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WO2002066046A1 - Agent anticancereux contenant un thiopeptide a multiples noyaux thiazole - Google Patents

Agent anticancereux contenant un thiopeptide a multiples noyaux thiazole Download PDF

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Publication number
WO2002066046A1
WO2002066046A1 PCT/KR2002/000256 KR0200256W WO02066046A1 WO 2002066046 A1 WO2002066046 A1 WO 2002066046A1 KR 0200256 W KR0200256 W KR 0200256W WO 02066046 A1 WO02066046 A1 WO 02066046A1
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WO
WIPO (PCT)
Prior art keywords
cancer
formula
thiopeptide
therapeutic agent
derivative
Prior art date
Application number
PCT/KR2002/000256
Other languages
English (en)
Inventor
Jonghee Kim
Original Assignee
Jonghee Kim
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 Jonghee Kim filed Critical Jonghee Kim
Publication of WO2002066046A1 publication Critical patent/WO2002066046A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C

Definitions

  • the present invention relates to cancer therapeutic agent comprising thiopeptide with multiple thiazole rings, its derivative or its pharmaceutically acceptable salt as an effective ingredient.
  • Cancer therapeutic agents refer to any compound exerting a cytotoxic or cytostatic effect against cancer cells by activating various metabolic pathways. Cancer therapeutic agents developed until now can be classified as metabolic antagonists, plant alkaloids, topoisomerase inhibitors, alkylatmg agents, cancer therapeutic antibiotics, hormonal agents and other drugs according to their action mechanism and chemical structure.
  • the above-mentioned cancer therapeutic agents have various target sites in the cells depending on the action mechanism.
  • the specific action mechanism of cancer therapeutic agents prevents DNA synthesis, transcription or translation of the cells, or inhibits the function of proteins having central roles in cell survival.
  • cancer cells die of necrosis or apoptosis.
  • cancer therapeutic agents In general, the metabolic pathways wherein cancer therapeutic agents act on against cancer cells do not differ from those of normal cells. Therefore, the damage (i.e. toxicity) of normal cells by cancer therapeutic agents cannot be avoidable. However, since there is a significant difference between the metabolisms of cancer cells and normal cells, which makes cancer therapeutic agents display more toxicity to " cancer cells than normal cells do, such selective toxicity of the cancer therapeutic agent makes cancer therapeutic chemotherapy clinically effective. Therefore, the bigger the specific therapeutic index, the safer the cancer therapeutic agents, wherein the specific therapeutic index means the selective killing of cancer cells without any toxicity against normal cells .
  • the protein synthesis inhibitor can show cancer therapeutic effects with selective toxicity against cancer cells.
  • kanamycm, tetracyclme, chloramphenicol, erythromycin, streptomycin, lincomycm, clindamycin, thiostrepton and micrococcm are used as antibiotics inhibiting protein synthesis.
  • Streptomyces actuosus ATCC No. 25,421
  • Streptomyces azureus ATCC No. 40,485
  • Thiostrepton targets the GTPase center which s well reserved among prokaryotic and eucaryotic cells as its target site.
  • Ribosome a protein synthesis machinery, is consisted of two subunits, and the GTPase center is located at the rRNA located in the bigger unit of the two subunits .
  • the GTPase center is located at the double hairpin structure of domain II in the 23 S-like rRNA, and the pentameric protein complex of Lll and L10(L12)4 protein combines to the double hairpin structure, performing its biological function.
  • thiostrepton serves as an antibiotic by inhibiting protein synthesis by preventing the GTPase activity at the ribosome in the presence of EF-G by being combined at the said GTPase center. Furthermore, it has been reported that thiostrepton inhibits the growth of protozoa by inhibiting protein synthesis at the plastid-like organelle of the malarial parasite ⁇ Proc . Na tl . Acad . Sci . USA, 1999, 96, 9586- 9590) . However, there has been no report that thiopeptide such as thiostrepton and its derivative show inhibition against eukaryotic cells.
  • the present inventors have designed the present invention to show that the side effects or problems in the clinical use of known chemotherapy can be overcome by confirming that cancer therapeutic agent having thiopeptide with multiple thiazole rings and its derivative which inhibits the function of ribosome in protein synthesis shows a cancer therapeutic effect completely different from that of the known antibiotic effects .
  • the present invention provides a cancer therapeutic agent comprising thiopeptide with multiple thiazole rings, its derivatives or its pharmaceutically acceptable salt.
  • Thiopeptide and its derivative of the present invention is preferably selected from a group consisting of compounds represented by formula 1 to formula 15, thiostrepton, micrococcin P, nosiheptide, siomycin, sporangiomycin, althiomycin, Promoinducin, Berninamycin, glycothiohexide alpha, Sch40832, GE37468A, GE37468B, GE37468C, GE2270, GE2270 factors C2a, GE2270 factors D2, GE2270 factors E, thiocillins, thiopeptin, amythiamicin A, sulfomycin, Thioxamycin and MJ3471F4A. More preferably, it can be selected from a group consisting of the compounds represented by formula 1 to formula 15, but is not limited to this compound, and can be selected from any known thiopeptide compound and its derivative.
  • Thiopeptide and its derivative of the present invention may be used in the form of pharmaceutically acceptable salts.
  • the acid salt formed by a pharmaceutically acceptable free acid is useful.
  • Thiopeptide and its derivative may form pharmaceutically acceptable acid salts using methods well known in the art. Both organic and inorganic acids may be used as free acids.
  • Hydrochloric acid bromic acid, sulfuric acid, phosphoric acid can be used as inorganic acid, and citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, proprionic acid, oxalic acid, trifluoroacetic acid, benzonic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluene sulfonic acid, galacturonic acid, glutamic acid or aspartic acid can be used as organic acid .
  • Thiopeptide and its derivative of the present invention can be used as a cancer therapeutic agent and can be extracted from microorganisms.
  • thiopeptide and its derivative can be obtained by a process comprising gathering mycelium after separating supernatant from the culture medium of a kind of actinomyces, Streptomyces lauren tii (ATCC NO. 31,255) by centrifugation, obtaining the mycelium extract by treating the gathered mycelium with an organic solvent, dissolving the said extract in the organic solvent again after concentrating it, eliminating impurities, and gathering crystallized thiopeptide by adding a small dosage of alcohol.
  • Thiopeptide and its derivative of the present invention can be obtained from other microorganisms such as Streptomyces a ctuosus (ATCC No. 25,421) and Streptomyces azureus (ATCC NO. 40,485) as well .
  • Thiopeptide and its derivative of the present invention show useful effects as a cancer therapeutic agent by inducing apoptosis of cancer cells. Cancer therapeutic effect is confirmed by showing selective toxicity against cancer cells, when cancer cells and normal cells were treated with thiopeptide and its derivative of the present invention dissolved in a pharmaceutically acceptable solvent, such as dimethyl sulfoxide .
  • Cancers wherein thiopeptide and its derivative of the present invention can be applied, can be selected from a group consisting of gastric cancer, liver cancer, colon cancer, lung cancer, cervical cancer, breast cancer, ovarian cancer and leukemia.
  • thiopeptide and its derivative of the present invention can be effectively applied, but is not limited, to gastric cancer and liver cancer. In addition, it can be effectively applied to any known cancer.
  • the IC 50 value of thiopeptide and its derivative of the present invention against cancer cells range from 0.2 ⁇ mol to 12 ⁇ mol (see table 1) .
  • a pharmaceutical composition containing thiopeptide with multiple thiazole rings and its derivative as an effective ingredient can be prepared by mixing thiopeptide with multiple thiazole rings and its derivative with a pharmaceutically acceptable carrier.
  • Cancer therapeutic agents comprising thiopeptide with multiple thiazole rings and its derivative may further include generally-used fillers, extenders, binders, wetting agents, disintegrating agents, diluents such as surfactant, or excipients, and may be formulated with tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, dusting powders and sprays by conventional methods .
  • solid formulations for oral administration of the cancer therapeutic agent of the present invention are tablets, pill, dusting powders and capsules
  • liquid formulations for oral administration are suspensions, solutions, emulsions and syrups
  • the abovementioned formulations can include various excipients such as wetting agents, sweeteners, aromatics and preservatives in addition to the generally-used simple diluents such as water and liquid paraffin.
  • Tablets, coated tablets, capsules, pills and granules can contain the active compound or compounds in addition to the customary excipients, such as (a) fillers and extenders, for example starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, for example carboxymethylcellulose, alginates, gelatine and polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) disintegrating agents, for example agar- agar, calcium carbonate and sodium carbonate, (e) solution retarders, for example paraffin, and (f) absorption accelerators, for example quaternary ammonium compounds, (g) wetting agents, for example cetyl alcohol and glycerol monostearate, (h) adsorbents, for example kaolin and bentonite, and (i) lubricants, for example talc, calcium stearate, magnesium stearate, and solid polyethylene
  • the tablets, coated tablets, capsules, pills and granules can be provided with the customary coatings and shells, optionally containing opacifying agents, and can also be of a composition such that they release the active compound or compounds only or preferentially in a certain part of the intestinal tract, if appropriate in a delayed manner.
  • opacifying agents for example, polymeric substances and waxes.
  • cancer therapeutic agent comprising thiopeptide with multiple thiazole rings and its derivative can be parenterally administered.
  • Parenteral administration can be performed by hypodermic, intravenous, intramuscular or subcutaneous injection.
  • the cancer therapeutic agent of the present invention can be prepared for parenterally administration by being mixed with generally-used fillers, extenders, binders, wetting agents, disintegrating agents, diluents such as surfactant, or excipients.
  • the dosage may be determined in light of various relevant factors including the absorption rate of the active ingredient, the inactivity rate, the excretion rate, the age, sex and body weight of the object to be treated, the nature and severity of the disease, the nature of the formulation and of the administration of the medicament and the period or interval wherein the administration takes place.
  • Example 1 Separation of thiopeptide with multiple thiazole rings
  • the mycelium extract was obtained using chloroform, and the chloroform extract was concentrated in vacuum at 40 ° C.
  • the impurity was eliminated using methanol, and the extract was dissolved again in the chloroform.
  • the extract was crystallized by adding methanol .
  • Example 2 Measurement of cancer therapeutic effect of thiopeptide
  • the present inventors estimated the effect of thiopeptide and its derivative on the growth of cancer cells by measuring the growth rate of cancer cells .
  • the present inventors treated gastric cancer, liver cancer, colon cancer, lung cancer, cervical cancer, breast cancer, ovarian cancer, leukemia cell lines and the monocyte (MNC) separated from the blood of a healthy person as a control with thiopeptide and its derivative of the present invention dissolved in DMSO (dimethyl sulfoxide) at various concentrations (from 10 nmol to 10 ⁇ mol) for 72 hours.
  • DMSO dimethyl sulfoxide
  • thiopeptide and its derivative of the present invention showed specific toxicity against various types of cancer cells in proportion to the concentration of thiopeptide and its derivative within the range of the concentration being administered.
  • MNC used as the control group MNC did not show toxicity from 10 nmol to 10 ⁇ mol (Table 1 and Table 2) .
  • Example 3 Acute toxicity in rats tested via oral
  • thiopeptide and its derivative of the present invention have acute toxicity m rats.
  • Six-week old specific- pathogen free (SPF) SD line rats were used in the tests for acute toxicity.
  • Thiopeptide and its derivative of the present invention were suspended in a methylcellulose solution of 0.5% and orally administered once to six rats per group at the dosage of 5 g/kg/15 ml. Death, clinical symptoms, and weight change in the tested animals were observed.
  • hematological and biochemical tests of blood were performed, and any abnormal signs in the gastrointestinal organs of chest and abdomen were visually (with the naked eye) checked during autopsy.
  • thiopeptide and its derivative of the present invention can be usefully used as a cancer therapeutic agent inducing the selective death of cancer cells, since they show selective toxicity against various types of cancer cells without showing any toxicity against normal cells.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un agent anticancéreux contenant un thiopeptide à multiples noyaux thiazole ou un dérivé de celui-ci. Elle concerne en particulier un agent anticancéreux contenant un thiopeptide ou un dérivé de celui-ci, sélectionnés dans le groupe comprenant des composés représentés par les formules chimiques 1 à 15, thiostrepton, micrococcine P, nosiheptide, siomycine, sporangiomycine, althiomycine, Promoinducine, Berninamycine, glycothiohexide alpha, Sch40832, GE37468A, GE37468B, GE37468C, GE2270, GE2270 facteur C2a, GE2270 facteur D2, GE2270 facteur E, thiocillines, thiopeptine amythiamycine A, sulfomycine, Thioxamycine et MJ3471F4A. Cet agent anticancéreux contenant un thiopeptide ou un dérivé de celui-ci présente une cytotoxicité sélective à l'égard de divers types de cellules cancéreuses, et n'est pas cytotoxique à l'égard des cellules normales. Il constitue par conséquent un candidat utile pour traiter des cancers, par induction d'apoptose ou de nécrose sélectives de cellules cancéreuses.
PCT/KR2002/000256 2001-02-20 2002-02-19 Agent anticancereux contenant un thiopeptide a multiples noyaux thiazole WO2002066046A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPR3207 2001-02-20
AUPR3207A AUPR320701A0 (en) 2001-02-20 2001-02-20 The new cancer therapeutic agent with a thiopeptides

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004074295A1 (fr) * 2003-02-21 2004-09-02 Keio University Polymeres cycliques de thiazole, leur procede de preparation, leurs intermediaires de synthese et leur utilisation
WO2005115374A1 (fr) * 2004-05-29 2005-12-08 7Tm Pharma A/S Ligands du recepteur crth2 utilises a des fins therapeutiques
JP2009534370A (ja) * 2006-04-18 2009-09-24 ピラマル・ライフ・サイエンシーズ・リミテッド 新規抗菌化合物
WO2011027290A1 (fr) * 2009-09-02 2011-03-10 Piramal Life Sciences Limited Composés antibiotiques
WO2012062906A1 (fr) 2010-11-11 2012-05-18 Instituto Biomar, S.A. Peptides en tant que composés bioactifs
WO2020127194A1 (fr) 2018-12-17 2020-06-25 Pharma Mar, S.A. Composés anticancéreux
CN113769060A (zh) * 2021-09-28 2021-12-10 上海交通大学医学院附属第九人民医院 那西肽在制备牙周炎治疗药物中的应用
CN113769064A (zh) * 2021-09-28 2021-12-10 上海交通大学医学院附属第九人民医院 硫链丝菌素在制备牙周炎治疗药物中的应用
JP2022518143A (ja) * 2019-01-04 2022-03-14 ユニバーシティ・オブ・バーモント・アンド・ステイト・アグリカルチュラル・カレッジ ビタミンｅならびにがん治療用組成物および方法
WO2024136758A1 (fr) * 2022-12-21 2024-06-27 Agency For Science, Technology And Research Composés de thiopeptide

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JPS5663918A (en) * 1979-10-30 1981-05-30 Shionogi & Co Ltd Antitumorigenic agent containing siomycin half ester
KR20000025145A (ko) * 1998-10-08 2000-05-06 김성년 치오아세틸 디펩티드 유도체와 이로부터 제조되는이기능성 리간드 및 그 제조방법

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5663918A (en) * 1979-10-30 1981-05-30 Shionogi & Co Ltd Antitumorigenic agent containing siomycin half ester
KR20000025145A (ko) * 1998-10-08 2000-05-06 김성년 치오아세틸 디펩티드 유도체와 이로부터 제조되는이기능성 리간드 및 그 제조방법

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Title
BOOK OF ABSTRACTS, 213TH ACS NATIONAL MEETING, April 1997 (1997-04-01) *
DATABASE CA [online] SHEN Y. AND CIUFOLINI M.A.: "Synthetic studies on thiostrepton antibiotics", Database accession no. 1997:162666 *
ZACHARIE B. ET AL.: "Thioamides: Synthesis, stability and immunological activities of tio-analogs of Imreg. Preparation of new thioacylating agents using fluorobenzimidazolone derivatives", JOURNAL OF MEDICINAL CHEMISTRY, vol. 42, no. 11, 1999, pages 2046 - 2052 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004074295A1 (fr) * 2003-02-21 2004-09-02 Keio University Polymeres cycliques de thiazole, leur procede de preparation, leurs intermediaires de synthese et leur utilisation
WO2005115374A1 (fr) * 2004-05-29 2005-12-08 7Tm Pharma A/S Ligands du recepteur crth2 utilises a des fins therapeutiques
JP2009534370A (ja) * 2006-04-18 2009-09-24 ピラマル・ライフ・サイエンシーズ・リミテッド 新規抗菌化合物
AU2010290872B2 (en) * 2009-09-02 2015-06-11 Piramal Enterprises Limited Antibiotic compounds
WO2011027290A1 (fr) * 2009-09-02 2011-03-10 Piramal Life Sciences Limited Composés antibiotiques
CN102574892A (zh) * 2009-09-02 2012-07-11 皮拉马尔生命科学有限公司 抗生素复合物
CN102574892B (zh) * 2009-09-02 2014-12-17 皮拉马尔企业有限公司 抗生素复合物
RU2536587C2 (ru) * 2009-09-02 2014-12-27 Пирамал Энтерпрайзис Лимитед Антибиотические соединения
WO2012062906A1 (fr) 2010-11-11 2012-05-18 Instituto Biomar, S.A. Peptides en tant que composés bioactifs
WO2020127194A1 (fr) 2018-12-17 2020-06-25 Pharma Mar, S.A. Composés anticancéreux
US12215100B2 (en) 2018-12-17 2025-02-04 Pharma Mar, S.A. Anticancer compounds
JP2022518143A (ja) * 2019-01-04 2022-03-14 ユニバーシティ・オブ・バーモント・アンド・ステイト・アグリカルチュラル・カレッジ ビタミンｅならびにがん治療用組成物および方法
JP7428352B2 (ja) 2019-01-04 2024-02-06 ユニバーシティ・オブ・バーモント・アンド・ステイト・アグリカルチュラル・カレッジ ビタミンｅならびにがん治療用組成物および方法
CN113769060A (zh) * 2021-09-28 2021-12-10 上海交通大学医学院附属第九人民医院 那西肽在制备牙周炎治疗药物中的应用
CN113769064A (zh) * 2021-09-28 2021-12-10 上海交通大学医学院附属第九人民医院 硫链丝菌素在制备牙周炎治疗药物中的应用
WO2024136758A1 (fr) * 2022-12-21 2024-06-27 Agency For Science, Technology And Research Composés de thiopeptide

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