WO2001005815A1 - Technique de deacylation de lipodepsipeptides - Google Patents

Technique de deacylation de lipodepsipeptides Download PDF

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Publication number
WO2001005815A1
WO2001005815A1 PCT/US2000/015018 US0015018W WO0105815A1 WO 2001005815 A1 WO2001005815 A1 WO 2001005815A1 US 0015018 W US0015018 W US 0015018W WO 0105815 A1 WO0105815 A1 WO 0105815A1
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WO
WIPO (PCT)
Prior art keywords
pseudomycin
nucleus
syringomycin
syringae
natural product
Prior art date
Application number
PCT/US2000/015018
Other languages
English (en)
Inventor
Adam Joseph Kreuzman
Palaniappan Kulanthaivel
Michael John Rodriguez
Original Assignee
Eli Lilly And Company
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 Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to EA200200162A priority Critical patent/EA200200162A1/ru
Priority to CA002378868A priority patent/CA2378868A1/fr
Priority to MXPA02000458A priority patent/MXPA02000458A/es
Priority to EP00938006A priority patent/EP1198471A1/fr
Priority to AU53106/00A priority patent/AU5310600A/en
Priority to JP2001511472A priority patent/JP2003505042A/ja
Priority to BR0012481-8A priority patent/BR0012481A/pt
Publication of WO2001005815A1 publication Critical patent/WO2001005815A1/fr
Priority to NO20020183A priority patent/NO20020183L/no

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the present invention relates to lipodepsipeptides, in particular, deacylation of the N-acyl side-chain of pseudomycin and syringomycin natural products and the compounds produced therefrom.
  • Pseudomycins and syringomycins are natural products isolated from liquid cultures of Pseudomonas syringae (plant-associated bacterium) and have been shown to have antifungal activities.
  • Pseudomonas syringae plant-associated bacterium
  • Pseudomonas syringae plant-associated bacterium
  • antifungal activities see i.e., Harrison, L., et al . , "Pseudomycins, a family of novel peptides from Pseudomonas syringae possessing broad-spectrum antifungal activity, " J. Gen. Microbiology, 137(12), 2857-65 (1991) and US Patent Nos. 5,576,298 and 5,837,685)
  • syringae e.g., syringomycins, syringotoxins and syringostatins
  • pseudomycins A-C contain hydroxyaspartic acid, aspartic acid, serine, dehydroaminobutyric acid, lysine and diaminobutyric acid.
  • the peptide moiety for pseudomycins A, A', B, B' , C, C corresponds to L-Ser-D-Dab-L-Asp-L-Lys-L-Dab-L-aThr-Z-Dhb-L- Asp(3-OH) -L-Thr (4-C1) with the terminal carboxyl group closing a macrocyclic ring on the OH group of the N-terminal Ser.
  • the analogs are distinguished by the N-acyl side chain, i.e., pseudomycin A is N-acylated by 3 , 4-dihydroxytetradeconoyl, pseudomycin A' by 3 , 4-dihydroxypentadecanoyl , pseudomycin B by 3-hydroxytetradecanoyl, pseudomycin B' by 3-hydroxydodecanoyl, pseudomycin C by 3 , 4-dihydroxyhexadecanoyl and pseudomycin C by 3-hydroxyhexadecanoyl . (see i.e., Ballio, A., et al .
  • Pseudomycins and syringomycins are known to have certain adverse biological effects. For example, destruction of the endothelium of the vein, destruction of tissue, inflammation, and local toxicity to host tissues have been observed when pseudomycin is administered intraveneously . Therefore, there is a need to identify compounds within this class that are useful for treating fungal infections without the currently observed adverse side effects.
  • BRIEF SUMMARY OF THE INVENTION The present invention provides a process for deacylating the N-acyl side-chain of a lipodepsipeptide natural product to produce the corresponding nucleus.
  • the deacylation of pseudomycin compounds produces the pseudomycin amino nucleus represented by the following structure I.
  • the nucleus is useful as a starting material for producing semi-synthetic derivatives of the corresponding natural product.
  • the process includes reacting a pseudomycin natural product with a deacylase enzyme selected from the group consisting of ECB deacylase and polymyxin acylase to produce the corresponding nucleus represented by structure I .
  • the free amine may rearrange to produce a cyclic peptide nucleus having a free hydroxy group represented by structure II below (also referred to as pseudomycin hydroxy nucleus) .
  • Compound II may then serve as starting material to generate novel derivatives which may be pharmaceutically active.
  • the process described above is used to deacylate syringomycin compounds to provide a syringomycin amino nucleus.
  • the amino nucleus of Syringomycin E has the following structure III.
  • the syringomycin amino nucleus may rearrange to form the following Compound IV (also referred to as syringomycin hydroxy nucleus) .
  • pseudomycin refers to compounds having the following formula:
  • R is a lipophilic moiety.
  • the lipophilic moiety includes C 9 -C 15 alkyl, C 9 -C 15 hydroxyalkyl , C 9 -C 15 dihydroxya1ky1 , C 9 -C 15 alkenyl, C 9 -C1 5 hydroxyalkenyl, or C 9 - C1 5 dihydroxyalkenyl .
  • the pseudomycin compounds A, A', B, B', C, C are represented by the formula I above where R is as defined below.
  • Pseudomycin A R 3 , 4-dihydroxytetradecanoyl
  • Pseudomycin C R 3 , 4-dihydroxyhexadecanoyl
  • Applicants have discovered a process for enzymatically deacylating the N-acyl side-chain of a broad spectrum of lipodepsipeptide natural products to produce the corresponding nucleus.
  • the free amine nucleus rearranges to produce the free hydroxy derivative such as the compounds shown above as structures II and IV.
  • Compounds I and III can be converted to Compounds II and IV, respectively, by exposing Compound I or III to a pH > 6. If the desired product is Compound I or III, then one could reduce the rate at which the rearranged product forms from the deacylated pseudomycin or deacylated syringomycin with the addition of an acid, such as trifluoroacetic acid.
  • the addition of an acid could result in lower yields of the amine nucleus.
  • the enzyme may precipitate out of the reaction mixture thus stopping the conversion. Therefore, the pH of the reaction mixture is preferably not lowered less than about 5.5.
  • One could prevent enzyme precipitation by separating the enzyme from the reaction through a molecular weight membrane (i.e., 10,000 to 50,000 molecular weight cutoff).
  • the effluent through the membrane would contain compounds having a molecular weight less than 10,000 to 5,000 (e.g., Compounds I-IV) and would exclude the higher molecular weight enzyme. The effluent could then be pH adjusted down to stabilize the product.
  • the inventive enzymatic process may be used to deacylate pseudomycin or syringomycin analogs with or without gamma or delta hydroxy side chains. Therefore, the spectrum of starting natural products is expanded significantly. For example, one may deacylate pseudomycin A, A', B, B', C or C using the inventive process. Whereas, the acid deacylation process is useful only with pseudomycin A, A' and C.
  • Suitable enzymes include ECB deacylase and Polymyxin acylase (available in both a crude & pure form as 161-16081 Fatty Acylase, Pure and 164-16081 Fatty Acylase, Crude, from Wako Pure Chemical Industries, Ltd.)
  • ECB deacylase can be obtained from Actinoplanes utahensis (see e.g., LaVerne, D, et al, "Deacylation of Echinocandin B by Actinoplanes utahensis, " J. of Antibiotics , 42(3), 382-388 (1989).)
  • the Actinoplanes utahensis ECB deacylase enzyme may be purified by the process described in U.S.
  • the enzymatic deacylation may be accomplished using standard deacylation procedures well known to those skilled in the art.
  • general procedures for using Polymyxin acylase may be found in Yasuda, N. , et al, Agri c . Biol . Chem. , 53, 3245 (1989) and Kimura, Y., et al . , Agric . Biol . Chem. , 53, 497 (1989).
  • the deacylation process is generally ran at temperatures between about 20°C and about 60°C, preferably
  • the enzyme is optimally active at pH 8.0 and at a temperature between about 50°C and
  • the pH of the reaction is generally kept between about 5.5 and about 8.0.
  • the reaction time will vary depending upon the pH and the temperature. However, with limiting enzyme concentration and saturated substrate concentration at high temperatures and pH, the reaction is linear through 10 minutes. Since Pseudomcyin A is unstable at higher pHs, deacylation of Pseudomycin A is generally ran at a lower pH (between about
  • deacylation of Pseudomycin A can be ran in a buffered solution containing 0.05 M KP0 4 and 0.8 M KC1.
  • a saturated level of substrate is generally between about 0.5 mg and about 1 mg per ml of reaction.
  • pseudomycins are natural products isolated from the bacterium Pseudomonas syringae that have been characterized as lipodepsinonapetpides containing a cyclic peptide portion closed by a lactone bond and including the unusual amino acids 4-chlorothreonine (ClThr) , 3-hydroxyaspartic acid (HOAsp) , 2 , 3-dehydro-2-aminobutyric acid (Dhb) , and 2 , 4-diaminobutyric acid (Dab).
  • Isolated strains of P. syringae that produce one or more pseudomycins are known in the art. Wild type strain MSU 174 and a mutant of this strain generated by transposon mutagenesis, MSU 16H are described in U.S. Patent Nos. 5,576,298 and 5,837,685; Harrison, et al . , "Pseudomycins, a family of novel peptides from Pseudomonas syringae possessing broad-spectrum antifungal activity, " J . Gen . Microbiology, 137, 2857-2865 (1991); and Lamb et al .
  • a strain of P. syringae that is suitable for production of one or more pseudomycins can be isolated from environmental sources including plants (e.g., barley plants, citrus plants, and lilac plants) as well as, sources such as soil, water, air, and dust.
  • a preferred stain is isolated from plants.
  • Strains of P. syringae that are isolated from environmental sources can be referred to as wild type.
  • wild type refers to a dominant genotype which naturally occurs in the normal population of P. syringae ( e . g . , strains or isolates of P. syringae that are found in nature and not produced by laboratory manipulation) .
  • pseudomycin-producing cultures such as MSU 174, MSU 16H, MSU 206, 25-B1, 7H9-1
  • progeny of these strains e.g., recombinants, mutants and variants
  • Mutant strains of P. syringae are also suitable for production of one or more pseudomycins.
  • mutant refers to a sudden heritable change in the phenotype of a strain, which can be spontaneous or induced by known mutagenic agents, such as radiation (e.g., ultraviolet radiation or x-rays), chemical mutagens (e.g., ethyl methanesulfonate (EMS) , diepoxyoctane, N-methyl-N- nitro-N' -nitrosoguanine (NTG) , and nitrous acid), site- specific mutagenesis, and transposon mediated mutagenesis.
  • EMS ethyl methanesulfonate
  • NTG N-methyl-N- nitro-N' -nitrosoguanine
  • nitrous acid nitrous acid
  • syringae can be produced by treating the bacteria with an amount of a mutagenic agent effective to produce mutants that overproduce one or more pseudomycins, that produce one pseudomycin (e.g., pseudomycin B) in excess over other pseudomycins, or that produce one or more pseudomycins under advantageous growth conditions. While the type and amount of mutagenic agent to be used can vary, a preferred method is to serially dilute
  • NTG to levels ranging from 1 to 100 ⁇ g/ml.
  • Preferred mutants are those that overproduce pseudomycin B and grow in minimal defined media.
  • Environmental isolates, mutant strains, and other desirable strains of P. syringae can be subjected to selection for desirable traits of growth habit, growth medium nutrient source, carbon source, growth conditions, amino acid requirements, and the like.
  • a pseudomycin producing strain of P. syringae is selected for growth on minimal defined medium such as N21 medium and/or for production of one or more pseudomycins at levels greater than about 10 ⁇ g/ml.
  • Preferred strains exhibit the characteristic of producing one or more pseudomycins when grown on a medium including three or fewer amino acids and optionally, either a lipid, a potato product or combination thereof .
  • Recombinant strains can be developed by transforming the P. syringae strains, using procedures known in the art. Through the use of recombinant DNA technology, the P. syringae strains can be transformed to express a variety of gene products in addition to the antibiotics these strains produce. For example, one can modify the strains to introduce multiple copies of the endogenous pseudomycin- biosynthesis genes to achieve greater pseudomycin yield.
  • the organism is cultured with agitation in an aqueous nutrient medium including an effective amount of three or fewer amino acids, preferably glutamic acid, glycine, histidine, or a combination thereof.
  • glycine is combined with one or more of a potato product and a lipid.
  • Culturing is conducted under conditions effective for growth of P. syringae and production of the desired pseudomycin or pseudomycins .
  • Effective conditions include temperatures from about 22 2 C to about 27 2 C, and a duration of about 36 hours to about 96 hours.
  • Controlling the concentration of oxygen in the medium during culturing of P . syringae is advantageous for production of a pseudomycin.
  • oxygen levels are maintained at about 5 to 50% saturation, more preferably about 30% saturation. Sparging with air, pure oxygen, or gas mixtures including oxygen can regulate the concentration of oxygen in the medium.
  • Controlling the pH of the medium during culturing of P. syringae is also advantageous.
  • Pseudomycins are labile at basic pH, and significant degradation can occur if the pH of the culture medium is above about 6 for more than about 12 hours.
  • the pH of the culture medium is maintained between 6 and 4.
  • P. syringae can produce one or more pseudomycins when grown in batch culture.
  • fed-bath or semi-continuous feed of glucose and optionally, an acid or base (e.g., ammonium hydroxide) to control pH enhances production.
  • Pseudomycin production can be further enhanced by using continuous culture methods in which glucose and ammonium hydroxide are fed automatically.
  • Choice of P. syringae strain can affect the amount and distribution of pseudomycin or pseudomycins produced.
  • strains MSU 16H and 67 HI each produce predominantly pseudomycin A, but also produce pseudomycin B and C, typically in ratios of 4:2:1.
  • Strain 67 Hi typically produces levels of pseudomycins about three to five fold larger than are produced by strain MSU 16H.
  • strain 25-B1 produces more pseudomycin B and less pseudomycin C.
  • Strain 7H9-1 are distinctive in producing predominantly pseudomycin B and larger amount of pseudomycin B than other strains . For example, this strain can produce pseudomycin B in at least a ten fold excess over either pseudomycin A or C .
  • Syringomycin E, syringotoxin B, and syringostatin A may be produced from cultures of Pseudomonas syringae pv. syringae strains B301D, PS268, and SY12, respectively.
  • Syringomycin Ai and G may be isolated from Pseudomonas syringae pv. syringae as well.
  • Strains B301D and PS268 are grown in potato dextrose broth as described by Zhang, L., and J. Y.
  • the pseudomycin or syringomycin nucleus or corresponding rearranged compounds may be isolated and used per se or in the form of its pharmaceutically acceptable salt or solvate.
  • pharmaceutically acceptable salt refers to non-toxic acid addition salts derived from inorganic and organic acids.
  • Suitable salt derivatives include halides, thiocyanates, sulfates, bisulfates, sulfites, bisulfites, arylsulfonates, alkylsulfates, phosphonates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphonates, alkanoates, cycloalkylalkanoates, arylalkonates , adipates, alginates, aspartates, benzoates, fumarates, glucoheptanoates, glycerophosphates, lactates, maleates, nicotinates, oxalates, palmitates, pectinates, picrates, pivalates, succinates, tartarates, citrates, camphorates, camphorsulfonates, digluconates, trifluoroacetates, and the like.
  • solvate refers to an aggregate that comprises one or more molecules of the solute (i.e., pseudomycin and syringomycin compound) with one or more molecules of a pharmaceutical solvent, such as water, ethanol, and the like.
  • a pharmaceutical solvent such as water, ethanol, and the like.
  • the solvent is water, then the aggregate is referred to as a hydrate.
  • Solvates are generally formed by dissolving the nucleus or rearranged compound (Compounds II or IV) in the appropriate solvent with heat and slowing cooling to generate an amorphous or crystalline solvate form.
  • Example illustrates the deacylation of Pseudomycin A using ECB Deacylase enzyme .
  • protons in addition to the proton, correlated to an amide proton at 8.04 ppm in the TOCSY spectrum indicated that the lactone of the macrocycle rearranged to a peptide core as depicted in II.
  • pseudomycin or syringomycin compounds having an N-acyl group may be deacylated using the same general procedures described above .

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Abstract

L'invention concerne une technique de déacylation d'un lipodepsipeptide, qui permet de produire le noyau correspondant. Elle porte également sur les produits obtenus à partir de ladite technique (par exemple, un noyau de pseudomycine représenté par les structures (I) ou (II)).
PCT/US2000/015018 1999-07-15 2000-06-08 Technique de deacylation de lipodepsipeptides WO2001005815A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EA200200162A EA200200162A1 (ru) 1999-07-15 2000-06-08 Способ деацилирования липодепсипептидов
CA002378868A CA2378868A1 (fr) 1999-07-15 2000-06-08 Technique de deacylation de lipodepsipeptides
MXPA02000458A MXPA02000458A (es) 1999-07-15 2000-06-08 Proceso para la desacilacion de lipodepsipeptidos.
EP00938006A EP1198471A1 (fr) 1999-07-15 2000-06-08 Technique de deacylation de lipodepsipeptides
AU53106/00A AU5310600A (en) 1999-07-15 2000-06-08 Process for deacylation of lipodepsipeptides
JP2001511472A JP2003505042A (ja) 1999-07-15 2000-06-08 リポデプシペプチド天然物の脱アシル化
BR0012481-8A BR0012481A (pt) 1999-07-15 2000-06-08 Processo para desacilação de lipodepsipeptìdeos
NO20020183A NO20020183L (no) 1999-07-15 2002-01-14 Fremgangsmåte for deacylering av lipodepsipeptider

Applications Claiming Priority (2)

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US14396899P 1999-07-15 1999-07-15
US60/143,968 1999-07-15

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WO2001005815A1 true WO2001005815A1 (fr) 2001-01-25

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EP (1) EP1198471A1 (fr)
JP (1) JP2003505042A (fr)
CN (1) CN1361791A (fr)
AU (1) AU5310600A (fr)
BR (1) BR0012481A (fr)
CA (1) CA2378868A1 (fr)
EA (1) EA200200162A1 (fr)
HU (1) HUP0202315A2 (fr)
MX (1) MXPA02000458A (fr)
NO (1) NO20020183L (fr)
WO (1) WO2001005815A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012541A1 (fr) * 2003-07-31 2005-02-10 TransMIT Gesellschaft für Technologietransfer mbH Procede pour produire des molecules cycliques
US7442683B2 (en) 2001-02-19 2008-10-28 Takara Bio Inc. Cyclic peptide
US8343912B2 (en) 2008-12-23 2013-01-01 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
US8415307B1 (en) 2010-06-23 2013-04-09 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
WO2014044803A1 (fr) * 2012-09-24 2014-03-27 Dsm Sinochem Pharmaceuticals Netherlands B.V. Procédé de production d'un peptide cyclique
US8889826B2 (en) 2004-07-01 2014-11-18 Biosource Pharm, Inc. Peptide antibiotics and methods for making same

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004060750A1 (de) * 2004-12-15 2006-07-13 Sanofi-Aventis Deutschland Gmbh Verfahren zur Deacylierung von Lipopeptiden

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0460882A2 (fr) * 1990-06-07 1991-12-11 Eli Lilly And Company Lipopeptide déacylase

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0460882A2 (fr) * 1990-06-07 1991-12-11 Eli Lilly And Company Lipopeptide déacylase

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
A BALLIO ET AL: "Novel bioactive lipodepsipeptides from Pseudomonas syringae: the pseudomycins", FEBS LETTERS,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 355, no. 1, 21 November 1994 (1994-11-21), pages 96 - 100, XP002125309, ISSN: 0014-5793 *
KIMURA E.A.: "Polymixin acylase: purification and characterization, with special reference to broad substrate specificity", AGRIC.BIOL.CHEM., vol. 53, no. 2, 1989, pages 497 - 504, XP002149548 *
N FUKUCHI ET AL: "Isolation and structural elucidation of syringostatins, phytotoxins produced by Pseudomonas syringae pv. syringae Lilac isolate", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1,GB,CHEMICAL SOCIETY. LETCHWORTH, vol. 7, 1992, pages 875 - 880, XP002125311, ISSN: 1470-4358 *
YASUDA E.A.: "Polymixin acylase: an enzyme causing intramolecular N2-N6 acyl ttransfer in N-monooctanoyl-L-lysine", AGRIC.BIOL.CHEM., vol. 53, no. 12, 1989, pages 3245 - 3249, XP002149547 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7442683B2 (en) 2001-02-19 2008-10-28 Takara Bio Inc. Cyclic peptide
WO2005012541A1 (fr) * 2003-07-31 2005-02-10 TransMIT Gesellschaft für Technologietransfer mbH Procede pour produire des molecules cycliques
US8063181B2 (en) 2003-07-31 2011-11-22 ZYRUS Beteiligungsgesellschaft mbH & Co. Patent I KG Method for the production of cyclic molecules
US8889826B2 (en) 2004-07-01 2014-11-18 Biosource Pharm, Inc. Peptide antibiotics and methods for making same
US8343912B2 (en) 2008-12-23 2013-01-01 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
US8937040B2 (en) 2008-12-23 2015-01-20 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
US8415307B1 (en) 2010-06-23 2013-04-09 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
US8906866B2 (en) 2010-06-23 2014-12-09 Biosource Pharm, Inc. Antibiotic compositions for the treatment of gram negative infections
WO2014044803A1 (fr) * 2012-09-24 2014-03-27 Dsm Sinochem Pharmaceuticals Netherlands B.V. Procédé de production d'un peptide cyclique

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NO20020183D0 (no) 2002-01-14
CA2378868A1 (fr) 2001-01-25
MXPA02000458A (es) 2002-07-02
CN1361791A (zh) 2002-07-31
EP1198471A1 (fr) 2002-04-24
JP2003505042A (ja) 2003-02-12
NO20020183L (no) 2002-03-13
EA200200162A1 (ru) 2002-06-27
AU5310600A (en) 2001-02-05
BR0012481A (pt) 2002-04-02
HUP0202315A2 (en) 2002-10-28

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