Model studies towards prodrugs of the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) containing a diazo precursor

Run-Duo Gao; Niyada Hin; Eva Prchalová; Arindom Pal; Jenny Lam; Rana Rais; Barbara S Slusher; Takashi Tsukamoto

doi:10.1016/j.bmcl.2021.128321

Model studies towards prodrugs of the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) containing a diazo precursor

Bioorg Med Chem Lett. 2021 Oct 15:50:128321. doi: 10.1016/j.bmcl.2021.128321. Epub 2021 Aug 13.

Authors

Run-Duo Gao¹, Niyada Hin², Eva Prchalová¹, Arindom Pal¹, Jenny Lam³, Rana Rais¹, Barbara S Slusher¹, Takashi Tsukamoto⁴

Affiliations

¹ Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
² Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
³ Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
⁴ Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: ttsukamoto@jhmi.edu.

Abstract

Two distinct diazo precursors, imidazotetrazine and nitrous amide, were explored as promoieties in designing prodrugs of 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist. As a model for an imidazotetrazine-based prodrug, we synthesized (S)-2-acetamido-6-(8-carbamoyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)-5-oxohexanoic acid (4) containing the entire scaffold of temozolomide, a precursor of the DNA-methylating agent clinically approved for the treatment of glioblastoma multiforme. For a nitrous amide-based prodrug, we synthesized 2-acetamido-6-(((benzyloxy)carbonyl)(nitroso)amino)-5-oxohexanoic acid (5) containing a N-nitrosocarbamate group, which can be converted to a diazo moiety via a mechanism similar to that of streptozotocin, a clinically approved diazomethane-releasing drug containing an N-nitrosourea group. Preliminary characterization confirmed formation of N-acetyl DON (6), also known as duazomycin A, from compound 4 in a pH-dependent manner while compound 5 did not exhibit sufficient stability to allow further characterization. Taken together, our model studies suggest that further improvements are needed to translate this prodrug approach into glutamine antagonist-based therapy.

Keywords: 6-Diazo-5-oxo-l-norleucine; Prodrug; α-Diazoketone.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Diazooxonorleucine / analogs & derivatives*
Diazooxonorleucine / chemistry
Diazooxonorleucine / pharmacology*
Drug Design
Drug Stability
Glutamine / antagonists & inhibitors*
Molecular Structure
Prodrugs / chemistry*
Prodrugs / pharmacology*

Substances

Prodrugs
Diazooxonorleucine
Glutamine

Abstract

Publication types

MeSH terms

Substances

Grants and funding