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

Lukáš Tenora, Jesse Alt, Ranjeet P. Dash, Alexandra J. Gadiano, Kateřina Novotná, Vijayabhaskar Veeravalli, Jenny Lam, Quinn R. Kirkpatrick, Kathryn M. Lemberg, Pavel Majer, Rana Rais, Barbara Slusher

Research output: Contribution to journalArticle

Abstract

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; AUC 0-t = 5.1 nmol h/g) versus GI tissues (toxicity tissue; AUC 0-t = 0.45 nmol h/g). In summary, these studies describe the discovery of a glutamine antagonist prodrug that provides selective tumor exposure.

Original languageEnglish (US)
Pages (from-to)3524-3538
Number of pages15
JournalJournal of medicinal chemistry
Volume62
Issue number7
DOIs
StatePublished - Apr 11 2019

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Diazooxonorleucine
Prodrugs
Lysine
Neoplasms
Glutamine
Area Under Curve
Adamantane
Carboxylesterase
Plasmacytoma
Knockout Mice
Lymphoma
Cell Proliferation
Liver

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Tumor-Targeted Delivery of 6-Diazo-5-oxo- l -norleucine (DON) Using Substituted Acetylated Lysine Prodrugs. / Tenora, Lukáš; Alt, Jesse; Dash, Ranjeet P.; Gadiano, Alexandra J.; Novotná, Kateřina; Veeravalli, Vijayabhaskar; Lam, Jenny; Kirkpatrick, Quinn R.; Lemberg, Kathryn M.; Majer, Pavel; Rais, Rana; Slusher, Barbara.

In: Journal of medicinal chemistry, Vol. 62, No. 7, 11.04.2019, p. 3524-3538.

Research output: Contribution to journalArticle

Tenora, L, Alt, J, Dash, RP, Gadiano, AJ, Novotná, K, Veeravalli, V, Lam, J, Kirkpatrick, QR, Lemberg, KM, Majer, P, Rais, R & Slusher, B 2019, 'Tumor-Targeted Delivery of 6-Diazo-5-oxo- l -norleucine (DON) Using Substituted Acetylated Lysine Prodrugs', Journal of medicinal chemistry, vol. 62, no. 7, pp. 3524-3538. https://doi.org/10.1021/acs.jmedchem.8b02009
Tenora, Lukáš ; Alt, Jesse ; Dash, Ranjeet P. ; Gadiano, Alexandra J. ; Novotná, Kateřina ; Veeravalli, Vijayabhaskar ; Lam, Jenny ; Kirkpatrick, Quinn R. ; Lemberg, Kathryn M. ; Majer, Pavel ; Rais, Rana ; Slusher, Barbara. / Tumor-Targeted Delivery of 6-Diazo-5-oxo- l -norleucine (DON) Using Substituted Acetylated Lysine Prodrugs. In: Journal of medicinal chemistry. 2019 ; Vol. 62, No. 7. pp. 3524-3538.
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