Evidence map›Paper›PMID 28807574›Full record

ArticleBioorganic & medicinal chemistry2017

Synthesis and evaluation of analogs of 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (MDL 73811, or AbeAdo) - An inhibitor of S-adenosylmethionine decarboxylase with antitrypanosomal activity.

Anthony J Brockway, Oleg A Volkov, Casey C Cosner, Karen S MacMillan, Stephen A Wring, Thomas E Richardson, Michael Peel, Margaret A Phillips, Jef K De Brabander

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Bioorganic & medicinal chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
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

4 citing papers in PubMed.

  1. Review
  2. Polyamine Metabolism inMedical sciences (Basel, Switzerland) · 2022
    Review
  3. Polyamines in protozoan pathogens.The Journal of biological chemistry · 2018
    Review
  4. Article
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

9 authors.

Anthony J BrockwayDepartment of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA.
Oleg A VolkovDepartment of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390-9041, USA.
Casey C CosnerDepartment of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA.
Karen S MacMillanDepartment of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA.
Stephen A WringScynexis, Inc. (now Avista Pharma Solutions), 3501 Tricenter Blvd, Suite C, Durham, NC 27713, USA.
Thomas E RichardsonScynexis, Inc. (now Avista Pharma Solutions), 3501 Tricenter Blvd, Suite C, Durham, NC 27713, USA.
Michael PeelScynexis, Inc. (now Avista Pharma Solutions), 3501 Tricenter Blvd, Suite C, Durham, NC 27713, USA.
Margaret A PhillipsDepartment of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390-9041, USA. Electronic address: Margaret.Phillips@UTSouthwestern.edu.
Jef K De BrabanderDepartment of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA. Electronic address: Jef.DeBrabander@UTSouthwestern.edu.

Funding

Targeting S-adenosylmethionine decarboxylase for HAT drug discoveryR01AI090599 · NIAID · UT SOUTHWESTERN MEDICAL CENTER · PI PHILLIPS, MARGARET A. · 2010 to 2014
$4.1M
Polyamine and trypanothione metabolism in Trypanosoma bruceiR37AI034432 · NIAID · UT SOUTHWESTERN MEDICAL CENTER · PI PHILLIPS, MARGARET A. · 2009 to 2018
$4.0M
NIAID NIH HHS R01 AI090599NIAID NIH HHS R37 AI034432
6 · The paper itself

Abstract

We describe our efforts to improve the pharmacokinetic properties of a mechanism-based suicide inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC), essential for the survival of the eukaryotic parasite Trypanosoma brucei responsible for Human African Trypanosomiasis (HAT). The lead compound, 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (1, also known as MDL 73811, or AbeAdo), has curative efficacy at a low dosage in a hemolymphatic model of HAT but displayed no demonstrable effect in a mouse model of the CNS stage of HAT due to poor blood-brain barrier permeation. Therefore, we prepared and evaluated an extensive set of analogs with modifications in the aminobutenyl side chain, the 5'-amine, the ribose, and the purine fragments. Although we gained valuable structure-activity insights from this comprehensive dataset, we did not gain traction on improving the prospects for CNS penetration while retaining the potent antiparasitic activity and metabolic stability of the lead compound 1.

Indexed as

Adenosylmethionine DecarboxylaseAnimalsDeoxyadenosinesDisease Models, AnimalDose-Response Relationship, DrugEnzyme InhibitorsMiceMolecular ConformationParasitic Sensitivity TestsStructure-Activity RelationshipTrypanocidal AgentsTrypanosoma brucei bruceiTrypanosomiasis, AfricanAdenosylmethionine DecarboxylaseDeoxyadenosinesEnzyme InhibitorsMDL 73811Trypanocidal AgentsAntitrypanosomalHuman African TrypanosomiasisMetabolismPermeabilityS-adenosylmethionine decarboxylaseStructure-activity relationship

Identifiers

PMID28807574
PMCPMC5632197

What OpenQuestion holds

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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.