WO2000075126A1 - Mycolactone and related compounds, compositions and methods of use - Google Patents
Mycolactone and related compounds, compositions and methods of use Download PDFInfo
- Publication number
- WO2000075126A1 WO2000075126A1 PCT/US2000/015428 US0015428W WO0075126A1 WO 2000075126 A1 WO2000075126 A1 WO 2000075126A1 US 0015428 W US0015428 W US 0015428W WO 0075126 A1 WO0075126 A1 WO 0075126A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- polyketide
- mammal
- mixture
- ulcerans
- aseptic
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
- C12N1/20—Bacteria; Culture media therefor
- C12N1/205—Bacterial 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
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/08—Oxygen as only ring hetero atoms containing a hetero ring of at least seven ring members, e.g. zearalenone, macrolide aglycons
-
- 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
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/32—Mycobacterium
Definitions
- the present invention relates to pharmacoactive polyketide macrolides obtained from M. ulcerans, semi-synthetic derivatives thereof, aseptic mixtures of polyketide macrolides obtained from M. ulcerans. and methods of using the same.
- Mycobacteria ulcerans is the causative agent of buruli ulcers. Buruli ulcers are progressive necrotic skin lesions that can persist for decades without treatment and which are not uncommonly suffered by persons living in tropical climates, including parts of Africa. Buruli ulcers are painless, not accompanied by symptoms of systemic disease, and are generally not accompanied by an initial acute inflammatory response.
- M. ulcerans produces a toxin, although the identity of this toxin or toxins has heretofore remained unknown. Read et al., Infect. Immun., 9, 1 1 14 (1974), reported that the sterile filtrate of an M.
- the present invention provides a polyketide macrolide that can be isolated from virulent cell cultures of Mycobacterium ulcerans.
- the inventive polyketide macrolide has the formula of formula 1 :
- Suitable pharmacologically acceptable esters, ethers and prodrugs of the polyketide macrolide include those of Formula 2:
- R'-R 3 are the same or different and each is independently selected from the group consisting of hydrogen, R 6 , a C(O)R 7 , a C(S)R 7 , a C(O)NHR 7 , and a C(S)NHR 7 , each occurrence of R is independently selected from the group consisting of a C ⁇ -C 6 alkyl, a C 5 -C1 .2 aryl, and a sugar, each occurrence of R 7 is independently selected from the group consisting of hydrogen, a C ⁇ -C 6 alkyl, and a C 5 -C12 aryl, and wherein R 1 and R 2 , R 2 and R 3 , and/or R 4 and R 3 can be taken together to form a ketal ring.
- Suitable sugars in the context of the present invention include, but are not limited tetroses, pentoses, hexoses, heptoses, and disaccharides and polysacchafides comprising tetroses, pentoses, hexoses, and heptoses.
- Suitable aryl substituents of the present invention include heteroaryl substituents comprising a nitrogen, oxygen, or sulfur heteroatom.
- polyketide macrolide While it may be desirable for many uses of the polyketide macrolide to isolate a composition comprising only one type of polyketide macrolide, for example mycolactone (Formula 1), mixtures polyketide macrolides are also useful in the context of the present inventive methods.
- Mycolactone. in the TLC system described above has an Rf of about 0.23 (i.e., between about 0J9 and about 0J7).
- the polyketide macrolides of the present invention are susceptible to molecular damage induced by prolonged exposure to light. For example, if a polyketide macrolide is maintained at room temperature for about one week or so, an approximate 50% reduction in activity will be realized. Accordingly, the polyketide macrolide or mixtures thereof can be isolated and provided in a sterile, aseptic solution suitable for administration to humans and to other mammals in order to preserve bioactivity.
- the mixture can be packaged in light-resistant bottles meeting U.S. Food and Drug Administration standards, or ISO standards, for the shipment of light-sensitive bottles.
- the bottle or container is labeled with a label indicating the concentration of polyketide macrolides in the mixture and, optionally, a date of preparation or manufacture.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Immunology (AREA)
- General Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Neurology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Pyrane Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002376010A CA2376010A1 (en) | 1999-06-03 | 2000-06-02 | Mycolactone and related compounds, compositions and methods of use |
US09/980,063 US6680055B1 (en) | 1999-06-03 | 2000-06-02 | Mycolactone and related compounds, compositions and methods of use |
AU51798/00A AU5179800A (en) | 1999-06-03 | 2000-06-02 | Mycolactone and related compounds, compositions and methods of use |
EP00936488A EP1192147A1 (en) | 1999-06-03 | 2000-06-02 | Mycolactone and related compounds, compositions and methods of use |
JP2001502409A JP2003501423A (ja) | 1999-06-03 | 2000-06-02 | マイコラクトンおよび関連化合物、組成物、ならびに使用方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13736799P | 1999-06-03 | 1999-06-03 | |
US60/137,367 | 1999-06-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000075126A1 true WO2000075126A1 (en) | 2000-12-14 |
Family
ID=22477090
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/015428 WO2000075126A1 (en) | 1999-06-03 | 2000-06-02 | Mycolactone and related compounds, compositions and methods of use |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1192147A1 (ja) |
JP (1) | JP2003501423A (ja) |
AU (1) | AU5179800A (ja) |
CA (1) | CA2376010A1 (ja) |
WO (1) | WO2000075126A1 (ja) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002041888A1 (en) * | 2000-11-23 | 2002-05-30 | Biogenia Co., Ltd. | Anticancer agent comprising mycolactone |
WO2002060890A1 (fr) * | 2001-02-01 | 2002-08-08 | Mercian Corporation | Nouvelles substances physiologiquement actives |
WO2003099813A1 (fr) * | 2002-05-29 | 2003-12-04 | Mercian Corporation | Nouvelles substances physiologiquement actives |
WO2005047509A2 (en) * | 2003-11-14 | 2005-05-26 | University Of Tennessee Research Foundation | The mycolactone locus : an assembly line for producing novel polyketides, with therapeutic and prophylatic uses |
WO2006000923A2 (en) * | 2004-06-03 | 2006-01-05 | Novimmune Sa | Macrolide compositions as therapeutic agent |
US7576204B2 (en) | 2002-07-31 | 2009-08-18 | Mercian Corporation | Heterocyclic macrolide pharmaceutical agent, a method of producing the same and use of the same |
US7745198B2 (en) | 2002-11-29 | 2010-06-29 | Mercian Corporation | Method of producing macrolide compound |
US7790887B2 (en) | 2007-01-29 | 2010-09-07 | Eisai R&D Management Co., Ltd. | Macrolide compound in solid form, process for preparation thereof, and pharmaceutical composition containing the same |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998050576A1 (en) * | 1997-05-02 | 1998-11-12 | Integrated Research Technology, Llc | Betaines as adjuvants to susceptibility testing and antimicrobial therapy |
-
2000
- 2000-06-02 CA CA002376010A patent/CA2376010A1/en not_active Abandoned
- 2000-06-02 JP JP2001502409A patent/JP2003501423A/ja active Pending
- 2000-06-02 WO PCT/US2000/015428 patent/WO2000075126A1/en not_active Application Discontinuation
- 2000-06-02 AU AU51798/00A patent/AU5179800A/en not_active Abandoned
- 2000-06-02 EP EP00936488A patent/EP1192147A1/en not_active Ceased
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998050576A1 (en) * | 1997-05-02 | 1998-11-12 | Integrated Research Technology, Llc | Betaines as adjuvants to susceptibility testing and antimicrobial therapy |
Non-Patent Citations (5)
Title |
---|
ALI A. PAHLEVAN ET. AL.: "The Inhibitory Action of Mycobacterium ulcerans Soluble Factor on Monocyte/T-Cell Cytokine Production and NF-kB Function", JOURNAL OF IMMUNOLOGY, vol. 163, no. 7, 1 October 1999 (1999-10-01), pages 3928 - 35, XP002148652 * |
G. GUNAWARDANA ET. AL.: "Characterization of Novel Macrolide Toxins, Mycolactones A and B, from a Human Pathogen, Macobacterium ulcerans", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 121, no. 25, 30 June 1999 (1999-06-30), pages 6092 - 3, XP002148651 * |
K. M. GEORGE ET. AL.: "Mycolactone. A Polyketide Toxin from Mycobacterium Ulcerans Required for Virulence.", SCIENCE, vol. 283, no. 5403, 5 February 1999 (1999-02-05), pages 854 - 7, XP002148650 * |
K. M. GEORGE ET. AL.: "Partial Purification and Characterization of Biological Effects of a Lipid Toxin Produced by Mycobacterium Ulcerans.", INFECTION AND IMMUNITY, vol. 66, no. 2, February 1998 (1998-02-01), pages 587 - 93, XP000918628 * |
M. PIMSLER ET. AL.: "Immunosuppressive Properties of the Soluble Toxin from Mycobacterium ulcerans.", JOURNAL OF INFECTIOUS DISEASES, vol. 157, no. 1, January 1988 (1988-01-01), pages 577 - 80, XP000918626 * |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1343496A1 (en) * | 2000-11-23 | 2003-09-17 | Biogenia Co., Ltd | Anticancer agent comprising mycolactone |
WO2002041888A1 (en) * | 2000-11-23 | 2002-05-30 | Biogenia Co., Ltd. | Anticancer agent comprising mycolactone |
EP1343496A4 (en) * | 2000-11-23 | 2006-03-15 | Biogenia Co Ltd | ANTICANCER AGENT COMPRISING MYCOLACTONE |
US7026352B1 (en) | 2001-02-01 | 2006-04-11 | Mercian Corporation | Physiologically active substances |
WO2002060890A1 (fr) * | 2001-02-01 | 2002-08-08 | Mercian Corporation | Nouvelles substances physiologiquement actives |
US7667052B2 (en) | 2001-02-01 | 2010-02-23 | Eisai R&D Management Co., Ltd. | Bioactive substance |
EP2292610A1 (en) * | 2001-02-01 | 2011-03-09 | Mercian Corporation | Macrolides with VEGF transcription suppression activity |
EP2927228A1 (en) * | 2002-05-29 | 2015-10-07 | Eisai R&D Management Co., Ltd. | Novel physiologically active substances |
CN1665807B (zh) * | 2002-05-29 | 2013-09-11 | 日本迈科洛生物制药有限公司 | 生理活性物质 |
US7893068B2 (en) | 2002-05-29 | 2011-02-22 | Mercian Corporation | Physiologically active substances |
US7550503B2 (en) | 2002-05-29 | 2009-06-23 | Eisai R& D Management Co., Ltd. | Physiologically active substances |
US7619100B2 (en) | 2002-05-29 | 2009-11-17 | Mercian Corporation | Physiologically active substances |
EP2266978A1 (en) * | 2002-05-29 | 2010-12-29 | Mercian Corporation | Novel physiologically active substances |
KR100954401B1 (ko) * | 2002-05-29 | 2010-04-26 | 메루샹가부시키가이샤 | 신규한 생리 활성 물질 |
WO2003099813A1 (fr) * | 2002-05-29 | 2003-12-04 | Mercian Corporation | Nouvelles substances physiologiquement actives |
US7576204B2 (en) | 2002-07-31 | 2009-08-18 | Mercian Corporation | Heterocyclic macrolide pharmaceutical agent, a method of producing the same and use of the same |
US7745198B2 (en) | 2002-11-29 | 2010-06-29 | Mercian Corporation | Method of producing macrolide compound |
WO2005047509A3 (en) * | 2003-11-14 | 2006-07-20 | Univ Tennessee | The mycolactone locus : an assembly line for producing novel polyketides, with therapeutic and prophylatic uses |
WO2005047509A2 (en) * | 2003-11-14 | 2005-05-26 | University Of Tennessee Research Foundation | The mycolactone locus : an assembly line for producing novel polyketides, with therapeutic and prophylatic uses |
WO2006000923A3 (en) * | 2004-06-03 | 2006-12-28 | Novimmune Sa | Macrolide compositions as therapeutic agent |
WO2006000923A2 (en) * | 2004-06-03 | 2006-01-05 | Novimmune Sa | Macrolide compositions as therapeutic agent |
US7790887B2 (en) | 2007-01-29 | 2010-09-07 | Eisai R&D Management Co., Ltd. | Macrolide compound in solid form, process for preparation thereof, and pharmaceutical composition containing the same |
Also Published As
Publication number | Publication date |
---|---|
EP1192147A1 (en) | 2002-04-03 |
CA2376010A1 (en) | 2000-12-14 |
AU5179800A (en) | 2000-12-28 |
JP2003501423A (ja) | 2003-01-14 |
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