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Tumor-Targeted Delivery of 6-Diazo-5-oxo-l-norleucine (DON) Using Substituted Acetylated Lysine Prodrugs

  • Lukáš Tenora
    Lukáš Tenora
    Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Prague 166 10, Czech Republic
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  • , 
  • Jesse Alt
    Jesse Alt
    Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
    More by Jesse Alt
  • , 
  • Ranjeet P. Dash
    Ranjeet P. Dash
    Johns Hopkins Drug Discovery  and  Departments of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
    More by Ranjeet P. Dash
  • , 
  • Alexandra J. Gadiano
    Alexandra J. Gadiano
    Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
    More by Alexandra J. Gadiano
  • , 
  • Kateřina Novotná
    Kateřina Novotná
    Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Prague 166 10, Czech Republic
    More by Kateřina Novotná
  • , 
  • Vijayabhaskar Veeravalli
    Vijayabhaskar Veeravalli
    Johns Hopkins Drug Discovery  and  Departments of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
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  • , 
  • Jenny Lam
    Jenny Lam
    Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
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  • , 
  • Quinn R. Kirkpatrick
    Quinn R. Kirkpatrick
    Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
    More by Quinn R. Kirkpatrick
  • , 
  • Kathryn M. Lemberg
    Kathryn M. Lemberg
    Johns Hopkins Drug Discovery  and  Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
    More by Kathryn M. Lemberg
  • , 
  • Pavel Majer*
    Pavel Majer
    Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i., Prague 166 10, Czech Republic
    *E-mail: [email protected]. Tel: +420-220183125 (P.M.).
    More by Pavel Majer
  • , 
  • Rana Rais*
    Rana Rais
    Johns Hopkins Drug Discovery  and  Departments of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
    *E-mail: [email protected]. Tel: 410-502-0497. Fax: 410-614-0659 (R.R.).
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    Orcidhttp://orcid.org/0000-0003-4059-2453
  • , and 
  • Barbara S. Slusher*
    Barbara S. Slusher
    Johns Hopkins Drug Discovery,  Departments of Neurology,  Psychiatry and Behavioral Sciences,  Neuroscience,  Medicine  and  Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States
    *E-mail: [email protected]. Tel: 410-614-0662. Fax: 410-614-0659 (B.S.S.).
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    Orcidhttp://orcid.org/0000-0001-9814-4157
Cite this: J. Med. Chem. 2019, 62, 7, 3524–3538
Publication Date (Web):March 20, 2019
https://doi.org/10.1021/acs.jmedchem.8b02009
Copyright © 2019 American Chemical Society
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    Abstract

    Abstract Image

    6-Diazo-5-oxo-l-norleucine (DON) is a glutamine antagonist with robust anticancer efficacy; however, its therapeutic potential was hampered by its biodistribution and toxicity to normal tissues, specifically gastrointestinal (GI) tissues. To circumvent DON’s toxicity, we synthesized a series of tumor-targeted DON prodrugs designed to circulate inert in plasma and preferentially activate over DON in tumor. Our best prodrug 6 (isopropyl 2-(6-acetamido-2-(adamantane-1-carboxamido)hexanamido)-6-diazo-5-oxohexanoate) showed stability in plasma, liver, and intestinal homogenates yet was readily cleaved to DON in P493B lymphoma cells, exhibiting a 55-fold enhanced tumor cell-to-plasma ratio versus that of DON and resulting in a dose-dependent inhibition of cell proliferation. Using carboxylesterase 1 knockout mice that were shown to mimic human prodrug metabolism, systemic administration of 6 delivered 11-fold higher DON exposure to tumor (target tissue; AUC0–t = 5.1 nmol h/g) versus GI tissues (toxicity tissue; AUC0–t = 0.45 nmol h/g). In summary, these studies describe the discovery of a glutamine antagonist prodrug that provides selective tumor exposure.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.8b02009.

    • Details of 1H and 13C NMR and HPLC analysis, 1H and 13C NMR spectra, HPLC chromatograms; table containing mass transitions for LC–MS analysis; figures showing molecular structures of internal standards, stability of 6 in human liver fractions, tumor cell/plasma partitioning in three different cell lines, HRMS chromatogram and spectra of 6 and its de-esterified product (PDF)

    • Molecular formula strings and associated biological data (CSV)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

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