Evidence map›Paper›PMID 34400301›Full record

ArticleBioorganic & medicinal chemistry letters2021

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

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Bioorganic & medicinal chemistry letters, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
0.4field-weighted citation impact, top 41% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed, 6 citations in OpenAlex.

  1. Trial
  2. Article
  3. Review
  4. Review
  5. Article
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  7. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 1 institution in 1 country.

Run-Duo GaoDepartment of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
Niyada HinDepartment of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
Eva PrchalováDepartment of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
Arindom PalDepartment of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
Jenny LamJohns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
Rana RaisDepartment of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
Barbara S SlusherDepartment of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA; Johns Hopkins Drug Discovery, Johns Hopkins University, Baltimore, MD 21205, USA.
Takashi TsukamotoDepartment 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.
Johns Hopkins University · US

Funding

Therapeutic CoreP30MH075673 · NIMH · JOHNS HOPKINS UNIVERSITY · PI Barbara Stauch Slusher · 2006 to 2026
$33.2M
Cell-targeted glutamine antagonists as a novel therapy for lymphomaR01CA229451 · NCI · JOHNS HOPKINS UNIVERSITY · PI SLUSHER, BARBARA STAUCH · 2018 to 2022
$2.3M
Novel brain penetrant metabolic inhibitors to treat MYC-driven medulloblastomaR01NS103927 · NINDS · JOHNS HOPKINS UNIVERSITY · PI RAABE, ERIC HUTTON, SLUSHER, BARBARA STAUCH · 2018 to 2021
$1.6M
NCI NIH HHS R01 CA229451NIMH NIH HHS P30 MH075673NINDS NIH HHS R01 NS103927
6 · The paper itself

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.

Indexed as

DiazooxonorleucineDrug DesignDrug StabilityGlutamineMolecular StructureProdrugsDiazooxonorleucineGlutamineProdrugs6-Diazo-5-oxo-l-norleucineProdrugα-Diazoketone

Identifiers

PMID34400301
PMCPMC8607733
OpenAlexW3194918457

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.