N‑Methyldihydroquinazolinone Derivatives of Retro‑2 with Enhanced Efficacy against Shiga Toxin

The Retro-2 molecule protects cells against Shiga toxins by specifically blocking retrograde transport from early endosomes to the trans-Golgi network. A SAR study has been carried out to identify more potent compounds. Cyclization and modifications of Retro-2 led to a compound with roughly 100-fold...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 56; no. 8; pp. 3404 - 3413
Main Authors Noel, Romain, Gupta, Neetu, Pons, Valérie, Goudet, Amélie, Garcia-Castillo, Maria Daniela, Michau, Aurélien, Martinez, Jennifer, Buisson, David-Alexandre, Johannes, Ludger, Gillet, Daniel, Barbier, Julien, Cintrat, Jean-Christophe
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 25.04.2013
Amer Chemical Soc
Subjects
Benzamides - pharmacology
Biological Transport - drug effects
Chemistry, Medicinal
Endosomes - drug effects
Endosomes - metabolism
HeLa Cells
Humans
Inhibitory Concentration 50
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Quinazolinones - chemical synthesis
Quinazolinones - pharmacology
Science & Technology
Shiga Toxin - antagonists & inhibitors
Shiga Toxin - metabolism
Shiga Toxins - antagonists & inhibitors
Structure-Activity Relationship
Thiophenes - pharmacology
CELLS
HEMOLYTIC-UREMIC SYNDROME
B-FRAGMENT
RICIN
RETROGRADE TRANSPORT
ESCHERICHIA-COLI
TRAFFICKING
INHIBITORS
IDENTIFICATION
PROTECTS
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Summary:The Retro-2 molecule protects cells against Shiga toxins by specifically blocking retrograde transport from early endosomes to the trans-Golgi network. A SAR study has been carried out to identify more potent compounds. Cyclization and modifications of Retro-2 led to a compound with roughly 100-fold improvement of the EC50 against Shiga toxin cytotoxicity measured in a cell protein synthesis assay. We also demonstrated that only one enantiomer of the dihydroquinazolinone reported herein is bioactive.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/jm4002346