US20110269698A1 - Novel Cyclic Pentadepsipeptide Derivative and Fusarium Strain Producing The Same - Google Patents

Novel Cyclic Pentadepsipeptide Derivative and Fusarium Strain Producing The Same Download PDF

Info

Publication number
US20110269698A1
US20110269698A1 US12/600,830 US60083009A US2011269698A1 US 20110269698 A1 US20110269698 A1 US 20110269698A1 US 60083009 A US60083009 A US 60083009A US 2011269698 A1 US2011269698 A1 US 2011269698A1
Authority
US
United States
Prior art keywords
fusarium
cyclic
acid
chemical formula
strain
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.)
Abandoned
Application number
US12/600,830
Other languages
English (en)
Inventor
Chan Lee
Hyuk-Hwan Song
Hee-Seok Lee
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.)
Industry Academic Cooperation Foundation of Chung Ang University
Original Assignee
Industry Academic Cooperation Foundation of Chung Ang 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 Industry Academic Cooperation Foundation of Chung Ang University filed Critical Industry Academic Cooperation Foundation of Chung Ang University
Assigned to CHUNG-ANG UNIVERSITY INDUSTRY-ACADEMY COOPERATION FOUNDATION reassignment CHUNG-ANG UNIVERSITY INDUSTRY-ACADEMY COOPERATION FOUNDATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEE, CHAN, LEE, HEE-SEOK, SONG, HYUK-HWAN
Publication of US20110269698A1 publication Critical patent/US20110269698A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K11/02—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof cyclic, e.g. valinomycins ; Derivatives thereof
    • 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
    • A61K38/15—Depsipeptides; Derivatives thereof
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi
    • C12R2001/77—Fusarium

Definitions

  • the present invention relates to medicinally useful compounds and a microorganism producing the same. More particularly, the present invention relates to novel cyclic pentadepsipeptides with excellent multidrug resistance-reversing activity and inhibitory activity against cancer cells, which are produced by a soil stain of the genus Fusarium.
  • a fungus of the genus Fusarium distributed in association with higher marine plants has proven to be a promising source for the production of sansalvamide, a kind of cytotoxic cyclic depsipeptide.
  • Sansalvamide A was first reported to be produced by Halodule wrightii, a kind of marine microorganisms [Belofsky G N, Jensen P R, Fenical W. (1999) Sansalvamide: A new cytotoxic cyclic depsipeptide produced by a marine fungus of the genus Fusarium. Tetrahedron Lett. 40, 2913-2916]. It is composed of four hydrophobic amino acid residues (phenylalanine, two leucines, valine) and one hydroxy acid ((S)-2-hydroxy-4-methylpentanoic acid; O-Leu) with five stereogenic centers all having S-stereochemistry.
  • Sansalvamide A was found to have marked anti-proliferative effects on 60 cell lines of the National Cancer Institute, with inhibitory activity against topoisomerase I. Anti-cancer effects of Sansalvamide A may be, at least in part, mediated by this mechanism. Further, the analogues formed by N-methylation or para-bromination of sansalvamide A of FIG. 1 were also found to exhibit remarkable cytotoxicity against human pancreatic cancer cells, suggesting that these cyclic compounds may be highly useful as anti-cancer agents [Ujiki M B, Milam B, Ding X Z, Roginsky A B, Salabat M R, Talamonti M S, Bell R H, Gu W, Silverman R B, Adrian T E. (2006) A novel peptide sansalvamide analogue inhibits pancreatic cancer cell growth through G0/G1 cell-cycle arrest. Biochem. Bioph. Res. Co. 340, 1224-1228].
  • N-methylsansalvamide a sansalvamide analogue with N-methylation
  • N-Methylsansalvamide was reported to exhibit in vitro cytotoxicity in the NCI human tumor cell line screen [Cueto M, Jensen P R, Fenical W. (2000) N-Methylsansalvamide, a cytotoxic cyclic depsipeptide from a marine fungus of the genus Fusarium. Phytochemistry. 55, 223-226].
  • Multidrug resistance is arising as one of the major obstacles to successful chemotherapy for human cancer.
  • a variety of biochemical, pharmacological and clinical strategies for overcoming MDR have been designed and suggested [Teodori E, Dei S, Scapecchi S, Gualtieri F. (2002) The medicinal chemistry of multidrug resistance (MDR) reversing drugs. II Farmaco 57, 385-415].
  • P-gp P-glycoproteins
  • MRP multidrug resistance-associated proteins
  • Sansalvamide A is a lipophilic, cyclic depsipeptide, which is of protease resistance and membrane permeability, so that it may advantageously take an oral route, compared to other drugs.
  • a cyclic core structure composed of four amino acids and one hydroxy acid, in which rotation around C—C bonds is restricted, sansalvamide A has a firm conformation which is of excellent compatibility to the body and enjoys a long half life.
  • sansalvamide analogues synthesized to utilize the structural merits and the cytotoxicity against cancer cells of sansalvamide A or N-methylsansalvamide, none of them are concerned with separated, cyclic pentadepsipeptides.
  • the present invention pertains to a novel cyclic peptadepsipeptide represented by Chemical Formula 1 or 2:
  • organic synthesis for altering the sequence of the constitutional amino acids and hydroxy acid is accompanied by the interruption of the ester bond between the hydroxy acid ((S)-2-hydroxy-4-methylpentanoic acid; OLeu) and the phenylalanine within the core structure.
  • the novel, cyclic pentadepsipeptides represented by Chemical Formulas 1 and 2, according to the present invention have cytotoxicity over a wide spectrum of types of cancer that is as potent as that of sansalvamide A.
  • the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 show the drug resistance-reversing activity which has not yet been reported in conventional analogues synthesized on the basis of the sansalvamide A or N-methylsansalvamide. Excellent drug resistance-reversing activity is found in the cyclic pentadepsipeptide of Chemical Formula 1.
  • pathogens or cells When pathogens or cells are exposed to chemotherapy, they may become resistant to the drug and possibly to other structurally unrelated drugs.
  • the pathogens or cells are said to be drug-resistant when drugs meant to neutralize them have a reduced effect.
  • drug resistance-reversing activity is intended to mean not only suppressing the generation of drug-resistant cells or keeping the cells sensitive to the drugs, but also increasing or recuperating the sensitivity of drug-resistant cells to the drugs.
  • the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 according to the present invention or pharmaceutically acceptable salts thereof may be useful in the treatment of multidrug-resistant cancer.
  • the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 or pharmaceutically acceptable salts thereof may be used in combination with conventional drug-resistant inhibitors such as cyclosporine or analogues, phenothiazine, thioxantheres, verapamil, etc.
  • cyclic pentadepsipeptides of Chemical Formulas 1 and 2 according to the present invention or pharmaceutically acceptable salts thereof may be used in combination with anticancer agents, that is, standard chemotherapy agents, in the treatment of cancer and preferably in the treatment of tumors resistant to drugs a priori or a posteriori.
  • the present invention pertains to a Fusarium strain producing the cyclic pentadepsipeptide of Chemical Formula 1 or 2.
  • the Fusarium strain producing the novel compound is Fusarium solani KCCM90040 [Accession No.: KCCM10881P].
  • the present invention pertains to a method for producing the cyclic pentadepsipeptide of Chemical Formula 1 or 2 by culturing the strain.
  • This culturing is preferably conducted on a cereal substance.
  • the cereal substance useful in the present invention is selected from among rice, wheat, maize, rye, Indian millet, barley and a combination thereof, preferably from among rice, wheat, maize and rye, more preferably from among rice and wheat, and most preferably rice.
  • the marine Fusarium strains Being produced from the marine Fusarium strains, sansalvamide or N-methylsansalvamide requires a seawater-based medium for the production thereof. Further, the marine strains are very poor in the productivity of sansalvamide or N-methylsansalvamide per volume of medium.
  • the Fusarium strain of the present invention is of soil origin and can produce the compound of Chemical Formula 1 or 2 in high yield on a solid cereal substance.
  • the cereal substance useful for culturing the strain is preferably rice.
  • the strain of the present invention is preferably cultured at a temperature of from 20 to 30° C. and at an RH of from 20 to 50% for 10 ⁇ 20 days. Optimally, it is cultured at 25.84° C. and 37.99% RH for 16.03 days.
  • a strain producing a cyclic depsipeptide was isolated from potatoes grown in Munkyoung Korea and identified as a strain of Fusarium solani. It was named Fusarium solani KCCM90040 and deposited with the Korean Culture Center of Microorganisms on Jan. 15, 2008 with accession No. KCCM10881P according to the Budapest Treaty.
  • the compounds of produced by the strain were analyzed to be 15-membered ring compounds different from sansalvamide A and N-methylsansalvamide in the sequence of constitutional amino acids and hydroxy acid and identified as cyclic pentadepsipeptides of Chemical Formulas 1 and 2.
  • the cyclic pentadepsipeptides of Chemical Formula 1 or 2 in accordance with the present invention or pharmaceutically acceptable salts thereof shows inhibitory activity against drug-resistant cells, which may be tumor cells or antibiotic-resistant cells, and thus can be used as an active ingredient of a pharmaceutical composition for inhibiting the drug resistance of cells.
  • the pentadepsipeptides of Chemical Formula 1 and 2 in accordance with the present invention may also be used as an active ingredient of a pharmaceutical composition for the treatment of cancer.
  • pharmaceutically acceptable salt means non-toxic organic or inorganic acid addition salts of the compounds of interest.
  • inorganic acids useful in the present invention include hydrochloric acid, hydrobromic acid, sulfuric acid, acid metal salts (e.g., sodium hydrogen phosphate, potassium hydrogen sulfate), etc.
  • organic acid useful in the present invention include mono-, di- and tricarboxylic acid.
  • acetic acid glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid and 2-phenoxybenzoic acid.
  • Other organic acids may be exemplified by methane sulfonic acid and 2-hydroxyethane sulfonic acid.
  • Such salts can be either in hydrated or anhydrous form.
  • the acid addition salts of these compounds are prepared using a typical method, for example, by dissolving a free base in a suitable solvent such as an aqueous solvent, an alcohol solvent or another acid-containing solvent, and then evaporating the solvent, or by reacting the free base with the organic solvent (in this case, the salt may be directly separated or obtained via concentration).
  • a suitable solvent such as an aqueous solvent, an alcohol solvent or another acid-containing solvent
  • the salt may be directly separated or obtained via concentration
  • the acid addition salts of the compounds of the present invention are crystalline materials which can be dissolved in water or various hydrophilic organic solvents and generally display higher melting points compared to the free base forms thereof.
  • compositions of the present invention for the treatment of cancer or diseases associated with multidrug resistance may be administered to subjects in need thereof.
  • subject is intended to include mammals such as goats, horses, cow, pigs, dogs, cats, mice, rats, etc. as well as primates such as humans.
  • the effective dosages of the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 or pharmaceutically acceptable salts thereof may vary depending on various factors including dosage units, the duration of treatment, the age and sex of the patient, traits of the tumor to be treated, drug resistance, etc.
  • the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 or pharmaceutically acceptable salts thereof may be used.
  • the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 or pharmaceutically acceptable salts thereof may be administered at an effective dose of from 15 mg/kg to 500 mg/kg.
  • a unit daily dosage may contain 25 to 500 mg of the cyclic pentadepsipeptide of Chemical Formula 1 or 2 or a pharmaceutically acceptable salt thereof.
  • the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 or pharmaceutically acceptable salts thereof may be in an oral or parenteral dosage form formulated with a pharmaceutically acceptable carrier.
  • the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 or pharmaceutically acceptable salts thereof are preferably administered at an effective dose, in combination with an anticancer agent, particularly, an agent for chemotherapy.
  • tumors which can be treated with the compounds of the present invention are benign or malignant tumors, neoplasms, melanoma, lymphoma, leukemia and sarcoma.
  • tumors include skin tumors (e.g., malignant melanoma and cutaneous mycosis fungoides), blood tumors (e.g, acute lymphocytic leukemia, acute or chronic myelogenous leukemia), lymphoma (e.g.
  • gynecologic tumors ovarian tumor, uterine tumor
  • urologic tumors prostate tumor, bladder tumor, seminoma
  • soft tissue sarcoma osteo- or non-osteosarcoma
  • breast tumors pituitary tumors, thyroid gland tumors, adrenal cortex tumors
  • gastrointestinal tumors esophagus tumor, stomach tumors, intestine tumor, and colon tumor
  • pancreatic tumors liver tumors, larynx tumors, papilloma and lung tumors.
  • the best therapeutic effects may be elicited when the compounds of the present invention are applied to multidrug-resistant tumors or tumors which become multidrug resistant.
  • these tumors are colon tumors, lung tumors, stomach tumors and liver tumors.
  • a cytotoxic agent is typical of the chemical agents which can be applied together with the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 or pharmaceutically acceptable salts thereof.
  • the agents for chemotherapy include cyclophosphamide, methotrexate, prednisone, 6-mercaptopurine, procarbazine, daunorubicin, vincristine, vinblastine, chlorambucil, cytosine arabinoside, 6-thioguanine, thio TEPA, 5-fluorouracil, 5-fluoro-2-deoxyuridine, 5-azacytidine, nitrogen mustard, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea) (CCNU), busulfan, adriamycin, bleomycin, vindesine, Cycloleucine and methylglyoxal bis(guany
  • the effective dosage of the chemical agent useful in the present invention may vary depending on various factors including the condition of the patient, the morphology and size of the tumor, kind of the agents, etc, and may be readily determined by those skilled in the art.
  • the chemical agent may be administered in a smaller dose when administered in combination with the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 or pharmaceutically acceptable salts thereof than when administered alone. The reason is because a large amount of the chemical agent may cause drug resistance.
  • a cocktail of chemical agents or surgery or radiotherapy may be used, together with the administration of the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 or pharmaceutically acceptable salts thereof.
  • the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 or pharmaceutically acceptable salts thereof and the chemical agent may not be in the same dosage form or may not be administered at the same time. Accordingly, the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 or pharmaceutically acceptable salts thereof and the chemical agent may be administered in a mixture or at different times.
  • the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 or pharmaceutically acceptable salts thereof may be formulated into solid or liquid forms, such as capsules, pills, tablets, troches, lozenge, melts, powders, liquids, suspensions and emulsions.
  • solid dosage forms Typical of the solid dosage forms is a capsule.
  • a capsule with a soft or hard gelatin envelope may contain a surfactant, a lubricant, and an inert filler such as lactose, sucrose, calcium phosphate and corn starch.
  • the compounds of the present invention may be formulated into a tablet, together with a tablet base (e.g., lactose, sucrose, corn starch), a binder (e.g, acacia, corn starch or gelatin), a disintegrant (e.g., potato starch, alginic acid, corn starch and guar gum) for facilitating the degradation and dissolution of the tablet after administration, a lubricant (e.g., talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate) for enhancing the release of tablet granules and preventing the attachment of the tablet drug to the tabletting die or punch, and a dye, a colorant and a fragrant for improving the color and taste of the tablet.
  • Carriers suitable for use in oral liquid dosage forms include suspension agents, water mixed with or without an emulsifier, and a diluent such as an alcohol (ethanol, benzyl alcohol and polyethylene alcohol).
  • cyclic pentadepsipeptides of Chemical Formulas 1 and 2 or pharmaceutically acceptable salts thereof may be administered in the form of a solution in a diluent, together with a pharmaceutically acceptable carrier, through a parenteral route, that is, a subcutaneous, intravenous, intramuscular or intraperitoneal route.
  • Examples of the carrier for use in injection include pharmaceutically acceptable surfactants (e.g., soap or detergent), suspending agents (pectin, carbomer, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose), water or saline mixed with an emulsifier or another pharmaceutical adjuvant, aqueous solutions of dextrose or corresponding sugars, alcohols (e.g., ethanol, isopropanol, hexadecylalcohol), glycol (e.g., propylene glycol, or polyethylene glycol), glycerol ketal (e.g., 2,2-dimethyl-1,3-dioxolan-4-methanol), ethers (e.g., poly(ethylene-glycol)400), oils, and germ-free solutions or mixture containing fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides.
  • pharmaceutically acceptable surfactants e.g., soap or
  • oil useful in the formulation of parenteral dosage forms examples include petroleum, animal oil, vegetable oil, or synthetic oil, such as peanut oil, soybean oil, sesame oil, cotton seed oil, corn oil, olive oil, mineral oil and inorganic oil.
  • fatty acids are oleic acid, stearic acid and isostearic acid.
  • the fatty acid esters may be exemplified by oleic acid ethyl and myristic acid isopropyl.
  • Alkaline metal salts, ammonium salt and triethanolamine salts of fatty acids may be suitable as the surfactant.
  • the detergent examples include cationic detergents (e.g., dimethyl dialkyl ammonium halide, alkyl pyridium halide and alkylamine acetate), anionic detergents (e.g., alkyl, aryl and olefin sulfonate, alkyl, olefin, ether and monoglyceride sulfate and sulfosuccinate), non-ionic detergents (lipid amine oxide, fatty acid alkanolamide and polyoxyethylenepolypropylene copolymer), and amphiphatic detergents (e.g., alkyl- ⁇ -amino propionate and 2-alkylimidazolin quarternary ammonium salt) and a combination thereof.
  • cationic detergents e.g., dimethyl dialkyl ammonium halide, alkyl pyridium halide and alkylamine acetate
  • anionic detergents e.g., alkyl, aryl
  • the parenteral compositions of this invention will contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5% to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • the present invention pertains to a method of producing the cyclic pentadepsipeptide of Chemical Formula 1 or 2 by culturing a strain of the genus Fusarium, preferably Fusarium solani, more preferably Fusarium solani KCCM90040 [accession No.: KCCM10881P].
  • the compound of the present invention may be prepared through biosynthesis or organic synthesis.
  • FIG. 1 shows the chemical structure of sansalvamide A analogues.
  • FIG. 2 is a photograph showing microconidia of the strain of the present invention.
  • FIG. 3 is a photograph showing the conidiophores of the Fusarium strain according to the present invention.
  • FIG. 4 is a photograph showing the appearances of the surface and backside of an agar on which the strain of the present invention is grown.
  • FIG. 5 is a photograph showing PCR products amplified from DNA templates of Fusarium strain (M, 100-bp DNA ladder; F, Fusarium strain; S-1, Fusarium moniliforme NRRL 13569; S-2, Fusarium oxysporum KCCT 16909).
  • FIG. 6 shows an array of ITS-5.8 rDNA sequences of the strain of the present invention (sample) and Fusarium solani for homology comparison therebetween.
  • FIG. 7 is an HPLC chromatogram of an extract from a submerged culture of the strain of the present invention after incubation in a Fusarium defined medium.
  • FIG. 8 is an HPLC chromatogram of an extract from a cereal culture of the strain of the present invention after incubation on a cereal culture.
  • FIG. 9 is of electrospray ionization mass spectra illustrating the molecular weight of Compound A produced by the strain of the present invention.
  • FIG. 10 is of electrospray ionization mass spectra illustrating the molecular weight of Compound B produced by the strain of the present invention.
  • FIG. 11 is of infrared spectra of Compound A, measured by an FT IR-8400S infrared spectrophotometer.
  • FIG. 12 is a diagram showing the HMBC correlations of compound A.
  • FIG. 13 is of infrared spectra of Compound B, measured by an FT IR-8400S infrared spectrophotometer.
  • FIG. 14 is a diagram showing the HMBC correlations of compound B.
  • FIG. 15 is an HPLC chromatogram for determining the stereochemical structure of amino acids in Compound A.
  • FIG. 16 is an HPLC chromatogram for determining the stereochemical structure of amino acids in Compound B.
  • FIG. 17 is a graph showing the cytotoxic effect of the compound of Chemical Formula 1 on non-multidrug resistant cancer cell lines.
  • FIG. 18 is a graph showing the cytotoxic effect of the compound of Chemical Formula 1 on multidrug resistant cancer cell lines.
  • FIG. 19 is a graph showing the cytotoxic effect of the compound of Chemical Formula 2 on non-multidrug resistant cancer cell lines.
  • FIG. 20 is a graph showing the cytotoxic effect of the compound of Chemical Formula 2 on non-multidrug resistant cancer cell lines.
  • FIG. 21 is a graph showing the multidrug resistance-reversing activity of the compounds of Chemical Formulas 1 and 2 against the HCT15 cell line.
  • FIG. 22 is a graph showing the multidrug resistance-reversing activity of the compounds of Chemical Formulas 1 and 2 against the HCT15/CL02 cell line.
  • FIG. 23 is a graph showing the multidrug resistance-reversing activity of the compounds of Chemical Formulas 1 and 2 against the MEA-SA cell line.
  • FIG. 24 is a graph showing the multidrug resistance-reversing activity of the compounds of Chemical Formulas 1 and 2 against the MEA-SA/DX5 cell line.
  • FIG. 25 is a photograph showing the anti-fungal activity of the compounds of Chemical Formulas 1 and 2 against Mucor rouxii grown on PDA, with 10 mM of compounds of Chemical Formulas 1 and 2 placed thereon.
  • FIG. 26 is a photograph showing the anti-fungal activity of the compounds of Chemical Formulas 1 and 2 against Fusarium oxysporum grown on PDA, with 10 mM of compounds of Chemical Formulas 1 and 2 placed thereon.
  • FIG. 27 is a graph in which the produced amounts of the compound of Chemical Formula 1 are plotted against the time of growth for six different cereal media.
  • FIG. 28 is a graph in which the produced amounts of the compound of Chemical Formula 2 are plotted against the time of growth for six different cereal media.
  • FIG. 29 is a graph showing the production of the compounds of Chemical Formulas 1 and 2 with the time of growth.
  • FIG. 30 is a graph showing the production of the compounds of Chemical Formulas 1 and 2 with culture temperature.
  • FIG. 31 is a graph showing the production of the compounds of Chemical Formulas 1 and 2 with moisture content.
  • Fusarium strains were isolated from Fusarium -contaminated potatoes in Munkyeong, Korea and its identification was determined using the methods of Samson, et al. and the method of Nelson et al. [Samson R A, Hoekstra ES, Oorschot V, Connie A N. (1981) Introduction to food-borne fungi. Published and distributed by Centraalbureau voor Schimmelcultures; Nelson P E, Toussoun T A, Marasas W F. (1983) Fusarium species: An illustrated manual for identification. The Pennsylvania State University Press].
  • the isolated Fusarium strain was transferred on carnation leaf agar (CLA) and real potato dextrose agar (RPDA) and analyzed for morphological characteristics.
  • the microconidia were present in abundance generally in the form of single cells of an oval to kidney shape ( FIG. 2 ). Conidiophores of the Fusarium strain put out branches as shown FIG. 3 .
  • the microconidia and conidiophores of F. solani are morphologically similar to those of Fusarium oxysporum.
  • the microconidia of F. oxysporum were observed to be larger in size and have thicker walls and conidiophores were formed on short monophialides, compared to those of F. solani (Nelson et al., 1983).
  • the isolated Fusarium strains grew fast. The slant surface of the agar was almost covered with white mycelia with the back being a dark cream ( FIG. 4 ).
  • the Fusarium strain was identified as F. solani.
  • the total genomic DNA of the isolated Fusarium strain was extracted from the mycelia grown on PDA (potato dextrose agar) using the method of Correll [Correll J C, Klittich C J R, Leslie J F. (1987) Nitrate nonutilizing mutants of Fusarium oxysporum and their use in vegetative compatibility tests. Phytopathology, 77, 16401646].
  • mycelium-covered agar was placed in a tube filled with liquid nitrogen, followed by evaporating the liquid nitrogen at room temperature. This procedure of liquid nitrogen filling and evaporation was repeated again. After evaporation of the liquid nitrogen, 0.5 mL of a lysis buffer [50 mM Tris pH 8.0, 50 mM ethylenediaminetetraacetic acid(EDTA), 3% sodium dodecylsulfate (SDS), 1% 2-mercaptoethanol and 0.1 m/ml proteinase K] warmed to 65° C. was added into the tube and incubated for 1 hr at 65° C.
  • a lysis buffer [50 mM Tris pH 8.0, 50 mM ethylenediaminetetraacetic acid(EDTA), 3% sodium dodecylsulfate (SDS), 1% 2-mercaptoethanol and 0.1 m/ml proteinase K] warmed to 65° C. was added into the tube and incubated for 1
  • Fusarium specific primers P28SL (5′-ACA AAT TAC AAC TCG GGC CCG AGA-3′) of SEQ ID NO: 1 and P58SL (5′-AGT ATT CTG GCG GGC ATG CCT GT-3′) of SEQ ID NO. 2, designed as described by Hue et al. [Hue, F. X., M. Huerre, M. A. Rouffault, and C. D. Bievre. Specified detection of Fusarium species in blood and tissues by a PCR technique. Journal of Clinical Microbiology, 37: 2434-2438. 1999] were used for a control PCR assay.
  • a pair of the Fusarium specific primers amplified a fragment of DNA coding for the ribosomal DNA (rDNA) of Fusarium strains by PCR.
  • the binding sites of the P28SL and P58SL primers, corresponding to the ITS2 region and a portion of 5.8s and 28s rDNA, are conserved among Fusarium strains.
  • PCR For PCR, 1 ng of the DNA isolated in A was used together with a primer pair of the primers P28SL and P58SL, and a PCR pre-mixture purchased from Promega. Starting by denaturation at 94° C. for 10 min, PCR was performed with 40 cycles of denaturation at 94° C. for 1 min, annealing at 60° C. for 1 min and extension at 72° C. for 1 min, followed by a final extension at 72° C. for 10 min.
  • the PCR product thus obtained was run on a 2% agarose gel in Tris-acetate-EDTA buffer in the presence of an electric field. After completion of the electrophoresis, the gel was stained with ethidium bromide and visualized under UV light.
  • the PCR product (F) amplified from Fusarium stains was detected at a position between 300 and 400 bp, which matched with the sizes of PCR products from two controls Fusarium moniliforme NRRL 13569 and Fusarium oxysporum KCTC 16909 ( FIG. 5 ).
  • the PCR product obtained with the Fusarium -specific primers was purified and sequenced commercially (Macrogen Inc. Seoul, Korea).
  • BLAST search for homology in the GenBank database showed that the ITS-5.8 rDNA sequence of the Fusarium strain of the present invention shared more than 98% homology with those of F. solani ( FIG. 6 ).
  • the ITS-5.8 rDNA sequence of the Fusarium strain is given in SEQ ID NO. 3.
  • This Fusarium strain was named Fusarium solani KCCM90040 and deposited with the Korean Culture Center of Microorganisms on Jan. 15, 2008 with accession No. KCCM10881P, according to the Budapest Treaty.
  • Fusarium solani KCCM90040 was inoculated at a density of 1 ⁇ 10 5 spores/mL into 100 mL of a Fusarium defined medium (FDM) broth (25 g of sucrose, 4.25 g of NaNO 3 , 5 g of NaCl, 2.5 g of MgSO 4 7H2O, 1.36 g of KH 2 PO 4 , 0.01 g of FeSO 4 7H2O, and 0.0029 g of ZnSO 4 7H2O per liter) and incubated at 25° C. for 7 days.
  • FDM Fusarium defined medium
  • Fusarium solani KCCM90040 was inoculated at a density of 1 ⁇ 10 5 spores/mL to a rice medium which was prepared from 50 g of autoclaved rice with the water content thereof adjusted to 40 wt % with sterile distilled water, followed by culturing at 25° C. for 7 days.
  • the cereal medium in which the Fusarium of (2) was cultured was dried at room temperature for 12 hrs.
  • the mycelia thus dried were homogenized, extracted overnight with 75 ml of a solvent mixture of 16:3:1 (v/v/v) acetonitrile: MeOH: water, and filtered through sterile filter paper.
  • the filtrate was defatted twice with 25 mL of n-heptane and the bottom layer was evaporated to dryness.
  • the residue was dissolved in 50 mL of a solvent mixture of 55:45 (v/v) MeOH: water and extracted twice with 25 mL of CH 2 Cl 2 .
  • the CH 2 Cl 2 layer was evaporated to dryness, and the residue was resuspended in methanol.
  • the compounds were separated using a GROM-sil pack ODS preparative column (1.0 ⁇ 25 cm) with a mixture of acetonitrile: water solution (65:35, v/v) serving as a mobile phase at a flow rate of 3 ml/min for 60 min, followed by further purification through a Shiseido pack C18 column (0.46 ⁇ 25 cm) with a mixture of acetonitrile: water (70:30, v/v) at a flow rate of 1 mL/min.
  • the functional group of compound 1 was investigated by an FT IR-8400S infrared spectrophotometer (Shimadzu, Japan). IR analysis of Compound A showed amide (1654.42 cm ⁇ 1 ) and ester (1745.52 cm ⁇ 1 ) bonds ( FIG. 10 ). The maximum UV spectrum of compound 1 was determined at 287 nm in methanol. Compound A was found to have a melting point of 82° C. as measured by a melting point apparatus (Thermo Fisher scientific Inc. Waltham. USA).
  • Compound A was composed of five units: leucic acid (OLeu), leucine (Leu), valine (Val), phenylalanine (Phe) and leucine (Leu).
  • the sequence of the five units in Compound A was determined by analyzing HMBC correlation data ( FIG. 12 ).
  • the compound of Chemical Formula 2 was a novel cyclic pentadepsipeptide and named neo-sansalvamide.
  • IR spectra of Compound B showed amide (1653.24 cm ⁇ 1 ) and ester (1742.65 cm ⁇ 1 ) bonds ( FIG. 13 ).
  • the maximum UV spectrum was determined at 213 nm in methanol and the melting point was measured to be about 82° C.
  • Compound B was composed of five units: leucic acid (OLeu), N-methylleucine (N-MeLeu), valine (Val), phenylalanine (Phe) and leucine (Leu).
  • the sequence of the five units in Compound B was determined by analysis of the HMBC correlation data ( FIG. 14 ).
  • the compound of Chemical Formula 1 was a novel cyclic pentadepsipeptide and was named neo-Nmethylsansalvamide.
  • HCT-15 Colorectal carcinoma cancer cell line
  • NCI National Cancer Institute
  • HCT15/CL02 cell lines were established from HCT15 cells by continuous and stepwise exposure of the cells to doxorubicin in the Korea Research Institute of Chemical Technology (Korea). The inhibitory activities were quantified as the concentration required for inhibiting cell growth in vitro by 50% (EC 50 ) under the assay conditions, with doxorubicin serving as a control.
  • the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 exhibit cytotoxicity against most cell lines as potent as that of sansalvamide A or N-methylsansalvamide irrespective of the possession of multidrug resistance.
  • the cyclic pentadepsipeptide of Chemical Formula 1 was of more potent inhibitory activity against MDR cancer lines than was that of Chemical Formula 2 ( FIGS. 17 to 20 ).
  • the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 were analyzed for MDR-reversing activity by comparing inhibitory activities against multidrug-resistant cancer cell lines (MES-SA/DX5 and HCT15/CL02) with those against non-multidrug-resistant cancer cell lines (MES-SA and HCT15).
  • MES-SA/DX5 and HCT15/CL02 inhibitory activities against multidrug-resistant cancer cell lines
  • MES-SA and HCT15 non-multidrug-resistant cancer cell lines
  • the effects of the cyclic pentadepsipeptides of Chemical Formulas 1 and 2 on paclitaxel's cytotoxicity against MDR tumor cells were measured (Table 6).
  • Verapamil (VER) an MDR-reversing agent with inhibitory activity against P-glycoprotein, was used as a control.
  • the cyclic pentadepsipeptide of Chemical Formula 2 increased the cytotoxicity of paclitaxel against MDR cell lines, but only slightly.
  • the cyclic pentadepsipeptide of Chemical Formula 1 remarkably enhanced the cytotoxicity of paclitaxel ( FIGS. 21 to 24 ). Therefore, the N-methyl group in the cyclic pentadepsipeptide may be a factor crucial for the expression of the MDR reversal activity.
  • the MDR-reversing activity of the cyclic pentadepsipeptide of Chemical Compound 1 was similar to that of the positive control verapamil.
  • Assays for antibacterial activity were performed with Gram-positive ( Listeria monocytogenes ATCC 14028, Staphylococcus aureus ATCC 35556 and Bacillus cereus ATCC 13061) and 3 Gram-negative bacteria ( Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9026 and Salmonella typhimurium ATCC 14028).
  • Gram-positive Listeria monocytogenes ATCC 14028, Staphylococcus aureus ATCC 35556 and Bacillus cereus ATCC 13061
  • 3 Gram-negative bacteria Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9026 and Salmonella typhimurium ATCC 14028.
  • Each of the compounds of Chemical Formulas 1 and 2 was dissolved in different concentrations (0.1, 0.5, 1, and 2 mM) in dimethyl sulfoxide (DMSO). The solutions were applied to a sterile paper disc (5 mm
  • Bacteria was inoculated at a density of 1 ⁇ 10 7 CFU/ml on Tryptic soy agar (TSA) and then, the paper disc was placed on the bacteria-inoculated agars. After incubation at 37° C. for 24 hr, the clear zone around each disc was observed and its diameter was measured.
  • TSA Tryptic soy agar
  • Inhibitory activity was performed against four fungus strains ( Mucor rouxii, Penicillium citrinum, Fusarium oxysporum, and Aspergillus oryzae ).
  • Fusarium solani KCCM90040 was inoculated at a density of 1>10 5 spores/mL on a cereal medium which was prepared from 50 g of an autoclaved cereal substance with the water content thereof adjusted to 40 wt % with sterile distilled water. The microorganism was grown at 25° C. during which the medium was shaken once a day. The production of the compounds of Chemical Formulas 1 and 2 by F. solani KCCM 90040 upon culturing on six different solid cereal substrates is quantitatively depicted in FIGS. 27 and 28 , respectively.
  • the production of the compound of Chemical Formula 2 peaked on the 2 th week after incubation on rice (Avg. 0.375 g/kg).
  • Particularly low production (0.112 g/kg) was observed on barley.
  • Variables for the production of the novel compounds of Chemical Formulas 1 and 2 upon incubation on rice were determined to specify 20 ⁇ 30° C. for culture temperature, 20 ⁇ 50% for RH, and 10 ⁇ 20 days for growth period, preferably 23 ⁇ 28° C. for culture temperature, 35 ⁇ 45% for RH, and 13 ⁇ 18 days.
  • the microorganisms were cultured at 25.84° C. and 37.99 RH % for 16.03 days for optimal production of the cyclic pentadepsipeptide of Chemical Formula 1 ( FIGS. 29 to 31 ) and at 25.87° C. and 33.87 RH % for 15.58 days for the optimal production of the cyclic pentadepsipeptide of Chemical Formula 2.
  • the production was measured to be about 0.40 g/kg for the cyclic pentadepsipeptide of Chemical Formula 1 and about 0.70 g/kg for the cyclic pentadepsipeptide of Chemical Formula 2.
  • Cyclic pentadepsipeptide of Chemical Formula 1 or 2 100 mg Corn Starch 68 mg Lactose 90 mg Microcrystalline Cellulose 40 mg Mg Stearate 2 mg
  • the ingredients were added in the given amounts, homogeneously mixed together and granulized.
  • the granules were prepared into tablets, each containing 100 mg of the cyclic pentadepsipeptide of Chemical Formula 1 or 2, according to a typical method.
  • Cyclic pentadepsipeptide of Chemical Formula 1 or 2 50 mg Na metabisulfite 1.5 mg Methyl paraben 1.0 mg Propyl paraben 0.1 mg Pure water for injection q.s.
  • the ingredients were dissolved in the given amounts in boiling water with stirring, cooled and loaded into 2 mL sterile vials and supplemented with injection water to form a total volume of 2 mL to afford injections, each containing 50 mg of the cyclic pentadepsipeptide of Chemical Formula 1 or 2.
  • the ingredients were mixed in the given amounts, dissolved in water with heating, cooled and loaded into vessels, each containing 200 mg of Cyclic pentadepsipeptide of Chemical Formula 1 or 2, to afford syrups.
  • the cyclic pentadepsipeptides of the present invention can be used as therapeutics for tumors. Further, they are useful as multidrug resistance inhibitors. These novel cyclic pentadepsipeptides are produced by the Fusarium strains of the present invention.

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Biophysics (AREA)
  • Biomedical Technology (AREA)
  • Virology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Botany (AREA)
  • Mycology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
US12/600,830 2009-01-02 2009-01-02 Novel Cyclic Pentadepsipeptide Derivative and Fusarium Strain Producing The Same Abandoned US20110269698A1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/KR2009/000005 WO2010076905A1 (fr) 2009-01-02 2009-01-02 Penta-depsipeptide cyclique et micro-organisme fusarium sp. le produisant

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2009/000005 A-371-Of-International WO2010076905A1 (fr) 2009-01-02 2009-01-02 Penta-depsipeptide cyclique et micro-organisme fusarium sp. le produisant

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US14/502,520 Continuation US9145442B2 (en) 2009-01-02 2014-09-30 Cyclic pentadepsipeptides and microorganism of Fusarium strain producing the same

Publications (1)

Publication Number Publication Date
US20110269698A1 true US20110269698A1 (en) 2011-11-03

Family

ID=42309944

Family Applications (3)

Application Number Title Priority Date Filing Date
US12/600,830 Abandoned US20110269698A1 (en) 2009-01-02 2009-01-02 Novel Cyclic Pentadepsipeptide Derivative and Fusarium Strain Producing The Same
US14/502,520 Active US9145442B2 (en) 2009-01-02 2014-09-30 Cyclic pentadepsipeptides and microorganism of Fusarium strain producing the same
US14/626,435 Active US9260485B2 (en) 2009-01-02 2015-02-19 Cyclic pentadepsipeptide derivative and fusarium strain producing the same

Family Applications After (2)

Application Number Title Priority Date Filing Date
US14/502,520 Active US9145442B2 (en) 2009-01-02 2014-09-30 Cyclic pentadepsipeptides and microorganism of Fusarium strain producing the same
US14/626,435 Active US9260485B2 (en) 2009-01-02 2015-02-19 Cyclic pentadepsipeptide derivative and fusarium strain producing the same

Country Status (4)

Country Link
US (3) US20110269698A1 (fr)
EP (1) EP2374868B1 (fr)
JP (1) JP5053444B2 (fr)
WO (1) WO2010076905A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017181179A1 (fr) * 2016-04-15 2017-10-19 The Regents Of The University Of California Compositions antimicrobiennes
CN109689083A (zh) * 2017-02-09 2019-04-26 中央大学校产学协力团 含作为有效成分的环五缩酚酸肽的抗血管生成药物组合物

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9727330B2 (en) * 2015-11-25 2017-08-08 Red Hat, Inc. Source to image transformation pipeline for a platform-as-a-service system

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995017093A1 (fr) * 1993-12-21 1995-06-29 University Of Hawaii Nouvelles cryptophycines
WO2005034982A1 (fr) * 2003-10-08 2005-04-21 Northwestern University Agents antitumoraux peptidiques cycliques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Sansalvamide: A New Cytotoxic Cyclic Depsipeptide Produced by a Marine Fungus of the Genus Fusarium. Tetrahedron Letters, 1999. Vol. 40, pages 2913-2916. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017181179A1 (fr) * 2016-04-15 2017-10-19 The Regents Of The University Of California Compositions antimicrobiennes
US11046730B2 (en) 2016-04-15 2021-06-29 The Regents Of The University Of California Antimicrobial compositions
CN109689083A (zh) * 2017-02-09 2019-04-26 中央大学校产学协力团 含作为有效成分的环五缩酚酸肽的抗血管生成药物组合物
US10709757B2 (en) * 2017-02-09 2020-07-14 Chung-Ang University Industry-Academic Cooperation Foundation Pharmaceutical composition for anti-angiogenesis containing cyclic pentadepsipeptide as an effective ingredient

Also Published As

Publication number Publication date
EP2374868A4 (fr) 2012-07-25
JP5053444B2 (ja) 2012-10-17
US20150025219A1 (en) 2015-01-22
EP2374868B1 (fr) 2013-11-06
WO2010076905A1 (fr) 2010-07-08
US20150191507A1 (en) 2015-07-09
JP2011505877A (ja) 2011-03-03
US9260485B2 (en) 2016-02-16
EP2374868A1 (fr) 2011-10-12
US9145442B2 (en) 2015-09-29

Similar Documents

Publication Publication Date Title
US9260485B2 (en) Cyclic pentadepsipeptide derivative and fusarium strain producing the same
WO2005011699A1 (fr) Utilisation de la phenylahistine et de ses analogues pour le traitement d'infections fongiques
Fontana Current bioactive azole-containing natural products
US7186713B2 (en) Farnesyl dibenzodiazepinones and methods of treating cancer using same
KR101119561B1 (ko) 고리형 펜타뎁시펩타이드를 생산하는 푸사리움속 미생물
US11174291B2 (en) Silstatin compounds
US8241872B2 (en) Microorganism producing cyclic compound
KR101120565B1 (ko) 신규 고리형 펜타뎁시펩타이드(ⅰ) 및 그 이용
US20160354430A1 (en) Hexadepsipeptide analogues as anticancer compounds
US8598115B2 (en) Cyclic compound and salt thereof
US8633154B2 (en) Cyclodepsipeptides with antineoplastic activity and methods of using to inhibit cancer and microbial growth
KR101182589B1 (ko) 신규 고리형 펜타뎁시펩타이드(ⅱ) 및 그 이용
WO2002072617A1 (fr) Composes thiopeptides
US20040266008A1 (en) Polyene polyketides, processes for their production and their use as pharmaceuticals
EP3842447B1 (fr) Composé à activité antibiotique
Dischler Investigations of targeted natural sources in search of bioactive metabolites
US6818614B2 (en) Compounds having antifungal activity
US20060106028A1 (en) Polycyclic aromatics and derivatives thereof and processes for their preparation
US20040265280A1 (en) Phoma microorganism
US20200361981A1 (en) Glycosyltransferase inhibitors for treatment of solid tumors
WO1997043434A1 (fr) Nouvelle substance active sur le plan physiologique et son procede de preparation
CA2497031A1 (fr) Farnesyldibenzodiazepinones, procedes de production et utilisation comme medicaments

Legal Events

Date Code Title Description
AS Assignment

Owner name: CHUNG-ANG UNIVERSITY INDUSTRY-ACADEMY COOPERATION

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LEE, CHAN;SONG, HYUK-HWAN;LEE, HEE-SEOK;REEL/FRAME:023540/0321

Effective date: 20091117

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION