US20160145304A1 - Cystobactamides - Google Patents

Cystobactamides Download PDF

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Publication number
US20160145304A1
US20160145304A1 US14/904,654 US201414904654A US2016145304A1 US 20160145304 A1 US20160145304 A1 US 20160145304A1 US 201414904654 A US201414904654 A US 201414904654A US 2016145304 A1 US2016145304 A1 US 2016145304A1
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US
United States
Prior art keywords
group
alkyl
formula
hydrogen atom
optionally substituted
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
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US14/904,654
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English (en)
Inventor
Sascha Baumann
Jennifer Herrmann
Kathrin Mohr
Heinrich Steinmetz
Klaus Gerth
Ritesh Raju
Rolf Müller
Rolf Hartmann
Mostafa Hamed
Walid A.M. Elgaher
Maria Moreno
Franziska Gille
Liang Liang Wang
Andreas Kirschning
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.)
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
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Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
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Application filed by Helmholtz Zentrum fuer Infektionsforschung HZI GmbH filed Critical Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Publication of US20160145304A1 publication Critical patent/US20160145304A1/en
Assigned to HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH reassignment HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HERRMANN, Jennifer, KIRSCHNING, ANDREAS, MORENO, MARIA, WANG, LIANG LIANG, RAJU, Ritesh, BAUMANN, SASCHA, ELGAHER, WALID A.M., HAMED, MOSTAFA, HARTMANN, ROLF, MULLER, ROLF, GERTH, KLAUS, MOHR, Kathrin, STEINMETZ, HEINRICH, GILLE, FRANZISKA
Assigned to HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH reassignment HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GOTTFRIED WILHELM LEIBNIZ UNIVERSITAT HANNOVER
Abandoned legal-status Critical Current

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    • 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
    • A61P31/04—Antibacterial agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/52—Genes encoding for enzymes or proenzymes
    • 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
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Ar 2 is an optionally substituted phenylene group or an optionally substituted heteroarylene group having 5 or 6 ring atoms including 1, 2, 3 or 4 heteroatoms selected from oxygen, sulphur and nitrogen;
  • L 2 is NHCO (wherein the nitrogen atom is bound to Ar 1 ).
  • L 4 is absent or a group of formula —CONH—, —NHCO—, —SO 2 NH— or —NHSO 2 —;
  • group(s) R 22 are independently selected from halogen atoms, hydroxy groups, groups of formula —O-alkyl (e.g.
  • R 1 , R 2 , L 1 and L 2 are as defined above.
  • R 57 is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6 alkyl group or a group of formula —O—C 1-6 alkyl;
  • Ar 6 is an optionally substituted (by one, two or more substituents such as e.g. R 2 , R 8 or NHR 8 ) phenyl group or an optionally substituted (by one, two or more substituents such as e.g. R 2 , R 8 or NHR 8 ) heteroaryl group having 5 or 6 ring atoms including 1, 2, 3 or 4 heteroatoms selected from oxygen, sulphur and nitrogen;
  • M is N or CR 56 ;
  • R 56 is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6 alkyl group or a group of formula —O—C 1-6 alkyl;
  • R 57 is a hydrogen atom, F, Cl, a hydroxy group, a C 1-6 alkyl group or a group of formula —O—C 1-6 alkyl;
  • control sequences or “regulatory sequences” is defined herein to include at least any component which may be necessary and/or advantageous for the expression of a polypeptide.
  • Any control sequence may be native or foreign to the nucleic acid sequence of the invention encoding a polypeptide.
  • control sequences may include, but are not limited to, a promoter, a leader, optimal translation initiation sequences (as described in Kozak, 1991, J. Biol. Chem. 266:19867-19870), a secretion signal sequence, a pro-peptide sequence, a polyadenylation sequence, a transcription terminator.
  • the control sequences typically include a promoter, and transcriptional and translational stop signals.
  • the engineered host cells can be cultured in conventional nutrient media modified as appropriate for activating promoters, selecting transformants or amplifying the nucleic acids of the invention.
  • the selected promoter may be induced by appropriate means (e.g., temperature shift or chemical induction) and the cells may be cultured for an additional period to allow them to produce the desired polypeptide or fragment thereof.
  • Cells can be harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract is retained for further purification.
  • Microbial cells employed for expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents.
  • the strain produces in complex media. He prefers nitrogen containing nutrients like single cell protein (Probion) and products of protein decomposition like peptone, tryptone, yeast extract, soy flour and meat extract. Here the production is better with several of the mentioned proteinmixtures compared to a single one.
  • a knock-out (KO) experiment was carried out, where CysK (NRPS) and CysL (benzoyl-CoA ligase) was knocked out, respectively.
  • CysK NRPS
  • CysL benzoyl-CoA ligase
  • cystobactamide C (3) bearing resemblance to the eastern part of cystobactamide A and B, consisting of 3-isopropoxybenzoic acid, 2-hydroxy-3-isopropoxybenzamide and a para-aminobenzamide unit.
  • DNA/gyrase complex linearization assays A and ATP competition assays (B) were performed using cystobactamide D.
  • A Here, the complex of DNA and gyrase is trapped using SDS and the gyrase is digested using proteinase K. If the gyrase/DNA complex is trapped by a gyrase inhibitor of type 1 this will lead to the formation of linearized plasmid (as the religation is inhibited). Type 2 inhibitor-bound or compound-free samples will not show the formation of linearized plasmids. The results of the assay are shown in FIG. 10 a .
  • Cystobactamide A1 543.5 ⁇ M; 108.7 ⁇ M; 54 ⁇ M; 10.8 ⁇ M; 5.4 ⁇ M; 1.087 ⁇ M; 0.54 ⁇ M; 0.108 ⁇ M; 0.054 ⁇ M; 0.0108 ⁇ M
  • Cystobactamide A1 543.5 ⁇ M; 108.7 ⁇ M; 54 ⁇ M; 10.8 ⁇ M; 5.4 ⁇ M; 1.087 ⁇ M; 0.54 ⁇ M; 0.108 ⁇ M; 0.054 ⁇ M; 0.0108 ⁇ M
  • Cystobactamide C 300 ⁇ M; 60 ⁇ M; 30 ⁇ M; 6 ⁇ M; 3 ⁇ M; 0.6 ⁇ M; 0.3 ⁇ M; 0.06 ⁇ M; 0.03 ⁇ M; 0.006 ⁇ M
  • Cystobactamide A1 543 ⁇ M; 54.3 ⁇ M; 5.43 ⁇ M

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Biophysics (AREA)
  • Microbiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • Plant Pathology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)
  • Pyrrole Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pyridine Compounds (AREA)
US14/904,654 2013-07-12 2014-07-14 Cystobactamides Abandoned US20160145304A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP13003539 2013-07-12
EP13003539.7 2013-07-12
PCT/EP2014/001925 WO2015003816A2 (en) 2013-07-12 2014-07-14 Cystobactamides

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2014/001925 A-371-Of-International WO2015003816A2 (en) 2013-07-12 2014-07-14 Cystobactamides

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/042,753 Continuation US10793600B2 (en) 2013-07-12 2018-07-23 Cystobactamides

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US20160145304A1 true US20160145304A1 (en) 2016-05-26

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US14/904,654 Abandoned US20160145304A1 (en) 2013-07-12 2014-07-14 Cystobactamides
US16/042,753 Active US10793600B2 (en) 2013-07-12 2018-07-23 Cystobactamides
US16/897,497 Active US11225503B2 (en) 2013-07-12 2020-06-10 Crystobactamides

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US16/042,753 Active US10793600B2 (en) 2013-07-12 2018-07-23 Cystobactamides
US16/897,497 Active US11225503B2 (en) 2013-07-12 2020-06-10 Crystobactamides

Country Status (7)

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US (3) US20160145304A1 (enExample)
EP (1) EP3019615B1 (enExample)
JP (1) JP6730183B2 (enExample)
CN (1) CN105793424B (enExample)
AU (1) AU2014289663B2 (enExample)
CA (1) CA2917767C (enExample)
WO (1) WO2015003816A2 (enExample)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10973817B2 (en) 2014-02-10 2021-04-13 Sentinel Oncology Limited Pharmaceutical compounds
US11034648B2 (en) * 2017-08-23 2021-06-15 Helmholtz-Zentrum Für Cystobactamide derivatives
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11529350B2 (en) 2019-07-03 2022-12-20 Sumitomo Pharma Oncology, Inc. Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels

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Publication number Priority date Publication date Assignee Title
EP3019615B1 (en) 2013-07-12 2021-04-07 Helmholtz-Zentrum für Infektionsforschung GmbH Cystobactamides
KR101747702B1 (ko) 2014-05-15 2017-06-19 한국생명공학연구원 신규한 항균성 화합물 및 이의 용도
US10519099B2 (en) 2014-11-26 2019-12-31 Helmholtz-Zentrum für Infektionsforschung GmbH Cystobactamides
CN105712894A (zh) * 2016-03-23 2016-06-29 叶芳 一种3-甲氧基-4-氨基苯甲酸及其制备方法
JP7037122B2 (ja) * 2016-09-28 2022-03-16 日産化学株式会社 ジアミンおよびその利用
UY37806A (es) 2017-07-11 2020-01-31 Vertex Pharma Carboxamidas como moduladores de los canales de sodio
CA3070240A1 (en) * 2017-07-18 2019-01-24 Technische Universitat Berlin Novel albicidin derivatives, their use and synthesis
US11247987B2 (en) 2017-10-06 2022-02-15 Forma Therapeutics, Inc. Inhibiting ubiquitin specific peptidase 30
SG11202005985PA (en) 2018-01-10 2020-07-29 Recurium Ip Holdings Llc Benzamide compounds
ES2988920T3 (es) 2018-05-17 2024-11-22 Forma Therapeutics Inc Compuestos bicíclicos fusionados útiles como inhibidores de la peptidasa 30 específica de ubiquitina
MX2021002981A (es) 2018-10-05 2021-05-14 Forma Therapeutics Inc Pirrolinas fusionadas que actuan como inhibidores de la proteasa 30 especifica de la ubiquitina (usp30).
WO2020146612A1 (en) 2019-01-10 2020-07-16 Vertex Pharmaceuticals Incorporated Esters and carbamates as modulators of sodium channels
US12441703B2 (en) 2019-01-10 2025-10-14 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
CN117222438A (zh) * 2021-03-31 2023-12-12 麦迪贝肯有限公司 取代的二氨基吡嗪二甲酸的纯化
CN113563220B (zh) * 2021-06-25 2023-08-29 华中农业大学 一种抗菌化合物及其应用
WO2025003147A1 (en) 2023-06-26 2025-01-02 Helmholtz-Zentrum für Infektionsforschung GmbH Cystobactamid derivatives

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10973817B2 (en) 2014-02-10 2021-04-13 Sentinel Oncology Limited Pharmaceutical compounds
US11786524B2 (en) 2014-02-10 2023-10-17 Sentinel Oncology Limited Pharmaceutical compounds
US11034648B2 (en) * 2017-08-23 2021-06-15 Helmholtz-Zentrum Für Cystobactamide derivatives
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US12338233B2 (en) 2018-02-13 2025-06-24 Gilead Sciences, Inc. PD-1/Pd-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US12269812B2 (en) 2018-07-13 2025-04-08 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11529350B2 (en) 2019-07-03 2022-12-20 Sumitomo Pharma Oncology, Inc. Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof
US12247021B2 (en) 2019-12-06 2025-03-11 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US12258333B2 (en) 2021-06-04 2025-03-25 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

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US20200331964A1 (en) 2020-10-22
US11225503B2 (en) 2022-01-18
CN105793424A (zh) 2016-07-20
CN105793424B (zh) 2021-02-19
AU2014289663A1 (en) 2016-02-04
CA2917767A1 (en) 2015-01-15
WO2015003816A2 (en) 2015-01-15
JP2016527215A (ja) 2016-09-08
EP3019615A2 (en) 2016-05-18
JP6730183B2 (ja) 2020-07-29
AU2014289663B2 (en) 2019-03-07
US10793600B2 (en) 2020-10-06
EP3019615B1 (en) 2021-04-07
US20190185514A1 (en) 2019-06-20
CA2917767C (en) 2022-05-03
WO2015003816A3 (en) 2015-03-12

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