WO2008031358A1 - 1,2-dihydroxy-3-methyl-9,10-anthraquinone utile dans la fabrication de médicaments pour traiter les cancers - Google Patents

1,2-dihydroxy-3-methyl-9,10-anthraquinone utile dans la fabrication de médicaments pour traiter les cancers Download PDF

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Publication number
WO2008031358A1
WO2008031358A1 PCT/CN2007/070650 CN2007070650W WO2008031358A1 WO 2008031358 A1 WO2008031358 A1 WO 2008031358A1 CN 2007070650 W CN2007070650 W CN 2007070650W WO 2008031358 A1 WO2008031358 A1 WO 2008031358A1
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WO
WIPO (PCT)
Prior art keywords
cancer
compound
cancer cells
dihydroxy
methyl
Prior art date
Application number
PCT/CN2007/070650
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English (en)
Chinese (zh)
Inventor
Long Yu
Haoxing Zhang
Qingyu Lang
Lisha Tang
Jia Li
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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
Publication of WO2008031358A1 publication Critical patent/WO2008031358A1/fr

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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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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 s4 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 unrestricted proliferation, that is, mitosis loses its normal regulation.
  • Most tumors occur because of the instability of the genomic group caused by mitosis.
  • the instability of the genome is also derived from the instability of the chromosome.
  • the instability of the chromosome 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 ie 1,2-dihydroxy-3-methyl-9, 10-oxime, or a pharmaceutically acceptable salt or ester thereof Use in the preparation of anti-cancer compositions such as anti-cancer drugs.
  • the composition is a pharmaceutical composition, a nutraceutical composition or a dietary supplement composition.
  • 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 growth of a tumor cell in vitro comprising the steps of: adding a compound 1,2-dihydroxy-3-methyl-9, 10- in a culture system of the tumor cell Hey.
  • 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 1,2-dihydroxy-3-methyl-9, 10-oxime or a pharmaceutically thereof to a mammalian subject in need of treatment Acceptable salt.
  • 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 s4 against SW 620 cells. It can be seen that the IC50 (half lethal) of the s4 of the present invention against the human colon cancer cell line (sw620) is about 1 ⁇ . detailed description
  • the present invention provides the use of the compound represented by the following formula (I) in the preparation of an anticancer drug
  • the compound has the name 1,2-dihydroxy-3-methylanthra-9, 10- qui e [ 1 2-dihydroxy-3-methyl-9 10-oxime], abbreviated as s4, and has a molecular weight of 254. It is prepared by a commercially available or conventional method.
  • the invention also includes compounds obtained by conventional substitution of the compounds.
  • the s4 compound of the present invention can be used in the form of a salt or 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 s4 can be used for the preparation of an anticancer drug.
  • the present invention detects the action of the compound s4 on tumor cells and cancer cells according to a standard MTS assay, and the results show that the s4 of the present invention is applicable to 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 s4 of the present invention has an inhibitory effect on the phosphokinase Aurora-B. This further confirmed that the compound s4 of the present invention has an effect of inhibiting malignant tumors.
  • AIK Alzheimer's disease kinase
  • Aikl Aik2 Aurora-B
  • Aik3 Aik3 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 event, so staining
  • the separation of the body is related to 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 s4 on tumors and cancer cells in vivo. The results also show that s4 can inhibit tumor growth in vivo.
  • the anticancer drug prepared from the compound s4 is a pharmaceutical composition comprising a therapeutically effective amount of the compound s4 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, and pharmaceutically 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.
  • s4 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 s4 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 active ingredient is administered in a therapeutically effective amount, for example, from about 1 microgram per kilogram body weight to about 5 milligrams per kilogram body weight per day.
  • s4 of the invention may also be used with other therapeutic agents.
  • a therapeutically effective amount of s4 can be administered to a mammal, wherein the therapeutically effective dose is typically at least about 10 micrograms per kilogram of body weight, and in most cases no more than about 80 milligrams per kilogram.
  • the body weight preferably the dose 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 s4 of the present invention has a killing or inhibiting effect on various tumor cells and cancer cells; meanwhile, the compound s4 of the present invention has an inhibitory effect on the phosphokinase Aurora-B. This all proves that the compound s4 of the present invention has an effect of inhibiting malignant tumors.
  • the compound s4 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.
  • AURORAB phosphorylation substrate MBP (UPSTATE, CAT#13-110, lot#27845), covalently binds ⁇ - 33 [ on the [ ⁇ - 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.
  • the IC50 is 632nM.
  • Seed plate 1000 cells / hole
  • Cell line human colon cancer cell line (sw620)
  • 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)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'utilisation de 1,2-dihydroxy-3-methyl-9,10-anthraquinone dans la fabrication de médicaments pour traiter les cancers. Le composé précité permet d'inhiber des cellules cancéreuses du foie, du côlon, des poumons et de l'estomac et de la phosphokinase Aurora-B. Le composé de cette invention peut être formulé sous forme de compositions pharmaceutiques anticancéreuses comportant des excipients pharmaceutiquement acceptables pour supprimer des croissances tumorales continues.
PCT/CN2007/070650 2006-09-07 2007-09-07 1,2-dihydroxy-3-methyl-9,10-anthraquinone utile dans la fabrication de médicaments pour traiter les cancers WO2008031358A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNA2006100309167A CN101112368A (zh) 2006-09-07 2006-09-07 化合物s4在制备抗癌药物中的应用
CN200610030916.7 2006-09-07

Publications (1)

Publication Number Publication Date
WO2008031358A1 true WO2008031358A1 (fr) 2008-03-20

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CN (1) CN101112368A (fr)
WO (1) WO2008031358A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101988757B1 (ko) * 2017-12-19 2019-06-12 가톨릭대학교 산학협력단 1,2-디하이드록시-3-메틸안트라퀴논을 유효성분으로 하는 간암 예방 또는 치료용 조성물

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6875746B1 (en) * 2002-04-15 2005-04-05 Board Of Trustees Of Michigan State University Anticancer anthraquinones and method of use thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6875746B1 (en) * 2002-04-15 2005-04-05 Board Of Trustees Of Michigan State University Anticancer anthraquinones and method of use thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KANOKMEDHAKUL K. ET AL.: "Biological activity of Anthraquinones and Triterpenoids from Prismatomeris fragrans", JOURNAL OF ETHNOPHARMACOLOGY, vol. 100, no. 3, 2005, pages 284 - 288, XP025269900, DOI: doi:10.1016/j.jep.2005.03.018 *
WU T.-S. ET AL.: "Cytotoxic anthraquinones from the stems of Rubia wallichiana Decne", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 51, no. 8, 2003, pages 948 - 950 *
WU Y. ET AL.: "Advances in the Studies of Rubia Yunnanensis", CHINESE JOURNAL OF ETHNOMEDICINE AND ETHNOPHARMACY, vol. 64, 2003, pages 259 - 264 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101988757B1 (ko) * 2017-12-19 2019-06-12 가톨릭대학교 산학협력단 1,2-디하이드록시-3-메틸안트라퀴논을 유효성분으로 하는 간암 예방 또는 치료용 조성물

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