

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Publication number
WO2008040208A1
WO2008040208A1 PCT/CN2007/070651 CN2007070651W WO2008040208A1 WO 2008040208 A1 WO2008040208 A1 WO 2008040208A1 CN 2007070651 W CN2007070651 W CN 2007070651W WO 2008040208 A1 WO2008040208 A1 WO 2008040208A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
compound
cancer cells
dihydroxybenzylidene
benzofuran
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2007/070651
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English (en)
Chinese (zh)
Inventor
Long Yu
Haoxing Zhang
Qingyu Lang
Lisha Tang
Jia Li
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fudan University
Original Assignee
Fudan University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fudan University filed Critical Fudan University
Priority to CN2007800330141A priority Critical patent/CN101511355B/zh
Publication of WO2008040208A1 publication Critical patent/WO2008040208A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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

Definitions

  • the present invention relates to the field of cell biology, and provides the use of the compound s6 for the preparation of an anticancer drug. Background technique
  • Tumors are diseases that seriously endanger human health.
  • the incidence of cancer has increased in recent years. At present, more than 6 million people worldwide die of cancer every year, and the number of new cases is 8 million. This number is increasing year by year.
  • Malignant tumors commonly known as cancer, are unrestricted and diffuse masses caused by the mutating of organs and tissue cells of the human body. It can destroy the organs and tissues of the human body, consumes limited energy in the body, and damages human life and even causes death.
  • Mitosis is a very important stage in the cell cycle process.
  • the difference between a tumor and a normal cell is infinite hyperplasia, that is, mitosis loses its normal regulation.
  • Most tumors occur due to genomic instability caused by mitosis.
  • Genomic instability is caused by chromosome instability.
  • Chromosomal instability is a characteristic marker of cancer.
  • Abnormal chromosome segregation, central granule replication and segregation can lead to abnormalities in the number of chromosomes per cell, ie aneuploidy, increased chance of heterozygous deletion, loss of tumor suppressor gene or increased number of proto-oncogenes Disrupts cell life metabolism and signaling, increasing the chance of cancer.
  • Kinase plays an important role in the completion of mitosis and cell cycle regulation, and thus has become a research hotspot in molecular biology.
  • a compound of formula I namely (2Z)-2-(3,4-dihydroxybenzylidene;)-1-benzofuran-3 (2H ketone, Or the use of a pharmaceutically acceptable salt or ester thereof in the preparation of an anti-cancer composition, such as an anti-cancer drug;
  • the composition is a pharmaceutical composition, a nutraceutical composition or a dietary supplement combination.
  • the medicament is for killing cancer cells or inhibiting the growth of cancer cells.
  • the anticancer drug contains 0.001 to 99% by weight (; preferably 0.01 to 90% by weight;) a compound of the formula I and a pharmaceutically acceptable carrier or excipient.
  • the medicament is also for inhibiting phosphokinase Aurora-B.
  • the anticancer drug is an injection, granule, capsule, solution or tablet.
  • the cancer is selected from the group consisting of liver cancer, colon cancer, gastric cancer, and lung cancer.
  • a method for inhibiting tumor cell growth in vitro comprising the steps of: adding a compound (2 ⁇ )-2- ⁇ ; 3,4-dihydroxybenzylidene to a culture system of the tumor cell Base 1-benzofuran-3(2 ⁇ )-one.
  • the tumor cells are selected from the group consisting of liver cancer cells, colon cancer cells, gastric cancer cells, and lung cancer cells.
  • a method of treating cancer comprising the steps of: administering (2 ⁇ )-2-(3,4-dihydroxybenzylidene)-1-benzene to a mammalian subject in need of treatment Furan-3(2 ⁇ )-one or a pharmaceutically acceptable salt thereof.
  • the application amount is from 0.1 mg/kg to 20 mg/kg of body weight per day.
  • Figure 1 is a graph showing the inhibition results of s6 against SW 620 cells. It can be seen that the IC50 (half lethal) of the s6 of the present invention against the human colon cancer cell line (sw620) is about 1 ⁇ Mo.
  • Figure 2 is a graph showing the anti-tumor effect of s6. It can be seen that the tumor weight of mice decreased significantly after s6 administration. detailed description
  • the name of the compound is -2-(3,4-dihydroxybenzylidene) -1 - benzofuran-3 (2 ⁇ -one [(2 -2- (3, 4-dihydroxybenzylidene)-1-benzene) Furan-3(2-ketone), abbreviated as s6, having a molecular weight of 254, can be obtained by commercially available or conventional methods.
  • the present invention also includes compounds obtained by subjecting the compound to conventional substitution.
  • the s6 compound of the present invention can be used in the form of a salt or an ester derived from a pharmaceutically or physiologically acceptable acid or base.
  • These salts include, but are not limited to, salts or esters formed with: hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, succinic acid, oxalic acid, fumaric acid, Maleic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or isethionic acid.
  • the salts of halides are also suitable.
  • salts include: salts with alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, as well as esters, carbamates or other conventional "prodrugs" (when given in this form) In the case of medicine, it can be converted into an active part in the body).
  • the compound s6 can be used for the preparation of an anticancer drug.
  • the present invention detects the action of the compound s6 on tumor cells and cancer cells according to a standard MTS assay, and the results show that the s6 of the present invention acts on various tumor cells and cancer cells, such as liver cancer cells, colon cancer cells, gastric cancer cells, lung cancer cells, and the like. , have a killing or inhibition effect.
  • the compound s6 of the present invention has an inhibitory effect on the phosphokinase Aurora-B. This further confirmed that the compound s6 of the present invention has an effect of inhibiting malignant tumors.
  • Aik2 mainly plays a role in the mitosis of cells.
  • Aik2 acts as a chromosomal concomitant protein involved in the regulation of the interaction between the centromere and the spindle microtubule.
  • Aik2 migrates from the centromere to the middle zone of the cell, and is distributed at the end of the cell plate and the posterior mitotic bridge. Post-mitotic events are associated with chromosome segregation and cytokinesis. Mutations in Aik2 inhibit the formation of dividing sulcus and lead to the formation of multinucleated cells.
  • Aik2 is localized to 17ql3, an area that is abnormal in a variety of human cancer cells, and Aik2 is highly expressed in abnormally ploidy colon cancer cell lines. Therefore, researchers are looking for molecules that interact with Aik2 and use them as antitumor drugs.
  • the present invention also establishes a mouse model of transplanted tumor for detecting the effect of s6 on tumors and cancer cells in vivo. The results also show that s6 can inhibit tumor growth in vivo.
  • the anticancer drug prepared from the compound s6 is a pharmaceutical composition comprising a therapeutically effective amount of the compound s6 and a pharmaceutically acceptable carrier or excipient.
  • the effective application amount is 0.1 mg / kg to 20 mg / kg body weight per day.
  • the antitumor drug prepared may be an injection or a tablet or the like.
  • the present invention can provide different effects when administered (administered) therapeutically.
  • these materials can be formulated in a non-toxic, inert, andpharmaceutically acceptable aqueous carrier medium, wherein the pH is usually from about 5 to about 8, preferably from about 6 to about 8, although the pH may be The nature of the formulation and the condition to be treated vary.
  • the formulated pharmaceutical compositions can be administered by conventional routes including, but not limited to, intramuscular, intraperitoneal, subcutaneous, intradermal, intratumoral, or topical administration.
  • s6 of the present invention can be used in combination with a suitable pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carrier include, but are not limited to, saline, buffer, dextrose, water, glycerol, ethanol, and combinations thereof.
  • the pharmaceutical preparation should be matched to the mode of administration.
  • the s6 of the present invention can be prepared in the form of an injection, for example, by a conventional method using physiological saline or an aqueous solution containing glucose and other adjuvants.
  • Pharmaceutical compositions such as tablets and capsules can be prepared by conventional methods.
  • compositions such as injections, solutions, tablets and capsules are preferably prepared under sterile conditions.
  • the amount of active ingredient administered is a therapeutically effective amount, for example from about 1 microgram per kilogram body weight to about 5 milligrams per kilogram body weight per day.
  • the s6 of the present invention can also be used with other therapeutic agents.
  • a therapeutically effective dose of s6 can be administered to a mammal
  • the therapeutically effective dose is usually at least about 10 micrograms per kilogram of body weight, and in most cases does not exceed about 80 milligrams per kilogram of body weight, preferably the dosage is from about 500 micrograms per kilogram of body weight to about 2 milligrams per kilogram of body weight.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician. Cancer has become the first cause of death, and the substances that kill tumors and cancer cells have become the research hotspots in the biomedical field.
  • the s6 of the present invention has a killing or inhibiting effect on various tumor cells and cancer cells; meanwhile, the compound s6 of the present invention has an inhibitory effect on the phosphokinase Aurora-B. This all proves that the compound s6 of the present invention has an effect of inhibiting malignant tumors.
  • the compound s6 of the present invention can be used in combination with a suitable pharmaceutically acceptable carrier to prepare an anticancer drug to inhibit the continued growth of the tumor.
  • the invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
  • the human Aurora-B protein kinase (NCBI accession number NP-004208) was cloned, expressed and purified using E. coli expression system for high-throughput screening experiments.
  • AUR0RAB pity acidified substrate MBP (UPSTATE, CAT#13-110, lot#27845), covalently binds ⁇ - 33 [ on [ ⁇ - 33 ⁇ ]- ⁇ in solution to the substrate. Its Ser is phosphorylated to produce the substrate 33 P-MBP with isotopic labeling.
  • the activity of the enzyme was detected by counting the scintillation liquid by counting with a liquid scintillation counter, and the inhibition of the activity of the different compounds was observed to initially evaluate the activity of the compound.
  • Seed plate 1000 cells/well Compound: s6
  • Cell line human colon cancer cell line (sw620)
  • the drug was administered from the next day after the inoculation, and the administration volume was 0.5 ml/20 g body weight, and the intraperitoneal injection was continued for 7 days.
  • the animals were sacrificed by cervical dislocation, and the tumor mass was dissected and weighed. The results were determined. The results are shown in Figure 2. After inoculation of s6, the tumor weight of the mice decreased significantly, and the more s6 inoculated, the tumor weight decreased. The more obvious.
  • the pharmaceutical composition in the form of a tablet is prepared by a conventional technique by mixing the following components and then directly compressing the tablet, and the formulation is as follows:

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation de (2Z)-2-(3,4-dihydroxybenzylidène )- 1-benzofuran-3 (2H)-one pour la fabrication de médicaments destinés au traitement de cancers. Le composé permet l'inhibition des cellules cancéreuses du foie, du colon, des poumons et de l'estomac, ainsi que la phosphokinase Aurora-B. Le composés de l'invention peut être formulé dans des compositions pharmaceutiques anticancéreuses grâce à des excipients de qualité pharmaceutique acceptable, ce qui entraîne la suppression de la prolifération continue des tumeurs.
PCT/CN2007/070651 2006-09-07 2007-09-07 (2z)-2-(3,4-dihydroxybenzylidene)-1-benzofuran-3(2h)-one utilisé pour la fabrication de médicaments destinés au traitement de cancers Ceased WO2008040208A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2007800330141A CN101511355B (zh) 2006-09-07 2007-09-07 (2z)-2-(3,4-二羟基亚苄基)-1-苯并呋喃-3(2h)-酮在制备抗癌药物中的应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200610030918.6 2006-09-07
CNA2006100309186A CN101011377A (zh) 2006-09-07 2006-09-07 化合物s6在制备抗癌药物中的应用

Publications (1)

Publication Number Publication Date
WO2008040208A1 true WO2008040208A1 (fr) 2008-04-10

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PCT/CN2007/070651 Ceased WO2008040208A1 (fr) 2006-09-07 2007-09-07 (2z)-2-(3,4-dihydroxybenzylidene)-1-benzofuran-3(2h)-one utilisé pour la fabrication de médicaments destinés au traitement de cancers

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CN (2) CN101011377A (fr)
WO (1) WO2008040208A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101011377A (zh) * 2006-09-07 2007-08-08 复旦大学 化合物s6在制备抗癌药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991017749A1 (fr) * 1990-05-17 1991-11-28 Baylor College Of Medicine Inhibiteurs de croissance cellulaire et procedes servant a traiter le cancer et des maladies a proliferation cellulaire
WO2002083123A1 (fr) * 2001-04-18 2002-10-24 Pharmacia Italia Spa Aurones utiles comme inhibiteurs de la telomerase
WO2003105840A2 (fr) * 2002-06-17 2003-12-24 The Pennsylvania State Research Foundation Inhibiteurs de sphingosine kinase

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101011377A (zh) * 2006-09-07 2007-08-08 复旦大学 化合物s6在制备抗癌药物中的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991017749A1 (fr) * 1990-05-17 1991-11-28 Baylor College Of Medicine Inhibiteurs de croissance cellulaire et procedes servant a traiter le cancer et des maladies a proliferation cellulaire
WO2002083123A1 (fr) * 2001-04-18 2002-10-24 Pharmacia Italia Spa Aurones utiles comme inhibiteurs de la telomerase
WO2003105840A2 (fr) * 2002-06-17 2003-12-24 The Pennsylvania State Research Foundation Inhibiteurs de sphingosine kinase

Also Published As

Publication number Publication date
CN101511355A (zh) 2009-08-19
CN101511355B (zh) 2012-11-21
CN101011377A (zh) 2007-08-08

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