WO2006116897A1 - Diterpenes provenant de euphorbia kansui et leur utilisation - Google Patents

Diterpenes provenant de euphorbia kansui et leur utilisation Download PDF

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Publication number
WO2006116897A1
WO2006116897A1 PCT/CN2005/000610 CN2005000610W WO2006116897A1 WO 2006116897 A1 WO2006116897 A1 WO 2006116897A1 CN 2005000610 W CN2005000610 W CN 2005000610W WO 2006116897 A1 WO2006116897 A1 WO 2006116897A1
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WIPO (PCT)
Prior art keywords
compound according
diterpenoid
compound
topoisomerase
activity
Prior art date
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PCT/CN2005/000610
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English (en)
Chinese (zh)
Inventor
Liyan Wang
Susumu Kitanaka
Shohei Miyata
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Nihon University
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Publication date
Application filed by Nihon University filed Critical Nihon University
Priority to PCT/CN2005/000610 priority Critical patent/WO2006116897A1/fr
Publication of WO2006116897A1 publication Critical patent/WO2006116897A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/723—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic
    • C07C49/727—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system

Definitions

  • the present invention relates to the separation and extraction of diterpenoids from the medicinal plant Ganzi (scientific name: Euphorbia kansui L.), and more particularly to diterpenoid compounds having activity for inhibiting topoisomerase II and uses thereof.
  • Ganzi scientific name: Euphorbia kansui L.
  • Ganzi (scientific name: Euphorbia ka let i L., position, distributed in northwestern China. Ganzi is used in China to treat respiratory diseases such as chronic bronchitis and bronchial asthma, as well as the treatment of malignant tumors such as esophageal cancer and breast cancer.
  • the study of bismuth ingredients began in 1943, and now more than ten kinds of diterpenoids and triterpenoids have been discovered. Among these ingredients, several diterpenoids have been found to have anticancer, antiviral and cytotoxic effects, and have attracted much attention. .
  • Non-Patent Document 2 S. Morris Kupc an, et. al., Science, VoL 191, pp. 571-572, 13 3 Feb., 1976
  • DNA topology enzymes are divided into two categories, respectively called extension Topo I and Topozyme II ( ⁇ II).
  • Topotease covalently binds to double-stranded DNA, causing a transient single-strand (Topo I ) or double-stranded ( Topo II ) cleavage, allowing another intact strand to pass through the nick and then join the cleavage strand, thereby altering the topology of the DNA
  • the structure allows the DA to function as a normal physiological function.
  • Topo I includes bacteria Topo I, III, eukaryotes T opo I, 111 and inverse gyrase. It is a 100kD monomeric protein encoded by a single gene.
  • Topo II includes bacterial DNA gyrase, bacterial Topo IV and eukaryotic Topo II.
  • phage T4 and certain viruses such as the porcine heat virus of the African porcine fever virus are also class II topologies.
  • Topo ⁇ is a multi-subunit protein, and eukaryote Topo II consists of two subunits, each 160-180kD. It has been reported that topological enzymes are also present in mitochondria and chloroplasts of eukaryotes.
  • Topo I and II have in common in maintaining DNA topology, and phosphorylation enhances their activity. Inhibition of one type of topology enzyme results in an increase in the activity of another type of topology enzyme. For example, if Topo I is acted upon by Top 0 I active drugs, Topo II activity is compensatoryly increased, resulting in DNA synthesis and cell survival. However, there are still some major differences between the two: 1 Topo I is not essential for living cells, not cell cycle-specific enzymes, ie its activity does not change with different stages of cell growth; Topo II is required for cells And is the most active in log phase and fast growing tumors. 2 Topo I induces single-strand DNA breaks, while Topo II induces double-strand DNA breaks. 3 Topo I's functionality does not depend on ATP, while Topo II relies on ATP.
  • TOPO II Due to the rapid proliferation of tumor cells, the content and activity of TOPO II is much higher than that of normal somatic cells, so inhibition of TOPO II activity can prevent rapid growth of tumor cells. Colonization, which in turn kills the role of tumor cells.
  • TOPO II has become an important target for anticancer drugs. Drugs that primarily target TOPO II are collectively referred to as TOPO II inhibitors. In recent years, great progress has been made in the study of anticancer drugs targeting TOPO II and their modes of action.
  • Topo I DNA complexes The interaction between DNA synthesis and drug-Topo I-DNA complexes causes the formation of DSBs on replicating DNA. That is, if the cleavage complex encounters a moving replication fork, the replication fork can produce potentially lethal damage if it has a sequence that produces a DNA double-strand break. The longer the triple complex exists, the greater the likelihood of interaction with the moving replication fork lethality.
  • Topo II inhibitors have similar mechanisms. In addition to its role in DNA synthesis, Topo II forms part of a mitotic chromosome scaffold.
  • the enzyme is located at the bottom of the chromatin loop and anchors the matrix-associated region to the scaffold.
  • Some drugs can act on Topo II at the bottom of the chromosome ring, and their function does not require DNA replication.
  • the DNA fragment is released (or exchanged) from the chromatin, the remaining chromatin ring is morphologically intact. Exchange of the subunits of the chromatin loop bottom causes lethal or mutagenic tumor cells.
  • Topo II inhibitors can cause chromosomal aberrations at any stage of the cell cycle, called "S-independent,: treatment of cells with Topo II inhibitors in S phase also causes sister chromatid exchange (SCEs). Instead, only When the Topo I inhibitor camptothecin is treated with S phase or G2 phase cells, it causes chromosomal aberrations and has no effect on G1 phase cells. In the S phase, the replication fork caused by camptothecin-Topo I-DNA complex In addition to causing chromosomal aberrations, DSBs formed by cleavage can also produce SCEs. Undoubtedly, chromosomal aberrations and/or SCEs may lead to the ultimate death of tumor cells.
  • S-independent treatment of cells with Topo II inhibitors in S phase also causes sister chromatid exchange (SCEs).
  • SCEs sister chromatid exchange
  • paclitaxel also has a similar effect to TOPO II, and it has a unique mode of action, inhibiting the unwinding of TOPO II at low concentrations and promoting its unwinding at high concentrations, since the discovery of TOPO II 20 years ago, researchers It has been well recognized that TOPO II plays an important role in DNA metabolism, chromosome recombination and cell division. TOPO II has become an important target for intracellular anticancer drugs.
  • the treatment regimen of systemic chemotherapy in almost every cancer is focused on or includes drugs targeted at it. At present, there are hundreds of anti-cancer drugs targeting TOPO II in the world in preclinical or clinical research.
  • TOPO II has made great progress, there are still many problems to be further studied and discussed: such as the exact function and division of TOPO II ⁇ and ⁇ ; TOPO II catalytic inhibitor directly inhibits enzyme activity The exact mechanism; the effect of different mechanisms of action on clinical application; the interaction between TOPO II catalytic inhibitors and TOPO II agents.
  • Topo II is an essential ribozyme for DNA metabolism and an important target enzyme for chemotherapy.
  • tumors have multiple mechanisms of resistance to Topo II inhibitors, which can lead to chemotherapy failure. Therefore, there is an urgent need to design and develop new Topo II inhibitors. Summary of the invention
  • the present invention provides a compound extracted from kansui having the formula: (1):
  • Ri to R 3 may be the same or different and represent a hydrogen atom, a linear or branched saturated or unsaturated substituted or unsubstituted aliphatic substituent; or a substituent represented by the formula RCO - wherein R represents a linear or branched saturated or unsaturated substituted or unsubstituted aliphatic substituent, or a substituted or unsubstituted aryl or heteroaryl substituent.
  • the diterpenoid compound described in the general formula (I) of the present invention is preferably
  • the compound as described above is a topoisomerase II inhibitor.
  • the compound as described above is a topoisomerase II inhibitor having only the activity of inhibiting topoisomerase II and having no apoptotic activity.
  • a compound as described above for use in the manufacture of a medicament for the treatment of a neoplastic disease is described above for use in the manufacture of a medicament for the treatment of a neoplastic disease.
  • the tumor is a solid tumor.
  • the tumor is breast cancer.
  • the tumor is esophageal cancer.
  • a pharmaceutical composition comprising a compound as described above as an active ingredient and a pharmaceutically acceptable carrier and/or adjuvant.
  • the sexual anticancer drug and active ingredient include a pharmaceutical composition of the compound as described above.
  • the compound of the formula (I) exhibits cell division inhibitory activity against animal pole cells of the late cell embryo of the African clawed frog, and can be used as a therapeutic drug for malignant tumors such as esophageal cancer and breast cancer.
  • the compounds of the present invention are novel diterpenoids effective against malignant tumors and can be used against malignant tumors against drugs.
  • the cells cause necrosis.
  • the inhibitory concentration of the topoisomerase II inhibitor does not cause cell proliferation and necrosis at all, as cell division and cancer.
  • the reagents for pathogenesis studies are of high value.
  • the ingenol derivative inhibits only topoisomerase II activity and has no apoptotic activity, so it was found that the ingenol derivative is a novel topoisomerase II inhibitor.
  • a topoisomerase II inhibitor contains a specific compound specifically for the spread of breast cancer cells.
  • the topoisomerase II inhibitor of the present invention acts as a genetic
  • the reagents for analyzing the function of the topography in the discovery of interest, or the anticancer agents for the cancer molecules that are aimed at the topology II are all expected large populations of sterol derivatives. detailed description
  • the aliphatic group is preferably a linear or branched saturated or unsaturated aryl group having 1 to 30 carbon atoms, more preferably 1 to 16 An aliphatic group of carbon atoms.
  • substituent of the aliphatic group include a halogen atom, a hydroxyl group, an ether group, a carbonyl group, an amino group, an acylamino group and the like.
  • the carboxylic acid having R as a hydrocarbon group may, for example, be acetic acid, propionic acid, butyric acid, 2,3-dimethylbutyric acid, octanoic acid or decanoic acid.
  • a saturated fatty acid having 1 to 16 carbon atoms such as lauric acid, myristic acid or palmitic acid, and an unsaturated fatty acid having 1 to 16 carbon atoms such as 2,4-sebacic acid.
  • Examples of the carboxylic acid wherein R is an aryl group include aromatic carboxylic acids such as benzoic acid, phthalic acid, salicylic acid and anthranilic acid.
  • the carboxylic acid wherein R is a heteroaryl group may, for example, be an aromatic heterocyclic carboxylic acid such as citric acid, thiopheneic acid, pyridinecarboxylic acid, nicotinic acid or isonicotinic acid.
  • the substituent of the aryl group and the heteroaryl group include a halogen atom, a hydroxyl group, an ether group, a carbonyl group, a carboxyl group, an amino group, an acylamino group and the like.
  • Example 1 Chinese cabbage glutinous rice 15 kg (scientific name: Euphorbia kansui L.) was formulated into a 45 L solution with 60% ethanol, and this was subjected to two heating leaching, followed by concentration under reduced pressure to obtain 1200 g of an extract. This was dissolved in 4 L of water, and each of them was extracted three times with 4 L of chloroform, ethyl acetate and butanol. After concentrating under reduced pressure, 165 g of a chloroform fraction, 23 g of ethyl acetate fraction and 64 g of a butanol fraction were obtained.
  • ODS-751 5-12A reverse phase column
  • eluent water-methanol system
  • %, 40%, 30%, and 10% are sequentially expanded to perform separation.
  • a solution eluted near about 40% of water was taken and separated by normal phase HPLC.
  • the column was sieved
  • the peak eluted at a retention time of 11 minutes, 13 minutes, 21 minutes, and 27 minutes was separated by UV (210 nm).
  • the eluate of these peaks was concentrated under reduced pressure to give compound 5, 6, 7, 9 (11.lmg, 9.8mg, 4.1mg, 12.3mg) as a colorless oil.
  • a solution eluted near about 50% of water was taken and separated by normal phase HPLC.
  • YMC - P ack SIL - 06 manufactured by YMC, 1 50 x 20 mm
  • Example 4 specifically inhibits cell proliferation and inhibition mechanism
  • the compounds of the present invention can be used by oral, parenteral, and subcutaneous injection.
  • the daily dose per adult is 0.1 mg to 100 mg per 1 kg body weight.
  • the compounds of the invention may be used in a variety of pharmaceutical forms. For example, tablets, powders, granules, capsules, injections, suppositories, ointments, cataplasms, and the like.
  • a carrier or an additive which is commonly used in pharmaceuticals such as a solvent, a base, a diluent, a filler, and the like, a cosolvent can be used according to a normal method.
  • An agent such as an emulsifier, a dispersing agent, a disintegrating agent, a meltable agent, a thickener, a lubricant, and the like, an antioxidant, a preservative, a fragrance, a sweetener, and the like.
  • the compound provided by the present invention or a pharmaceutically acceptable salt, enantiomer, racemate, tautomer or physiological functional derivative thereof, is administered alone, it is preferably provided in a pharmaceutical preparation, the preparation including the present A pharmaceutically acceptable carrier or excipient of the compound or a pharmaceutically acceptable salt, enantiomer, racemate, tautomer or physiologically functional derivative thereof, and optionally one Or a variety of other therapeutic ingredients.
  • the preparation includes an orally administered preparation, an inhalation preparation (including a particulate aerosol or an aerosol produced by a different dose of a pressurized aerosol device, a nebulizer, an insufflator), a topical preparation (including skin administration, oral administration). Medicine, sublingual administration, intraocular administration). The most suitable route of administration depends on the condition and disease of the patient being administered.
  • the formulations are usually provided in unit dosage form and may be prepared by any methods known in the art of pharmacy. All methods include the step of mixing the active ingredient with a carrier which is comprised of one or more accessory ingredients.
  • the active ingredient is uniformly and tightly bound to a liquid or a fine solid carrier or both, and then the product is formulated as needed; the preparation of the invention suitable for oral administration can be in a separate unit such as a capsule.
  • a sputum or tablet is provided, and each unit contains a predetermined amount of the active ingredient; a powder or granule; a water-soluble liquid or suspension; or an oil-in-water emulsion or a water-in-oil emulsion; or a granule or a medicine Sugar or paste.
  • Tablets may be prepared by tableting or molding, optionally with one or more accessory ingredients; by compressing free-flowing forms such as powders or granules on a suitable machine (optional with binders, lubricants, inert diluents)
  • the active fraction in the mixture of surfactants or dispersing agents can be used to prepare compressed tablets; the tablets can optionally be coated or indented and formulated to provide sustained or controlled release of the active ingredient.
  • Formulations for topical administration to the oral cavity including lozenges of the active ingredient in a flavoring base such as sucrose, arabinose.
  • formulations of the present invention also include other conventional ingredients of the type of formulation in the art.
  • the following examples exemplified by the compound (1) are equally applicable to the other compounds in the present invention.
  • Compound (1) 40 g extracted from licorice is mixed with 100 g of lactose and 10 g of magnesium stearate to fill the intestinal sol with 600 mg of each of the intestinal sol elixirs. (1) 160 mg.

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

Abstract

La présente invention concerne des diterpènes originaux avec une activité anti-tumorale de formule (1), dans laquelle R1 à R3 représentent un groupe aliphatique; ou représentent un groupe de RCO-, dans laquelle R représente un groupe aliphatique, un groupe aryle, ou un groupe hétéroaryle. Les composés de la présente invention sont préparés par extraction de racines d’euphorbia kansui avec un solvant organique (chloroforme, acétate d’éthyle et butanol) et en traitant l’extrait au moyen de procédés conventionnels. Les composés de la présente invention ont une activité d’inhibition de la prolifération cellulaire, et peuvent inhiber la prolifération de lignées de cellules cancéreuses spécifiques via l’inhibition de la topoisomérase. Ces composés peuvent être utilisés pour la préparation de médicaments pour le traitement d’une tumeur maligne.
PCT/CN2005/000610 2005-04-30 2005-04-30 Diterpenes provenant de euphorbia kansui et leur utilisation WO2006116897A1 (fr)

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Cited By (12)

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CN102126941A (zh) * 2010-12-20 2011-07-20 南京春秋生物工程有限公司 一种用于制备抗肿瘤药物的大戟科大戟属植物提取物的制备方法
JP2014507393A (ja) * 2010-12-22 2014-03-27 レオ・ラボラトリーズ・リミテッド ３−アシル−イノゲノールｉｉ
JP2014507396A (ja) * 2010-12-22 2014-03-27 レオ・ラボラトリーズ・リミテッド イノゲノール−３−アシラートｉ
JP2014512331A (ja) * 2010-12-22 2014-05-22 レオ・ラボラトリーズ・リミテッド インゲノール−３−アシラートｉｉｉおよびインゲノール−３−カルバメート
CN103974926A (zh) * 2011-10-04 2014-08-06 因德纳有限公司 分离巨大戟醇的方法
CN104024212A (zh) * 2011-10-19 2014-09-03 韩国生命工学研究院 巨大戟烷型二萜化合物及含有它的用于治疗或预防病毒感染疾病的药物组合物
CN104136081A (zh) * 2012-03-02 2014-11-05 阿马佐尼亚菲托药品有限公司 再活化潜伏hiv病毒的巨大戟二萜醇衍生物
CN104622865A (zh) * 2013-11-14 2015-05-20 中国科学院上海药物研究所 巨大戟二萜类化合物在制备抗肿瘤药物中的应用
CN105153071A (zh) * 2014-11-28 2015-12-16 天津耀宇生物技术有限公司 一种萜类化合物的制备方法
JP2016502509A (ja) * 2012-11-01 2016-01-28 アマゾニア フィトメディカメントス リミターダＡｍａｚｏｎｉａ Ｆｉｔｏｍｅｄｉｃａｍｅｎｔｏｓ Ｌｔｄａ． がんを治療するのに有効なインゲノール誘導化合物
CN103974926B (zh) * 2011-10-04 2016-11-30 因德纳有限公司 分离巨大戟醇的方法
CN106749107A (zh) * 2016-11-24 2017-05-31 中国科学院新疆理化技术研究所 准噶尔大戟中的萜类化合物及其制备方法和用途

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WANG L.-Y. ET AL.: "Diterpenes from the Roots of Euphorbia Kansui and Their in Vitro Effects on the Cell Division of Xenopus", J. NAT. PROD., vol. 65, no. 9, 2002, pages 1246 - 1251 *
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Cited By (22)

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CN102126941A (zh) * 2010-12-20 2011-07-20 南京春秋生物工程有限公司 一种用于制备抗肿瘤药物的大戟科大戟属植物提取物的制备方法
US9388124B2 (en) 2010-12-22 2016-07-12 Leo Laboratories Limited Ingenol-3-acylates I
JP2014507393A (ja) * 2010-12-22 2014-03-27 レオ・ラボラトリーズ・リミテッド ３−アシル−イノゲノールｉｉ
JP2014507396A (ja) * 2010-12-22 2014-03-27 レオ・ラボラトリーズ・リミテッド イノゲノール−３−アシラートｉ
JP2014512331A (ja) * 2010-12-22 2014-05-22 レオ・ラボラトリーズ・リミテッド インゲノール−３−アシラートｉｉｉおよびインゲノール−３−カルバメート
US9708286B2 (en) 2010-12-22 2017-07-18 Leo Laboratories Limited Ingenol-3-acylates III and ingenol-3-carbamates
US9656945B2 (en) 2010-12-22 2017-05-23 Leo Laboratories Limited 3-acyl-ingenols II
JP2016029081A (ja) * 2010-12-22 2016-03-03 レオ・ラボラトリーズ・リミテッドＬｅｏ Ｌａｂｏｒａｔｏｒｉｅｓ Ｌｉｍｉｔｅｄ インゲノール−３−アシラートｉｉｉおよびインゲノール−３−カルバメート
CN103974926A (zh) * 2011-10-04 2014-08-06 因德纳有限公司 分离巨大戟醇的方法
CN103974926B (zh) * 2011-10-04 2016-11-30 因德纳有限公司 分离巨大戟醇的方法
CN104024212A (zh) * 2011-10-19 2014-09-03 韩国生命工学研究院 巨大戟烷型二萜化合物及含有它的用于治疗或预防病毒感染疾病的药物组合物
US9481630B2 (en) 2011-10-19 2016-11-01 Korea Research Institute Of Bioscience And Biotechnology Ingenane-type diterpene compound, and pharmaceutical composition for treating or preventing viral infectious diseases containing same
RU2609512C2 (ru) * 2012-03-02 2017-02-02 Амазония Фитомедикаментос Лтда. Производные ингенола для реактивации латентного вируса вич
EP2821105A4 (fr) * 2012-03-02 2015-11-04 Amazonia Fitomedicamentos Ltda Dérivés d'ingénol pour la réactivation du virus vih latent
CN104136081A (zh) * 2012-03-02 2014-11-05 阿马佐尼亚菲托药品有限公司 再活化潜伏hiv病毒的巨大戟二萜醇衍生物
AU2013225633B2 (en) * 2012-03-02 2017-11-23 Amazonia Fitomedicamentos Ltda. Ingenol derivatives in the reactivation of latent HIV
JP2016502509A (ja) * 2012-11-01 2016-01-28 アマゾニア フィトメディカメントス リミターダＡｍａｚｏｎｉａ Ｆｉｔｏｍｅｄｉｃａｍｅｎｔｏｓ Ｌｔｄａ． がんを治療するのに有効なインゲノール誘導化合物
CN104622865A (zh) * 2013-11-14 2015-05-20 中国科学院上海药物研究所 巨大戟二萜类化合物在制备抗肿瘤药物中的应用
CN104622865B (zh) * 2013-11-14 2019-07-09 中国科学院上海药物研究所 巨大戟二萜类化合物在制备抗肿瘤药物中的应用
CN105153071A (zh) * 2014-11-28 2015-12-16 天津耀宇生物技术有限公司 一种萜类化合物的制备方法
CN106749107A (zh) * 2016-11-24 2017-05-31 中国科学院新疆理化技术研究所 准噶尔大戟中的萜类化合物及其制备方法和用途
CN106749107B (zh) * 2016-11-24 2019-08-16 中国科学院新疆理化技术研究所 准噶尔大戟中的萜类化合物及其制备方法和用途

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